Publications by authors named "Hamed Sadeghipour"

27 Publications

  • Page 1 of 1

Blockade of IgM-Mediated Inflammation Alters Wound Progression in a Swine Model of Partial-Thickness Burn.

J Burn Care Res 2017 May/Jun;38(3):148-160

From the *Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; †Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; and ‡Department of Surgery, Division of Plastic and Reconstructive Surgery, Louisiana State University Health Sciences Center, New Orleans, Louisiana.

In a mouse model, a second-degree burn elicits a severe inflammatory response that is mediated by circulating autoantibody specific for a neoantigen (nonmuscle myosin). Nonmuscle myosin is expressed by injured tissue, leading to amplified ulceration and scarring. We hypothesize that a synthetic peptide (N2) can mimic the neoantigen and competitively inhibit the autoantibody, decreasing inflammation, and reducing the extent of burn injury in a preclinical swine model of burn. Second-degree burns were created on young swine using brass cylinders, warmed to varying temperatures before skin contact. Animals were treated in double-blind fashion with normal saline, control peptide, or blocking peptide. Biopsies were taken at 2 hours, 1, 4, 7, and 14 days after burn injury. Burn wound healing parameters were assessed. Immunohistochemical staining for Ki-67, immunoglobulin (Ig)M, and interleukin (IL)-8 were also performed. N2 blocking peptide administration decreased dermal injury at 4 days with increased reepithelization, indicating more rapid healing. N2 normalized skin histology by 14 days and showed improved epidermal healing. Granulation tissue thickness was decreased, and there was an accompanying decrease in neutrophil infiltration. The basal layer of epidermis in N2-treated animals displayed more cells positive for Ki-67, suggesting a prompter regenerative capacity. Immunohistochemical staining demonstrated decreased deposition of immunoglobulin M and interleukin-8 after thermal injury in animals treated with N2 peptide, in comparison to controls. The findings of this study identify N2 blocking a specific inflammatory pathway, as a novel therapeutic approach, preventing the evolution of cutaneous burn injuries in a preclinical animal model.
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http://dx.doi.org/10.1097/BCR.0000000000000459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397333PMC
February 2018

Effect of acute lithium administration on penile erection: involvement of nitric oxide system.

Int J Reprod Biomed 2016 Feb;14(2):109-16

Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: Lithium has been the treatment of choice for bipolar disorder (BD) for many years. Although erectile dysfunction is a known adverse effect of this drug, the mechanism of action by which lithium affects erectile function is still unknown.

Objective: The aim was to investigate the possible involvement of nitric oxide (NO) in modulatory effect of lithium on penile erection (PE). We further evaluated the possible role of Sildenafil in treatment of lithium-induced erectile dysfunction.

Materials And Methods: Erectile function was determined using rat model of apomorphine-induced erections. For evaluating the effect of lithium on penile erection, rats received intraperitoneal injection of graded doses of lithium chloride 30 mins before subcutaneous injection of apomorphine. To determine the possible role of NO pathway, sub-effective dose of N (G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, was administered 15 min before administration of sub-effective dose of lithium chloride. In other separate experimental groups, sub- effective dose of the nitric oxide precursor, L-arginine, or Sildenafil was injected into the animals 15 min before administration of a potent dose of lithium. 30 min after administration of lithium chloride, animals were assessed in apomorphine test. Serum lithium levels were measured 30 min after administration of effective dose of lithium.

Results: Lithium at 50 and 100 mg/kg significantly decreased number of PE (p<0.001), whereas at lower doses (5, 10 and 30 mg/kg) had no effect on apomorphine induced PE. The serum Li+ level of rats receiving 50 mg/kg lithium was 1±0.15 mmol/L which is in therapeutic range of lithium. The inhibitory effect of Lithium was blocked by administration of sub-effective dose of nitric oxide precursor L-arginine (100 mg/kg) (p<0.001) and sildenafil (3.5 mg/kg) (p<0.001) whereas pretreatment with a low and sub-effective dose of L-NAME (10mg/kg) potentiated sub-effective dose of lithium, (p<0.001).

Conclusion: These results suggest acute treatments with lithium cause erectile dysfunction in an in-vivo rat model. Furthermore it seems that the NO pathway might play role in erectile dysfunction associated with lithium treatment. Findings also suggest that Sildenafil may be effective in treatment of lithium-associated erectile dysfunction.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869162PMC
February 2016

A role for nitrergic system in the antidepressant-like effects of chronic lithium treatment in the mouse forced swimming test.

Behav Brain Res 2009 Jun 8;200(1):76-82. Epub 2009 Jan 8.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran. m82

In the present study we evaluated the involvement of nitric oxide (NO) system in the antidepressant-like effects of chronic lithium administration in the mouse forced swimming test (FST). Administration of lithium chloride (300 mg/L in drinking water for 21 days) had no effect on the immobility of mice in the FST, whereas 600 mg/L lithium caused a significant (P<0.001) decrease in the immobility time compared with control animals. Administration of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10mg/kg, daily for a week, i.p.) had no significant effect on the immobility time of either control or lithium (300 mg/L)-treated mice, whereas acute administration of non-effective dose of L-NAME (30 mg/kg, i.p.) caused a robust decrease (P<0.01) in the immobility time of lithium (300 mg/L)-treated animals in the FST. Moreover, chronic administration of low dose of the NO precursor L-arginine (200 mg/kg, daily for a week, i.p.) prevented (P<0.001) the antidepressant-like effects of lithium treatment (600 mg/L) in the FST. Acute treatment with L-arginine (200 mg/kg, i.p.) increased (P<0.05) the immobility time of lithium (600 mg/L)-treated mice in the FST. Chronic lithium treatment (600 mg/L but not 300 mg/L) caused a significant (P<0.05) decrease in the serum NO(X) levels in mice compared with controls. Our data suggested that the NO system could be involved in the antidepressant-like effect of chronic lithium treatment in the FST.
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http://dx.doi.org/10.1016/j.bbr.2008.12.032DOI Listing
June 2009

The nonadrenergic noncholinergic-mediated relaxation of corpus cavernosum was impaired in chronic lithium-treated rats: improvement with l-arginine.

Eur J Pharmacol 2008 May 29;586(1-3):300-5. Epub 2008 Feb 29.

Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran, P.O. Box: 13145-784, Tehran, Iran.

