Publications by authors named "Edilson Dantas da Silva Junior"

16 Publications

  • Page 1 of 1

Physiopharmacological properties of the testicular capsule: A concise review.

Eur J Pharmacol 2020 Sep 12;883:173345. Epub 2020 Jul 12.

Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil. Electronic address:

The testicular capsules of different mammalian species exhibit spontaneous motor activity. In addition, contractions can be mediated by neuronal stimulation or exogenous drug administration. However, the physiological role of testicular capsule motor activity is still not well understood. Nevertheless, there is evidence for putative roles in spermatozoa transport from the testis to the caput epididymis, control of interstitial/intratesticular pressure and testicular blood flow. In this review, we have collated information about the agents that regulate testicular capsule motor activity, their receptors and second messengers as well as the impact of altered testicular capsule function on the male reproductive system. Furthermore, we highlight the knowledge gaps in the physiology and pharmacology of the testicular capsule as indicators of future research directions that may lead to a better understanding of the physiological role of testicular capsule motor activity and its importance in male fertility.
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http://dx.doi.org/10.1016/j.ejphar.2020.173345DOI Listing
September 2020

Fluoxetine and sertraline effects on rat distal cauda epididymis contraction, sperm count and sperm transit time trough epididymis.

Eur J Pharmacol 2019 Dec 4;865:172774. Epub 2019 Nov 4.

Mode of Drug Action Laboratory, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil; Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil. Electronic address:

Fluoxetine and sertraline are antidepressants drugs capable to impair male fertility by decreasing the number of sperm cells in the ejaculate. However, the mechanism underlying these effects is still not fully understood. It is also reported that alterations in epididymis contraction induced by different drugs affect the number of sperm cells, leading to male fertility alterations. Therefore, this study aimed to investigate if both fluoxetine and sertraline could affect the rat epididymis contraction, altering the sperm transit and/or sperm count trough rat epididymis. In vitro effects of fluoxetine and sertraline (1, 3 and 10 μM) were evaluated in isolated distal cauda epididymis of rats by pharmacological experiments. The effects of long-term treatment with fluoxetine and sertraline (20 mg/kg, i.p., 21 days) were also checked on distal cauda epididymis contractions, serum testosterone levels, sperm production, sperm reserves and sperm transit time trough rat epididymis. In vitro fluoxetine and sertraline (>3 μM) impaired the contractions induced by KCl, phenylephrine or carbachol although fluoxetine 1 μM potentiate the phenylephrine-induced contractions. Long-term in vivo treatment with fluoxetine and sertraline promoted: (a) an enhancement of rat distal cauda spontaneous contractions; (b) a potentiation of phenylephrine-induced contractions; (c) a decreased in serum testosterone levels; and (d) a diminished daily sperm production, sperm reserves trough epididymis and sperm transit time in rat cauda epididymis. In conclusion, the alteration in the motor activity of epididymis could be associated to the low sperm count in this organ and accelerated transit time trough epididymal cauda of rats.
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http://dx.doi.org/10.1016/j.ejphar.2019.172774DOI Listing
December 2019

Intrinsic Adaptation of SHR Right Atrium Reduces Heart Rate.

J Cardiovasc Pharmacol 2019 12;74(6):542-548

Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), São Paulo, Brazil.