One-third of lithium-treated men complain from sexual dysfunction, although the exact mechanisms of which are not yet known. In this study we investigated the effect of chronic lithium (LiCl, 600 mg/l for 30 days) administration on the neurogenic relaxation of isolated rat corpus cavernosum. The corporal strips were precontracted with phenylephrine and electrical field stimulation (EFS) was applied to obtain relaxation. Relaxation to EFS was significantly (P<0.001) impaired in LiCl-treated rats. The nitric oxide (NO) synthase inhibitor Nomega-nitro-l-arginine methyl ester (l-NAME; 100 microM) inhibited the relaxation to EFS in both LiCl-treated and control rats. The NO precursor l-arginine, at per se noneffective concentration (0.1 mM), significantly (P<0.001) enhanced the EFS-induced relaxation of LiCl-treated corporal strips. The relaxation responses to the NO donor sodium nitroprusside were similar between two groups. These data demonstrate that chronic lithium treatment could impair the NO-mediated neurogenic relaxation of rat corpus cavernosum which could be prevented by l-arginine.
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http://dx.doi.org/10.1016/j.ejphar.2008.02.054DOI Listing
May 2008

Effect of chronic lithium administration on endothelium-dependent relaxation of rat mesenteric bed: role of nitric oxide.

Can J Physiol Pharmacol 2007 Oct;85(10):1038-46

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

The mechanism of action of lithium, an effective treatment for bipolar disease, is still unknown. In this study, the mesenteric vascular beds of control rats and rats that were chronically treated with lithium were prepared by the McGregor method, and the mesenteric vascular bed vasorelaxation responses were examined. NADPH-diaphorase histochemistry was used to determine the activity of NOS (nitric oxide synthase) in mesenteric vascular beds. We demonstrated that ACh-induced vasorelaxation increased in the mesenteric vascular bed of rats treated with lithium. Acute No-nitro-L-arginine methyl ester (L-NAME) administration in the medium blocked ACh-induced vasorelaxation in the control group more effectively than in lithium-treated rats, while the vasorelaxant response to sodium nitroprusside, a NO donor, was not different between lithium-treated and control groups. Acute aminoguanidine administration blocked ACh-induced vasorelaxation of lithium-treated rats, but had no effect in the control rats. Furthermore, NOS activity, determined by NADPH-diaphorase staining, was significantly greater in the mesenteric vascular beds from chronic lithium-treated rats than in those from control rats. These data suggest that the enhanced ACh-induced endothelium-derived vasorelaxation in rat mesenteric bed from chronic lithium-treated rats might be associated with increased NOS activity, likely via iNOS. Simultaneous acute L-NAME and indomethacin administration suggests the possible upregulation of EDHF (endothelium-derived hyperpolarizing factor) in lithium-treated rats.
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http://dx.doi.org/10.1139/y07-095DOI Listing
October 2007

Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart.

Eur J Pharmacol 2008 Jan 5;579(1-3):246-52. Epub 2007 Oct 5.

Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran, P.O. Box: 13145-784, Tehran, Iran.

In addition to well-known neurobehavioral effects, endogenous cannabinoids exert diverse cardiovascular actions. Recently, they have been suggested to protect the myocardium against ischemia/reperfusion injury. The aim of this study is to examine the contribution of endogenous cannabinoids to cardioprotection afforded by remote ischemic preconditioning. Three groups of remote preconditioned (15 min of mesenteric artery occlusion followed by 15 min of reperfusion) and three groups of sham-operated rats were included in the study. Animals were pretreated intravenously by vehicle, cannabinoid CB(1) (AM251, 1 mg/kg) or CB(2) (AM630, 1 mg/kg) receptor antagonist 15 min prior to remote preconditioning or sham operation. Myocardial injury was induced by 30 min of coronary artery occlusion followed by 2 h of reperfusion. The resultant arterial hypotension, ventricular arrhythmias, and infarct size were compared among the groups. Remote preconditioning exerted potent cardioprotection manifested as significant reductions in infarct size (P<0.001) as well as number and duration of arrhythmias (P<0.01, 0.01 and 0.05 for premature ventricular contractions, ventricular tachycardias and fibrillations; respectively). The cannabinoid CB(1) receptor antagonist pretreatment had no significant effect on ischemia-induced hypotension, arrhythmias or infarct size. On the other hand, the cannabinoid CB(2) receptor antagonist pretreatment abolished the protective effects of remote preconditioning on infarct size (P<0.01) and arrhythmias (P<0.01), without any significant effect on ischemia-induced hypotension. The results of this study suggest that endogenous cannabinoids, through acting on cannabinoid CB(2) receptors, are involved in the cardioprotective phenomenon of remote ischemic preconditioning, induced by mesenteric artery occlusion and reperfusion.
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http://dx.doi.org/10.1016/j.ejphar.2007.09.034DOI Listing
January 2008

Pharmacologic preconditioning of random-pattern skin flap in rats using local cyclosporine and FK-506: interaction with nitric oxide system.

Ann Plast Surg 2007 Oct;59(4):435-40

Basic Medical Sciences Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran.

It has been suggested that immunophilin ligands such as cyclosporine and FK-506 (tacrolimus) affect the survival of ischemic tissues. Our objective was to show an acute effect of local cyclosporin-A (CsA) and FK-506 on ischemic protection in a random-pattern skin-flap model in rats and investigate the effect of nitric oxide (NO) pathways as a modulator of protection of these agents. Ninety male Sprague-Dawley rats were randomly assigned to treatment groups. Bipedicled dorsal flaps (2 x 8 cm) were elevated at midline. Prior to cutting the cranial pedicle to induce permanent ischemia, pharmacologic preconditioning groups received local injection of CsA (0.3, 1, or 3 nmol/flap) or FK-506 (0.01, 0.03, or 0.1 pmol/flap), and the ischemic preconditioning (IPC) group underwent temporary clamping of the cranial pedicle. At the seventh day postoperatively, the survival of the flaps was measured. In other groups, nitric oxide synthase inhibitor N omega-nitro-l-arginine methyl ester hydrochloride (L-NAME) was administered with effective CsA and FK-506, and ischemic preconditioning. Nitric oxide precursor L-arginine doses were also studied, and a systemic subeffective dose (100 mg/kg) was coadministered with subeffective CsA and FK-506. Significant increase in flap survival was obtained with CsA (1 nmol/flap), FK-506 (0.1 pmol/flap), and IPC. These protections were abolished by systemic administration of L-NAME (10 mg/kg). Coadministration of subeffective doses of CsA (0.3 nmol/flap) and FK-506 (0.03 pmol/flap), with subeffective systemic l-arginine, significantly improved flap survival.Pharmacologic preconditioning with local, single, low doses of CsA or FK-506 is shown to be even more effective than IPC. Administration of the NOS substrate l-arginine potentiates these effects.
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http://dx.doi.org/10.1097/01.sap.0000258982.86308.f0DOI Listing
October 2007

Anandamide improves the impaired nitric oxide-mediated neurogenic relaxation of the corpus cavernosum in diabetic rats: involvement of cannabinoid CB1 and vanilloid VR1 receptors.

BJU Int 2007 Dec 10;100(6):1385-90. Epub 2007 Sep 10.

Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran, PO Box 13145-784, Tehran, Iran.

Objective: To investigate the ability of acute administration of the endogenous cannabinoid, anandamide, in vitro to alter the nonadrenegic noncholinergic (NANC)-mediated relaxation of corpus cavernosum (CC) in diabetic rats and the possible role of nitric oxide (NO), as it is well known that erectile dysfunction (ED) affects 35-75% of men with diabetes mellitus and several studies have been conducted to find appropriate strategies for treating diabetes-induced ED.

Materials And Methods: Diabetes was induced in rats by streptozotocin administration and was maintained for 8 weeks. The CC were removed and isolated in organ baths for pharmacological studies. Agonist-evoked or electrical-field stimulation (EFS)-evoked smooth muscle tensions in CC strips from control and diabetic rats were measured.

Results: The neurogenic relaxation of phenylephrine (7.5 microm)-precontracted isolated CC strips was impaired in diabetic rats. Anandamide (0.3, 1 and 3 microm) enhanced the relaxant responses to EFS in diabetic CC strips in a dose-dependent manner. This effect was antagonized by the selective cannabinoid CB(1) receptor antagonist AM251 (1 microm) and the selective vanilloid receptor antagonist capsazepine (3 microm). Concurrent administration of partially effective doses of l-arginine (10 microm) and anandamide (0.3 microm) exerted a synergistic improvement in EFS-induced relaxation of diabetic CC strips (P < 0.001). The relaxant responses to the NO donor, sodium nitroprusside, were similar between diabetic and control groups. CONCLUSION; For the first time, we show that acute administration of anandamide, an endogenous cannabinoid, alone or combined with l-arginine can improve nitrergic nerve-mediated relaxation of the CC in diabetic rats. This effect was mediated by cannabinoid CB(1) and vanilloid VR(1) receptors within the CC.
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http://dx.doi.org/10.1111/j.1464-410X.2007.07180.xDOI Listing
December 2007

Time-dependent alteration in cromakalim-induced relaxation of corpus cavernosum from streptozocin-induced diabetic rats.

Life Sci 2007 Sep 3;81(12):960-9. Epub 2007 Jul 3.

Department of Pharmacology, School of Medicine, Medical Sciences / University of Tehran, PO Box: 13145-784, Tehran, Iran.

The purpose of the present study was to investigate the relaxant responses to the ATP-sensitive potassium (K(ATP)) channel opener cromakalim in corpus cavernosum strips from 1-, 2-, 4-, 6-, and 8-week streptozocin-induced diabetic rats. Cromakalim (1 nM-0.1 mM) produced concentration-dependent relaxation in phenylephrine (7.5 microM)-precontracted isolated rat corporal strips. Compared with age-matched control animals, a significant enhancement in cromakalim-induced relaxation of corpus cavernosum was observed in 2-week diabetic animals, whereas the relaxant responses to cromakalim were decreased in 6-and 8-week diabetic animals. However, the cromakalim-induced relaxation was not altered in either 1-week or 4-week rat corporal strips in comparison with corresponding age-matched non-diabetic groups. Preincubation with the K(ATP) channel blocker glibenclamide (10 microM) significantly inhibited the cromakalim-induced relaxation in both non-diabetic and diabetic rat corpus cavernosum, but neither the voltage-dependent K(+) channel (K(V)) antagonist 4-aminopyridine (1 mM) nor the calcium-activated K(+) channel (K(Ca)) antagonist charybdotoxin (0.1 microM) had significant effect on cromakalim-induced relaxation in both control and diabetic rat corporal strips. Relaxation responses to the nitric oxide donor sodium nitroprusside (1 nM-0.1 mM) in diabetic rat corpus cavernosum were similar to that of age-matched controls. These data demonstrated that the relaxant responses to cromakalim were altered in diabetic cavernosal strips in a time dependent manner, suggesting that the period of diabetes mellitus may play a key role in the K(ATP) channels function in rat corpus cavernosum.
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http://dx.doi.org/10.1016/j.lfs.2007.06.020DOI Listing
September 2007

Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test.

Eur Neuropsychopharmacol 2008 May 28;18(5):323-32. Epub 2007 Aug 28.

Department of Pharmacology, School of Medicine, Medical Sciences/University of Tehran, Tehran, Iran.

In the present study we evaluated the involvement of l-arginine/nitric oxide (NO)/cGMP pathway in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test (FST). Lithium, at 30 and 100 mg/kg, significantly reduced the immobility times of mice in the FST, whereas at lower doses (0.5, 5 and 10 mg/kg) had no effect on the immobility time. The NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), at 10 and 30 mg/kg, and the selective neuronal NOS inhibitor N(omega)-propyl-L-arginine (L-NPA), at 5 and 15 mg/kg, had no significant effects on the FST, whereas they significantly decreased the immobility time at 100 and 30 mg/kg, respectively. Combination of non-effective dose of lithium (10 mg/kg) with low doses of L-NAME (30 mg/kg) or L-NPA (15 mg/kg) significantly reduced the immobility times in the FST. Moreover, the guanylyl cyclase inhibitor ODQ at 50 mg/kg significantly decreased the immobility time of mice, whereas it had not significant effects on the FST at 2, 10 and 20 mg/kg. Combination of lithium (10 mg/kg) with 20 mg/kg ODQ significantly decreased the immobility times in the FST. Non-effective doses of L-arginine (750 mg/kg) or sildenafil (5 mg/kg) significantly reversed the antidepressant-like effect of 30 mg/kg lithium in the FST. Neither of the drugs had effect on the locomotor activity. These data indicate the involvement of L-arginine/NO/cGMP pathway in the antidepressant-like effect of lithium in the mouse FST and also might suggest the concurrent administration of NOS inhibitors and lithium as an appropriate strategy for treatment of depression.
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http://dx.doi.org/10.1016/j.euroneuro.2007.07.011DOI Listing
May 2008

Role of ATP-sensitive potassium channels in the biphasic effects of morphine on pentylenetetrazole-induced seizure threshold in mice.

Epilepsy Res 2007 Jun 22;75(1):63-9. Epub 2007 May 22.

Department of Pharmacology, Tehran Medical Unit, Islamic Azad University, Tehran, Iran.