Hypertension represents an autonomic dysfunction, characterized by increased sympathetic and decreased parasympathetic cardiovascular tone leading to resting tachycardia. Therefore, studies assessing hypertension-associated changes in isolated cardiac tissues were conducted under electric field stimulation to stimulate the neurons. Herein, we characterize the influence of the autonomic neurotransmitter on the baseline atrial chronotropism of unpaced isolated right atria of normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR). Our results revealed a resting bradycardia in tissues from SHR in comparison to NWR. The release of autonomic neurotransmitters, acetylcholine or norepinephrine, still occurs in the electrically unstimulated right atrium, after excision of the sympathetic nerve, which could explain differences in basal heart rate between NWR and SHR. Nicotine and the acetylcholinesterase inhibitor physostigmine reduced the chronotropism of right atria from either NWR or SHR. Conversely, the muscarinic receptor antagonist atropine did not affect the basal chronotropism of tissues from both strains. Furthermore, tyramine increased the chronotropism of NWR and SHR atria indicating availability of the neuronal stocks of noradrenaline. Although the monoamine uptake inhibitor cocaine increased right atrium chronotropism in both strains, the basal heart rate was not affected by the β-adrenoceptor antagonist propranolol. In summary, after acute section of the sympathetic nerve, autonomic neurotransmitters are still released either in resting conditions or upon pharmacological stimulation of right atria from both strains. Nevertheless, autonomic neurotransmission does not affect resting chronotropism, nor is the responsible for reduced basal heart rate of the isolated right atrium of hypertensive rats.
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http://dx.doi.org/10.1097/FJC.0000000000000746DOI Listing
December 2019

What makes the α -adrenoceptor gene product assume an α -adrenoceptor phenotype?

Br J Pharmacol 2019 07 27;176(14):2358-2365. Epub 2019 Mar 27.

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.

The α -adrenoceptor is abundantly expressed in the lower urinary tract and is the principal therapeutic target for the symptomatic treatment of lower urinary tract symptoms in men. Prazosin has a lower affinity for the lower urinary tract α -adrenoceptor than α -adrenoceptors found in other parts of the body. This has led to the lower urinary tract α -adrenoceptor being subclassified as an α -adrenoceptor. It was demonstrated that this pharmacologically distinct α -adrenoceptor is a product of the α -adrenoceptor gene, but the mechanism by which this altered phenotype is achieved remains a mystery. Hypotheses for this altered pharmacology include the presence of an interacting protein such as cysteine-rich with EGF-like domain (CRELD) 1 or other GPCRs such as the CXCR2 chemokine or 5-HT receptor. Alternatively, the influence of breast cancer resistance protein (BCRP) efflux transporters on the pharmacology of α -adrenoceptors has also been investigated. These and other hypotheses will be described and discussed in this review. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.
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http://dx.doi.org/10.1111/bph.14599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592850PMC
July 2019

Mirabegron: potential off target effects and uses beyond the bladder.

Br J Pharmacol 2018 11 18;175(21):4072-4082. Epub 2018 Jan 18.

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.

The β -adrenoceptor was initially an attractive target for several pharmaceutical companies due to its high expression in rodent adipose tissue, where its activation resulted in decreased adiposity and improved metabolic outputs (such as glucose handling) in animal models of obesity and Type 2 diabetes. However, several drugs acting at the β -adrenoceptor failed in clinical trials. This was thought to be due to their lack of efficacy at the human receptor. Recently, mirabegron, a β -adrenoceptor agonist with human efficacy, was approved in North America, Europe, Japan and Australia for the treatment of overactive bladder syndrome. There are indications that mirabegron may act at other receptors/targets, but whether they have any clinical relevance is relatively unknown. Besides overactive bladder syndrome, mirabegron may have other uses such as in the treatment of heart failure or metabolic disease. This review gives an overview of the off-target effects of mirabegron and its potential use in the treatment of other diseases.

Linked Articles: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.
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http://dx.doi.org/10.1111/bph.14121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177610PMC
November 2018

Cardiac arrest induced by muscarinic or adenosine receptors agonists is reversed by DPCPX through double mechanism.

Eur J Pharmacol 2018 Jan 30;819:9-15. Epub 2017 Sep 30.