Although several studies have indicated that the opioid receptor agonist morphine exerts biphasic effects on clonic seizure threshold, as yet little is known of the underlying mechanisms in this effect. In the present study, using the specific ATP-sensitive K(+) (K(ATP)) channel blocker glibenclamide and the specific K(ATP) channel opener cromakalim, the possible involvement of K(ATP) channels in the effects of morphine on pentylenetetrazole (PTZ)-induced seizure threshold in mice was investigated. Acute administration of lower doses of morphine (1, 3 and 7.5 mg/kg, i.p.) increased and higher doses of morphine (30 and 60 mg/kg, i.p.) decreased the PTZ-induced seizure threshold. Glibenclamide (2.5-5 mg/kg) increased the PTZ-induced seizure threshold. Non-effective dose of cromakalim (0.1 microg/kg) inhibited anticonvulsant effect of glibenclamide (5 mg/kg). Acute administration of non-effective dose of glibenclamide (1 mg/kg) interestingly inhibited both anticonvulsant and pro-convulsant effects of morphine and this effect was significantly reversed by cromakalim (0.1 microg/kg). These results support the involvement of K(ATP) channels in the modulation of seizure threshold by morphine.
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http://dx.doi.org/10.1016/j.eplepsyres.2007.04.005DOI Listing
June 2007

Nitric oxide involvement in estrous cycle-dependent changes of the behavioral responses of female rats in the elevated plus-maze test.

Behav Brain Res 2007 Mar 4;178(1):10-7. Epub 2007 Jan 4.

Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Nitric oxide (NO)/cGMP pathway is known as a mediator in anxiety modulation. In this study, we assessed the involvement of NO pathway in the estrous cycle-related changes of anxiety level in rat. By using elevated plus-maze test, we studied the changes of serum nitrate and nitrite (NO(x)) levels in comparison to the estrous cycle-dependent changes of anxiety state. Then, we tested the effects of nitric oxide synthase (NOS) inhibitor, L-NAME (10, 60mg/kg, i.p.), and the NO precursor, l-arginine (100mg/kg, i.p.) on anxiety modulatory properties of exogenous ovarian hormones in ovariectomized (OVX) rats. Compared with other cycle phases and with OVX rats, cycling rats spent more time in open arms and had lower levels of serum NO(x) levels during metestrous while they spent less time in open arms and had lower levels of serum NO(x) levels during proestrous. In OVX rats, L-NAME (60mg/kg, i.p.) exerted anxiolytic effect while l-arginine showed no effect. In comparison with corn oil-treated controls, estradiol benzoate (10microg/kg, subcutaneously (s.c.)) significantly increased the serum NO(x) level and exerted anxiogenic effect, which was dose-dependently inhibited by L-NAME but was not changed by l-arginine. In contrast, progesterone (25mg/kg, s.c.) significantly decreased the serum NO(x) level and exerted anxiolytic effect, which was abolished by l-arginine but was not affected by L-NAME. These findings suggest that NO system might be involved in the estrous cycle-related changes of anxiety level, probably by mediating the effect of ovarian sex hormones.
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http://dx.doi.org/10.1016/j.bbr.2006.11.045DOI Listing
March 2007

Reduced susceptibility to epinephrine-induced arrhythmias in cirrhotic rats: the roles of nitric oxide and endogenous opioid peptides.

J Hepatol 2007 Mar 2;46(3):432-9. Epub 2006 Nov 2.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.

Background/aims: The clinical relevance of QT prolongation, the most widely recognized cardiac electrophysiological abnormality of cirrhosis, is still undefined. The aim of this study is to examine the susceptibility of chronic (4-week) bile duct-ligated rats to epinephrine-induced arrhythmias. The roles of nitric oxide and endogenous opioids were also evaluated.

Methods: Sham-operated and cirrhotic rats were treated with daily subcutaneous administrations of normal saline (1 ml/kg/day), L-NAME (a non-selective nitric oxide synthase inhibitor, 3mg/kg/day), and naltrexone (20mg/kg/day) during the fourth week after operation. In order to evaluate the effects of acute nitric oxide synthesis inhibition, additional groups of animals were treated by acute intraperitoneal L-NAME injections (3mg/kg). Arrhythmias were induced by intravenous injections of 10 microg/kg epinephrine.

Results: Despite QT prolongation (P<0.001), epinephrine induced fewer arrhythmias in cirrhotic rats compared to sham-operated animals (P<0.05). Chronic, but not acute, L-NAME administration corrected the QT prolongation in cirrhotic rats (P<0.001), and restored the susceptibility of cirrhotic rats to arrhythmias (P<0.05). Naltrexone injection without a significant effect on epinephrine-induced arrhythmias corrected QT interval in cirrhotic rats (P<0.001).

Conclusions: This study shows that despite QT prolongation, cirrhotic animals are resistant against epinephrine-induced arrhythmias. This resistance is mediated by chronic nitric oxide overproduction.
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http://dx.doi.org/10.1016/j.jhep.2006.09.013DOI Listing
March 2007

Effect of chronic lithium administration on endothelium-dependent relaxation of rat corpus cavernosum: the role of nitric oxide and cyclooxygenase pathways.

BJU Int 2007 Jan 11;99(1):177-82. Epub 2006 Oct 11.

Department of Pharmacology, School of Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Objective: To verify the effect of chronic lithium administration on the endothelium-dependent relaxation of rat corpus cavernosum, as lithium is a major drug for treating bipolar disorder and some studies showed that lithium might cause erectile dysfunction in such patients, by a mechanism as yet unknown.

Materials And Methods: LiCl (600 mg/L) was dissolved in drinking water and Sprague-Dawley rats received the solution for 30 days; control rats received tap water. After 30 days corporeal strips were prepared from both groups, mounted under tension in oxygenated organ baths, and pre-contracted with phenylephrine (7.5 microm). After equilibration, the strips were relaxed by acetylcholine (10 nm to 1 mm) in the presence or absence of indomethacin (a cyclooxygenase inhibitor; 20 microm). Furthermore, the relaxant responses to sodium nitroprusside (1 nm to 1 mm), a nitric oxide (NO) donor, were investigated in both groups. NADPH-diaphorase histochemistry was used to identify NO synthase within cavernosal tissue strips of both groups.

Results: The acetylcholine-dependent relaxation was significantly lower in lithium-treated rats than in controls. Although indomethacin decreased significantly the relaxant responses to acetylcholine in controls, it increased the relaxant responses in lithium-treated rats. NADPH-diaphorase staining was greater in the chronic lithium-treated than in control preparations. Sodium nitroprusside produced similar relaxation in both groups.

Conclusion: Chronic lithium administration can impair the endothelium-dependent relaxation of rat corpus cavernosum; NO availability might decrease after lithium administration and the cyclooxygenase pathways might have a role in this effect.
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http://dx.doi.org/10.1111/j.1464-410X.2006.06530.xDOI Listing
January 2007

Involvement of endogenous opioid peptides and nitric oxide in the blunted chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhotic rats.

Fundam Clin Pharmacol 2006 Oct;20(5):461-71

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box 13145-784, Tehran, Iran.

It is well known that chronotropic and inotropic responses to beta-adrenergic stimulation are impaired in cirrhosis, but the exact reason is not clear. Considering the inhibitory effect of endogenous opioid peptides and nitric oxide (NO) on beta-adrenergic pathway, we examined their roles in hyporesponsiveness of isolated atria and papillary muscles to isoproterenol stimulation in cirrhotic rats. Cirrhosis was induced by chronic bile duct ligation. Four weeks after ligation or sham operation, the responses of the isolated atria and papillary muscles to isoproterenol stimulation were evaluated in the absence and presence of naltrexone HCl (10(-6) m), N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-4) m), and naltrexone plus L-NAME in the organ bath. Considering the role of inducible NOS (iNOS) in hemodynamic abnormalities of cirrhotic rats, the chronotropic and inotropic responses of cirrhotic rats to isoproterenol stimulation were also assessed in the presence of aminoguanidine (a selective inhibitor of iNOS, 3 x 10(-4) m). Sham operation had no significant effect on basal atrial beating rate, contractile force, and maximal time derivatives for the development and the dissipation of papillary muscle tension. The basal atrial beating rate of cirrhotic rats did not show any significant difference compared with the sham-operated ones; however, the basal contractile parameters were significantly decreased in cirrhosis. Although the maximum effects of isoproterenol on chronotropic and inotropic responses were significantly reduced in cirrhotic rats, there was no difference in half-maximal effective concentrations of isoproterenol in these concentration-response curves. The basal abnormalities and the attenuated chronotropic and inotropic responses to isoproterenol were completely corrected by the administration of naltrexone, L-NAME and aminoguanidine. Concurrent administration of naltrexone and L-NAME also restored to normal the basal abnormalities and the blunted responses to isoproterenol in cirrhotic rats, and did not show any antagonistic effect. Based on these findings, both the endogenous opioid peptides and NO may be involved in the attenuated chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhosis. It seems that the iNOS activity results in NO-induced hyporesponsiveness to beta-adrenergic stimulation in cirrhosis.
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http://dx.doi.org/10.1111/j.1472-8206.2006.00431.xDOI Listing
October 2006

Effect of lithium on endothelium-dependent and neurogenic relaxation of rat corpus cavernosum: role of nitric oxide pathway.

Nitric Oxide 2007 Feb 2;16(1):54-63. Epub 2006 Jun 2.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Introduction: Some studies have reported erectile dysfunction in patients receiving lithium through a mechanism that has not yet been defined. The aim of the present study was to verify the effect of acute lithium administration on the nonadrenergic noncholinergic (NANC)- and endothelium-mediated relaxation of rat isolated corpus cavernosum.

Materials And Methods: The isolated rat corporeal strips were precontracted with phenylephrine hydrochloride (7.5 microM) and electrical field stimulation (EFS) was applied at different frequencies (2, 5, 10, and 15 Hz) to obtain NANC-mediated relaxation or relaxed by adding cumulative doses of acetylcholine (10nM-1mM) to obtain endothelium-dependent relaxation in the presence or absence of lithium (0.3, 0.5, 1, and 5mM). Also, effects of combining lithium (0.3mM) with 30 nM and 0.1 nM L-NAME (an NO synthase inhibitor) on NANC- and acetylcholine-mediated relaxation was investigated, respectively. Moreover, effects of combining lithium (1mM) with 0.1mM and 10 microM L-arginine (a precursor of NO) on NANC- and endothelium-mediated relaxation was assessed, respectively. Also, the effect of lithium (1mM) on relaxation to sodium nitroprusside (SNP; 1nM-1mM), an NO donor, was investigated.

Results: The NANC-mediated relaxation was significantly (P<0.001) reduced by 1 and 5mM, but not by 0.3 and 0.5mM lithium. Lithium significantly (P<0.001) attenuated the maximum response to acetylcholine in a concentration-dependent manner. Combination of lithium (0.3mM) with 30 and 0.1 nM L-NAME, which separately had a minimum effect on NANC- and endothelium-mediated relaxation, significantly (P<0.001) reduced the NANC- and endothelium-mediated relaxation, respectively. Although L-arginine at 10 microM and 0.1mM did not alter the relaxant responses to acetylcholine and EFS, it improved the inhibition by lithium (1mM) of relaxant responses to acetylcholine and EFS, respectively. Also, SNP produced similar concentration-dependent relaxations from both groups.

Discussion: Our experiments indicated that lithium likely by interfering with NO pathway in both endothelium and nitrergic nerve can result in impairment of both the endothelium- and NANC-mediated relaxation of rat corpus cavernosum.
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http://dx.doi.org/10.1016/j.niox.2006.05.004DOI Listing
February 2007

Effect of anandamide on nonadrenergic noncholinergic-mediated relaxation of rat corpus cavernosum.

Eur J Pharmacol 2006 Aug 14;544(1-3):138-45. Epub 2006 Jun 14.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box: 13145-784, Tehran, Iran.

The purpose of this study was to investigate the effect of the endogenous cannabinoid anandamide on the nonadrenergic noncholinergic (NANC) relaxant responses to electrical field stimulation in isolated rat corpus cavernosum. The corporal strips were mounted under tension in a standard oxygenated organ bath with guanethidine sulfate (5 microM) and atropine (1 microM) (to produce adrenergic and cholinergic blockade). The strips were precontracted with phenylephrine hydrochloride (7.5 microM) and electrical field stimulation was applied at different frequencies to obtain NANC-mediated relaxation. The expression of CB1, CB2 and vanilloid receptor proteins within the rat corpus cavernosum was evaluated using western blot analysis. The results showed that the relaxant responses to electrical stimulation were significantly enhanced in the presence of anandamide at 1 and 3 microM. The potentiating effect of anandamide (1 microM) on relaxation responses was significantly attenuated by either the selective cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251; 1 microM) or the vanilloid receptor antagonist capsazepine (3 microM), but not by the selective cannabinoid CB2 receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl) ethyl]-1H-indol-3-yl (4-methoxyphenyl)methanone (AM630; 1 microM). Neither of these antagonists had influence on relaxation responses. Indomethacin (20 microM) had no effect on NANC-mediated relaxation in the presence or absence of anandamide (1 microM). Preincubation with Nw-Nitro-L-Arginine Methyl Ester (L-NAME; 1 microM) significantly inhibited the relaxation responses in the presence or absence of 1 microM anandamide. Although at 30 nM, L-NAME did not cause a significant inhibition of relaxant responses individually, it significantly inhibited the potentiating effect of anandamide (1 microM) on relaxation responses. Anandamide (1 microM) had no influence on concentration-dependent relaxant responses to sodium nitroprusside (10 nM-1 mM), a nitric oxide (NO) donor. The western blotting of corporal tissues demonstrated the existence of both vanilloid and CB1 receptors in corporal strips. In conclusion, our results showed that anandamide has a potentiating effect on NANC-mediated relaxation of rat corpus cavernosum through both CB1 and vanilloid receptors and the NO-mediated component of the NANC relaxant responses to electrical stimulation is involved in this enhancement.
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http://dx.doi.org/10.1016/j.ejphar.2006.06.002DOI Listing
August 2006

Modulated hemodynamic response to clonidine in bile duct-ligated rats: the role of nitric oxide.