Department of Pharmacology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil. Electronic address:

In the right atrium (RA), adenosine and acetylcholine inhibit the pacemaker function of the sinoatrial node and induce cardiac arrest. Pre-incubation of receptor antagonists is known to inhibit the cardiac arrest induced by these agonists; however, the effect of antagonist administration after established cardiac arrest has not been described. Therefore, we assessed whether specific receptor antagonists could revert cardiac arrest induced by adenosine and muscarinic receptors activation. RA isolated from adults Wistar rats were mounted in an organ bath containing Krebs solution. Cardiac arrest was induced by adenosine or ATP (1mM), the A adenosine receptor agonist CPA (0.1-1µM), and muscarinic receptor agonists, carbachol (0.3-1µM) and acetylcholine (1mM). After establishing the cardiac arrest, the A adenosine receptor antagonist DPCPX (0.3-30µM), the muscarinic receptor antagonist atropine (10nM to 100µM) or the phosphodiesterase inhibitor IBMX (10-300µM) were incubated in order to check for the return of spontaneous contractions. DPCPX reversed the cardiac arrest induced by adenosine, ATP and CPA. In addition, atropine reversed the cardiac arrest induced by carbachol. Unexpectedly, DPCPX also reversed the cardiac arrest induced by carbachol. Similarly to DPCPX, the phosphodiesterase inhibitor IBMX reversed the cardiac arrest induced by adenosine, CPA and carbachol. The antagonism of adenosine and acetylcholine receptors activation, as well as phosphodiesterase inhibition, are able to revert cardiac arrest. DPCPX restore spontaneous contractions via the selective antagonism of A adenosine receptor and through a secondary mechanism likely related to phosphodiesterase inhibition.
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http://dx.doi.org/10.1016/j.ejphar.2017.09.030DOI Listing
January 2018

The Effect of Raddi (Anacardiaceae) Bark Extract on Histamine-Induced Paw Edema and Ileum Smooth Muscle Contraction.

Evid Based Complement Alternat Med 2017 27;2017:1416375. Epub 2017 Aug 27.

Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, PE, Brazil.

Raddi (Anacardiaceae), popularly known as red aroeira, is used in traditional medicine to treat inflammatory, gastric, and respiratory disorders. The aim of this study was to evaluate the antihistaminic activity of bark extract by using in vivo and in vitro experimental models. The effects of were investigated on contractions induced by histamine, carbachol, and potassium chloride in isolated guinea pig ileum. was also studied in response to hind paw edema induced by histamine in rats. Experiments revealed that although (250, 500, and 1,000 g/mL) reduced the histamine-induced contractions by 9.1 ± 1.8, 50.2 ± 2.0, and 68.9 ± 2.0%, respectively, it did not inhibit contractions induced by carbachol or KCl. The association of (250 and 500 g/mL) with hydroxyzine, an H-antihistamine (0.125 and 0.250 M), increased the inhibitory effect to 67.0 ± 3.2 and 85.1 ± 2.1%, respectively. Moreover, (100, 200, and 400 mg/kg) decreased paw edema from its peak by 33.9, 48.4, and 54.8%, respectively, whereas hydroxyzine (70 mg/kg) inhibited the peak edema by 56.5%. Altogether, the results suggest that the bark extract of has an antihistaminic effect (H).
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http://dx.doi.org/10.1155/2017/1416375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592001PMC
August 2017

Factors influencing biased agonism in recombinant cells expressing the human α -adrenoceptor.

Br J Pharmacol 2017 Jul 10;174(14):2318-2333. Epub 2017 Jun 10.

Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.

Background And Purpose: Agonists acting at GPCRs promote biased signalling via Gα or Gβγ subunits, GPCR kinases and β-arrestins. Since the demonstration of biased agonism has implications for drug discovery, it is essential to consider confounding factors contributing to bias. We have examined bias at human α -adrenoceptors stably expressed at low levels in CHO-K1 cells, identifying off-target effects at endogenous receptors that contribute to ERK1/2 phosphorylation in response to the agonist oxymetazoline.

Experimental Approach: Intracellular Ca mobilization was monitored in a Flexstation® using Fluo 4-AM. The accumulation of cAMP and ERK1/2 phosphorylation were measured using AlphaScreen® proximity assays, and mRNA expression was measured by RT-qPCR. Ligand bias was determined using the operational model of agonism.