Eur J Pharmacol 2006 Aug 7;542(1-3):148-53. Epub 2006 May 7.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.

Despite the well-known involvement of the peripheral sympathetic abnormalities in the development of cardiovascular complications of cholestasis, the role of the central sympathetic system is still elusive. The goal of this study was to evaluate the effects of central sympathetic tone reduction, through clonidine administration, on hemodynamic parameters of 7-day bile duct-ligated rats. The contributions of nitric oxide and endogenous opioids were also examined by acute intravenous (10 min before clonidine) or chronic daily subcutaneous administrations of N(omega)-nitro-L-arginine methyl ester (L-NAME, 3 mg/kg) or naltrexone (20 mg/kg). Seven days after bile duct ligation or sham operation, animals were anesthetized with sodium pentobarbital. After hemodynamic stabilization, clonidine (10 microg/kg) was injected intravenously, which elicited an initial hypertension (the peripheral effect) followed by persistent hypotension and bradycardia (the central effects). Cholestatic rats demonstrated significant basal bradycardia (P<0.001) and hypotension (P<0.05), which were corrected by chronic naltrexone but not L-NAME treatment. While the peripheral effect of clonidine was blunted, the central effects were exaggerated in cholestatic rats (P<0.01). Acute L-NAME treatment accentuated the hypertensive phase in sham-operated and cholestatic rats (P<0.05). However, the difference between the two groups was preserved (P<0.01). This treatment attenuated the central effects in both sham-operated and cholestatic rats to the same level (P<0.001). Chronic L-NAME treatment resulted in exaggeration of the peripheral response in cholestatic and central responses in sham-operated rats (P<0.05), and abolished the difference between the groups. Naltrexone treatment had no significant effect on either the central or the peripheral responses to clonidine. This study shows that both central and peripheral hemodynamic responses to clonidine are altered in cholestasis. It also provides evidence that nitric oxide contributes to the development of these abnormalities.
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http://dx.doi.org/10.1016/j.ejphar.2006.04.052DOI Listing
August 2006

Pentoxifylline improves reoxygenation-induced contractile recovery through a nitric oxide-dependent mechanism in rat papillary muscles.

J Cardiovasc Pharmacol 2006 Apr;47(4):571-7

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

In this study, the protective effect of pentoxifylline against hypoxia-reoxygenation injury and the possible involvement of nitric oxide (NO)-mediated pathways in this protection were investigated in isolated rat papillary muscles. Papillary muscles were excised and isolated in Krebs-Henseleit solution aerated with 95% O2 and 5% CO2. Hypoxia was simulated by substituting O2 with argon. Three sets of experiments, testing 30, 60, and 90 min of hypoxia, were performed. The effects of different pentoxifylline concentrations on papillary muscle contractile parameters and responsiveness to isoproterenol were assessed. To investigate the role of NO, N(omega)-nitro-L-arginine methyl ester was added before pentoxifylline treatment. Pentoxifylline did not show any inotropic effect on papillary muscles. Hypoxia caused a profound depression of contractile parameters, which was not affected by pentoxifylline treatment. Reoxygenation resulted in significant partial recovery of contractile parameters after 30 and 60 but not 90 min of hypoxia. In experiments with 30 and 60 min of hypoxia, reoxygenation-induced contractile recovery and responsiveness to isoproterenol were improved by pentoxifylline in a concentration-dependent fashion. These functional improvements were completely blocked by N(omega)-nitro-L-arginine methyl ester pretreatment. No improvement was observed in 90-min hypoxia experiment. In conclusion, pentoxifylline improved contractile recovery during reoxygenation and postreoxygenation responsiveness to beta-adrenergic stimulation through the NO-dependent mechanism.
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http://dx.doi.org/10.1097/01.fjc.0000211733.53798.d3DOI Listing
April 2006

Contribution of endogenous opioids and nitric oxide to papillary muscle contractile impairment in cholestatic rats.

Eur J Pharmacol 2005 Oct 13;523(1-3):93-100. Epub 2005 Oct 13.

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.

Attenuated responsiveness to adrenoceptor stimulation has been proposed as an important factor underlying cardiovascular complications of cholestasis. We examined isolated papillary muscle responsiveness to alpha (phenylephrine) and beta-adrenoceptor (isoproterenol) agonists in 7-day bile duct-ligated rats. We investigated the role of nitric oxide (NO) and endogenous opioids in papillary muscle hyporesponsiveness to isoproterenol stimulation. In order to evaluate the effect of NO and endogenous opioids, animals were treated with chronic subcutaneous injections of N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg/day) or naltrexone (20 mg/kg/day), or isolated papillary muscles were exposed acutely to the same drugs (10(-4) and 10(-6) M, respectively) in an organ bath. The basal contractile force of papillary muscle, +dT/dtmax and -dT/dtmax, was significantly decreased in bile duct-ligated rats compared to sham-operated ones (P<0.05, for each value). The concentration-response curve for phenylephrine and isoproterenol demonstrated a reduced maximum effect in bile duct-ligated rats compared to the sham-operated group (P<0.01 and 0.05, respectively). Basal contractile abnormalities of bile duct-ligated rats were corrected by L-NAME or naltrexone treatment, either acute or chronic. While chronic L-NAME treatment resulted in a left-ward shift (P<0.05), it had no effect on the maximum effect in bile duct-ligated rats. Acute L-NAME treatment did not influence isoproterenol responsiveness. Acute and chronic naltrexone treatment resulted in partial and complete correction of the hyporesponsiveness of bile duct-ligated rats, respectively (P<0.05). This investigation demonstrates that the papillary muscles of 7-day bile duct ligated-rats have an impaired basal contractility and hyporesponsiveness to both alpha and beta-adrenoceptor stimulation. It also provides evidence for the involvement of increased opioidergic tone and NO overproduction in cholestasis-induced cardiac impairment.
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http://dx.doi.org/10.1016/j.ejphar.2005.08.057DOI Listing
October 2005

Homocysteine alterations in experimental cholestasis and its subsequent cirrhosis.

Life Sci 2005 Apr;76(21):2497-512

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.

Homocysteine (Hcy), an intermediate in methionine metabolism, has been proposed to be involved in hepatic fibrogenesis. Impaired liver function can alter Hcy metabolism. The aim of the present study was to determine plasma Hcy alterations in acute obstructive cholestasis and the subsequent biliary cirrhosis. Cholestasis was induced by bile duct ligation and sham-operated and unoperated rats were used as controls. The animals were studied on the days 7th, 14th, 21st and 28th after the operation. Plasma Hcy, cysteine, methionine, nitric oxide (NO) and liver S-adenosyl-methionine (SAM), S-adenosyl-homocysteine (SAH), SAM to SAH ratio and glutathione were measured. Chronic L-NAME treatment was also included in the study. Plasma Hcy concentrations were transiently elevated by the day 14th after bile duct ligation (P < 0.01) and subsequently returned to control levels. Similar relative fluctuations in plasma Hcy were observed in BDL rats after intraperitoneal methionine overload. Plasma methionine, cysteine and nitrite and nitrate were significantly increased after bile duct ligation. SAM to SAH ratio was diminished by the 1st week of cholestasis and remained significantly decreased throughout the study. These events were accompanied by a decrease in GSH to GSSG ratio in the liver. Chronic L-NAME treatment improved SAM to SAH ratio and prevented the elevation of plasma Hcy and methionine (P < 0.05) while couldn't influence the other parameters. In conclusion, this study demonstrates alterations in plasma Hcy and liver SAM and SAH contents in precirrhotic stages and in secondary biliary cirrhosis, for the first time. In addition, we observed that plasma Hcy concentrations in BDL rats follow a distinct pattern of alteration from what has been previously reported in other models of cirrhosis. NO overproduction may contribute to plasma Hcy elevation and liver SAM depletion after cholestasis.
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http://dx.doi.org/10.1016/j.lfs.2004.12.009DOI Listing
April 2005

Resistance of cholestatic rats against epinephrine-induced arrhythmia: the role of nitric oxide and endogenous opioids.

Eur J Pharmacol 2004 Sep;499(3):307-13

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.

Short-term ligation of bile duct has been used as a model to study acute cholestasis and is associated with various cardiovascular abnormalities. We examined the role of nitric oxide (NO) and endogenous opioids on epinephrine-induced arrhythmia in 7-day bile duct-ligated (BDL) rats. Six groups of rats, each of which was subdivided into two subgroups (sham-operated and BDL), were examined. First group of animals were chronically treated with normal saline. In the second and third groups, single intraperitoneal administration of N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) or naltrexone (20 mg/kg) was performed 30 min before evaluation of epinephrine-induced arrhythmia. Two groups received chronic administration of low dose (3 mg/kg/day) or high dose (10 mg/kg/day) L-NAME; and the last group was treated chronically with naltrexone (20 mg/kg/day). Chronic drug administration was performed subcutaneously for 6 consecutive days following BDL or sham operation. After induction of arrhythmia by intravenous injection of 10 microg/kg epinephrine, mean arterial pressure and electrocardiogram were recorded for 1 min. Heart rate and mean arterial pressure were significantly lower in BDL rats (P<0.01). Chronic injection of naltrexone increased heart rate and mean arterial pressure in BDL (P<0.05). Chronic low dose L-NAME administration had no effect on baseline hemodynamic parameters. High dose L-NAME injection corrected hypotension in BDL rats, but not bradycardia (P<0.05). Epinephrine induced less arrhythmia in BDL rats (P<0.05). Acute and chronic injection of naltrexone had no effect on the resistance of BDL rats against epinephrine-induced arrhythmia. Although acute L-NAME administration enhanced arrhythmias in sham-operated rats (P<0.001), it had no effect on BDL animals. Chronic injection of low dose or high dose L-NAME, without having any effect on sham-operated animals, increased arrhythmias in BDL rats (P<0.01). This study showed that BDL animals are resistant against epinephrine-induced arrhythmia and this resistance depends on long-term NO overproduction.
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http://dx.doi.org/10.1016/j.ejphar.2004.07.099DOI Listing
September 2004

Sex and estrus cycle differences in the modulatory effects of morphine on seizure susceptibility in mice.

Epilepsia 2004 Sep;45(9):1035-42

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Purpose: To evaluate the effects of sex and estrus cycle on biphasic anticonvulsant and proconvulsant modulation of seizure threshold by morphine.

Methods: The threshold for the clonic seizures (CST) induced by acute intravenous administration of gamma-aminobutyric acid (GABA)-antagonist pentylenetetrazole (PTZ) was assessed in male and female mice. Estrus cycle was assessed by vaginal smears. The effect of removing circulating sex hormones was assessed by gonadectomy.

Results: At baseline, diestrus females had a higher CST compared with males and estrus females. Morphine at lower doses (0.5-3 mg/kg) had a significant anticonvulsant effect in males and estrus females compared with that in vehicle-treated controls, whereas female mice in diestrus phase showed a relative subsensitivity to this effect. Morphine at higher doses (30 and 60 mg/kg) significantly decreased CST in males and diestrus females, with less relative effect in estrus mice. In both phases, morphine exerted stronger effects in males compared with females. Ovariectomy brought the baseline CST to the male level and resulted in significant expression of both phases of morphine effect but did not abolish the sex difference in responsiveness to morphine.

Conclusions: The biphasic modulation of seizure threshold is subject to both constitutive sex differences in sensitivity to morphine and hormonal fluctuations during the estrus cycle.
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http://dx.doi.org/10.1111/j.0013-9580.2004.69903.xDOI Listing
September 2004

Time-dependent reduction of acetylcholine-induced relaxation in corpus cavernosum of cholestatic rats: role of nitric oxide and cyclooxygenase pathway.

Eur J Pharmacol 2004 Aug;496(1-3):181-7

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box 13145-784, Tehran, Iran.

The endothelium-dependent relaxation of corpus cavernosum smooth muscle and the roles of nitric oxide (NO) and arachidonic acid products of cyclooxygenase were investigated in non-operated, SHAM-operated, and bile duct-ligated rats. We further investigated the time-dependent alterations of corpus cavernosum relaxation in 2-, 7-, and 14-day bile duct-ligated animals. Acetylcholine produced concentration-dependent relaxation in phenylephrine-precontracted strips of corpus cavernosum. A significant reduction in the acetylcholine-induced relaxation was observed 2 days after bile duct ligation, and a greater reduction was observed on subsequent days. Incubation with 20 microM indomethacin reduced the acetylcholine-induced relaxation of the corpus cavernosum of unoperated rats while it had no effect in the corpus cavernosum of bile duct-ligated rats. Chronic treatment with Nomega-Nitro-L-Arginine Methyl Ester (L-NAME, 3 mg/kg/day, intraperitoneally) reduced the relaxation responses in the unoperated group while it had no effect in the bile duct-ligated group. These results show that acetylcholine-induced corporal relaxation is impaired in cholestatic rats, and this may be related to deficient nitric oxide production by the endothelium. The involvement of prostaglandins in this impairment seems unlikely.
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http://dx.doi.org/10.1016/j.ejphar.2004.06.013DOI Listing
August 2004

The interaction of cannabinoids and opioids on pentylenetetrazole-induced seizure threshold in mice.

Neuropharmacology 2004 Sep;47(3):390-400

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.

Cannabinoid and opioid receptor agonists show functional interactions in a number of their physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study examined the possibility of a functional interaction between these receptors. We used acute systemic administration of cannabinoid selective CB(1) receptor agonist (ACPA) and antagonist (AM251) and opioid receptor agonist (morphine) and antagonists (naltrexone and norbinaltorphimine) in a model of clonic seizure induced by pentylenetetrazole (PTZ). Acute administration of ACPA (1.5-2 mg/kg) increased the PTZ-induced seizure threshold. In contrast, AM251 (0.5-2 mg/kg) dose-dependently decreased the seizure threshold. Low dose of AM251 (0.5 mg/kg), which did not alter seizure threshold by itself, reversed the anticonvulsant effect of ACPA (2 mg/kg), showing a CB(1) receptor-mediated mechanism. Naltrexone (1 or 10 mg/kg) but not specific kappa-opioid receptor antagonist norbinaltorphimine (5 mg/kg) completely reversed the anticonvulsant effect of ACPA (2 mg/kg). Moreover, the combination of the lower doses of AM251 (0.5 mg/kg) and naltrexone (0.3 mg/kg) had an additive effect in blocking the anticonvulsant effect of ACPA. In accordance with previous reports, morphine exerted biphasic effects on clonic seizure threshold with anticonvulsant effect at lower (0.5-1 mg/kg) and proconvulsant effect at a higher (30 mg/kg) doses. The pretreatment with AM251 blocked the anticonvulsant effect of morphine at 1 mg/kg, while pretreatment with ACPA (1 mg/kg) potentiated the anticonvulsant effect of morphine at 0.5 mg/kg. The proconvulsant effect of morphine at 30 mg/kg was also inhibited by AM251 (2 mg/kg). A similar interaction between cannabinoids and opioids was also detected on their anticonvulsant effects against the generalized tonic-clonic model of seizure. In conclusion, cannabinoids and opioids show functional interactions on modulation of seizure susceptibility.
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http://dx.doi.org/10.1016/j.neuropharm.2004.04.011DOI Listing
September 2004

Role of opioid and nitric oxide systems in the nonadrenergic noncholinergic-mediated relaxation of corpus cavernosum in bile duct-ligated rats.

Eur J Pharmacol 2003 Jan;460(2-3):201-7

Department of Pharmacology, School of Medicine, Tehran University of Medical Science, P.O. Box 13145-784, Tehran, Iran.

Changes in nonadrenergic noncholinergic (NANC)-mediated relaxation of the anococcygeus muscle have been demonstrated in cholestasis. Cholestasis is also associated with accumulation of endogenous opioid peptides and nitric oxide (NO) overproduction. This study was therefore undertaken to investigate the effect of cholestasis on the NANC-mediated relaxation of corpus cavernosum in bile duct-ligated rats and to examine the possible roles of the opioid system and nitric oxide in the cholestasis-associated alterations of corpus relaxation. Bile duct-ligated and sham-operated rats were treated for 2 weeks with either normal saline, N (omega)-nitro L-arginine methylester (L-NAME) (3 mg/kg/day, i.p.) or naltrexone (20 mg/kg/day, i.p.). On the 14th day, the strips of corpus cavernosum were mounted under tension in a standard oxygenated organ bath with guanethidine sulfate (5 microM) and atropine sulfate (1 microM) (to produce adrenergic and cholinergic blockade). The strips were precontracted with phenylephrine hydrochloride (7.5 microM) and electrical field stimulation was applied at different frequencies to obtain NANC-mediated frequency-dependent relaxant responses. The results showed that the amplitudes of relaxation responses at each frequency in bile duct-ligated rats were greater than the responses of sham-operated animals. This increase in relaxation responses in bile duct-ligated rats was inhibited by chronic L-NAME administration for 2 weeks so it seemed that it might be due to the nitric oxide overproduction in cholestatic states. Chronic administration of naltrexone for 2 weeks to bile duct-ligated rats had the same inhibitory effect on the relaxation responses. Our results demonstrated that in cholestasis, there was an increase in NANC-mediated relaxation of corpus cavernosum and both opioid and nitric oxide systems were involved in this increase.
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http://dx.doi.org/10.1016/s0014-2999(02)02946-1DOI Listing
January 2003

The nonadrenergic noncholinergic relaxation of anococcygeus muscles of bile duct-ligated rats.

Eur J Pharmacol 2002 Jun;445(1-2):31-6

Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.

Previous studies have shown the naloxone-induced withdrawal syndrome and the development of tolerance in the tissues of cholestatic animals. Increased neuronal nitric oxide synthase (nNOS) expression is reported to exist in morphine-tolerant animals. This, together with evidence for nitric oxide (NO) overproduction in cholestasis, suggested the possibility of an alteration of nonadrenergic noncholinergic (NANC) relaxation of anococcygeus muscles of cholestatic rats. To study this, we used three main groups of animals: unoperated, sham-operated and bile duct-ligated. Electrical field stimulation, in the presence of atropine and guanethidine, caused NANC relaxation in the anococcygeus muscle which was enhanced in bile duct-ligated animals. N(G)-nitro-L-arginine methyl ester (L-NAME), a NOS blocker, caused a dose-dependent inhibition of the NANC relaxation. The IC(50)'s of L-NAME in 7-day (7.30+/-0.87 microM), 14-day (6.98+/-0.70 microM) and 21-day (8.25+/-1.40 microM) bile duct-ligated groups were significantly different from those of unoperated (1.69+/-0.30 microM) and sham-operated groups (1.90+/-0.27 microM). L-NAME (100 microM) completely inhibited the NANC relaxation response, suggesting that NANC relaxation in the rat anococcygeus muscle is mediated mainly via NO. The contraction response of the intact muscle to phenylephrine, an alpha(1)-adrenoceptor agonist, and the relaxation response of the phenylephrine-contracted muscle to sodium nitroprusside, an NO donor, were not different in unoperated, sham-operated and 7-day bile duct-ligated groups. These results showed that the smooth muscle component of NANC relaxation is not altered in anococcygeus muscles of bile duct-ligated rats. It can thus be concluded that the NANC relaxation in the anococcygeus of cholestatic rats is more resistant to a NOS blocker, providing evidence for increased nitrergic neurotransmission in the anococcygeus muscles of cholestatic rats.
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http://dx.doi.org/10.1016/s0014-2999(02)01659-xDOI Listing
June 2002