Key Results: Noradrenaline, phenylephrine, methoxamine and A61603 increased Ca mobilization, cAMP accumulation and ERK1/2 phosphorylation. However, oxymetazoline showed low efficacy for Ca mobilization, no effect on cAMP generation and high efficacy for ERK1/2 phosphorylation. The apparent functional selectivity of oxymetazoline towards ERK1/2 was related to off-target effects at 5-HT receptors endogenously expressed in CHO-K1 cells. Phenylephrine and methoxamine showed genuine bias towards ERK1/2 phosphorylation compared to Ca and cAMP pathways, whereas A61603 displayed bias towards cAMP accumulation compared to ERK1/2 phosphorylation.

Conclusion And Implications: We have shown that while adrenergic agonists display bias at human α -adrenoceptors, the marked bias of oxymetazoline for ERK1/2 phosphorylation originates from off-target effects. Commonly used cell lines express a repertoire of endogenous GPCRs that may confound studies on biased agonism at recombinant receptors.
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http://dx.doi.org/10.1111/bph.13837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481649PMC
July 2017

Effects of in vitro, acute and chronic treatment with fluoxetine on the sympathetic neurotransmission of rat vas deferens.

Auton Neurosci 2017 Mar 20;203:17-24. Epub 2016 Nov 20.

Department of Pharmacology, Federal University of Sao Paulo, Sao Paulo, Brazil. Electronic address:

It is described that fluoxetine treatment is able to induce ejaculatory disorders. However, the exact mechanism is still not fully understood. Therefore, this study was carried out to further evaluate the anti-ejaculatory effects of fluoxetine, using different approaches (in vitro or in vivo treatments), on the sympathetic neurotransmission of the rat vas deferens. Vas deferens from male Wistar rats were used to check the in vitro effects of fluoxetine 10M, 3.10M or 10M. Animals were also acutely (20mg/kg, i.p. 4h or 24h) or chronically (10mg/kg, i.p., 30days) treated with fluoxetine or drug-free vehicle. The vas deferens from non-treated and treated animals were isolated and mounted in an isolated organ bath for the study of the contractions induced by adrenergic agonists, tyramine, 5-HT, Ca or electrical field stimulation. In vitro or acute treatment with fluoxetine decreased the contraction induced by agonists, Ca or electrical field stimulation. The chronic treatment with fluoxetine decreased the contractions induced agonists, tyramine or Ca, but did not modify the contractions induced by electrical field stimulation. We have shown that in vitro or in vivo fluoxetine treatment is able to alter the sympathetic neurotransmission of the rat vas deferens which could be related to alterations in the calcium signalling.
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http://dx.doi.org/10.1016/j.autneu.2016.10.006DOI Listing
March 2017

Would calcium or potassium channels be responsible for cardiac arrest produced by adenosine and ATP in the right atria of Wistar rats?

Eur J Pharmacol 2015 Dec 31;768:199-206. Epub 2015 Oct 31.

Department of Pharmacology, Federal University of São Paulo (UNIFESP), Brazil. Electronic address:

Autonomic nerves release ATP, which is processed into adenosine in the synaptic cleft. Adenosine and ATP exert a negative chronotropic effect in the heart. This study aims to evaluate adenosine and P2 receptors and cellular signalling in cardiac arrest produced by purines in the heart. Right atria of adult Wistar rats were used to evaluate the effects of adenosine, ATP and CPA (an adenosine A1 receptor agonist), in the presence and absence of DPCPX, an adenosine A1 receptor antagonist. Effects of adenosine A2 and A3 receptors agonists and antagonists were also investigated. Finally, involvement of calcium and potassium channels in these responses was assessed using BayK 8644 and 4-Aminopyridine. Cumulative concentration-effect curves of adenosine and CPA resulted in a negative chronotropic effect culminating in cardiac arrest at 1000μM (adenosine) and 1µM (CPA). Furthermore, ATP produced a negative chronotropic effect at 1-300µM and cardiac arrest at 1000μM in the right atrium. ATPγS (a non-hydrolysable analogue of ATP) reduced chronotropism only. The effects of adenosine, CPA and ATP were inhibited by DPCPX, a selective adenosine A1 receptor antagonist. The selective adenosine A2 and A3 receptors antagonists did not alter the chronotropic response of adenosine. 4-Aminopyridine, a blocker of potassium channels at 10mM, prevented the cardiac arrest produced by adenosine and ATP, while BayK 8644, activator of calcium channels, did not prevent cardiac arrest. Adenosine A1 receptor activation by adenosine and ATP produces cardiac arrest in the right atrium of Wistar rats predominantly through activation of potassium channels.
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http://dx.doi.org/10.1016/j.ejphar.2015.10.054DOI Listing
December 2015

Could α1-adrenoceptors and androgen receptors be modified by sexual maturation and testosterone in the rat testicular capsule?

Life Sci 2015 Nov 24;141:212-20. Epub 2015 Sep 24.

Department of Pharmacology, Universidade Federal de São Paulo-Escola Paulista de Medicina (UNIFESP/EPM), 04044-020 São Paulo, SP, Brazil.

Aims: Testicular capsule contractile dysfunctions are recognized to contribute to male infertility, but the influence of sexual maturation and exogenous testosterone on the expression and function of androgen receptor and α1-adrenoceptors on rat testicular capsule is unclear. Here, these two biological parameters were evaluated on testicular capsule from sexually immature and young adult rats treated or not with exogenous testosterone.

Main Methods: Male Wistar rats (45- and 60-day-old) were assigned into groups: control (saline 0.9%) or testosterone-treated (propionate testosterone). Testicular capsule was isolated and processed for functional studies, immunohistochemistry, Western blot and RT-PCR studies.

Key Findings: Relative testicular capsule wet weight was not affected by sexual maturation or exogenous testosterone treatment. The expression and immunolocalization of androgen receptor (mRNA and protein) was identified in testicular capsule. Androgen receptor and α1-adrenoceptor (Adra1a, Adra1b, and Adra1d) mRNA levels were similar in testicular capsule from all experimental groups. Functional studies indicated that contractions produced by noradrenaline in testicular capsule from 45- and 60-day-old rats treated or not with testosterone were mainly mediated by α1A- and α1B-adrenoceptors. The L-type Ca(2+) channel blocker nifedipine induced a higher inhibitory effect on noradrenaline induced contractions in testicular capsule from 45- than 60-day-old rats treated with testosterone.

Significance: Molecular studies, immunohistochemistry and pharmacological functional assays used in this study provide evidences of the androgen receptor expression in testicular capsule and that function, and not mRNA and protein expression levels of the α1-adrenoceptor subtypes in this tissue, is differentially influenced by the rat androgen status.
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http://dx.doi.org/10.1016/j.lfs.2015.09.009DOI Listing
November 2015

A comparison of histamine effects on the sympathetic neurotransmission of testicular capsule and rat vas deferens.

Naunyn Schmiedebergs Arch Pharmacol 2014 Aug 16;387(8):719-31. Epub 2014 Apr 16.

Department of Pharmacology, Federal University of São Paulo (UNIFESP), Rua 3 de maio nº 100, 2°, Andar, São Paulo, 04044-020, Brazil.

Histamine is an important modulatory agent of the sympathetic neurotransmission, but its exact action on the testicular capsule or rat vas deferens is not fully understood. The present study sought to further investigate the functional effects of histamine on the neuronal and exogenous noradrenaline-induced contraction of the testicular capsule and rat vas deferens as well as to evaluate the contractile properties of this drug. The testicular capsule or vas deferens from Wistar rats, 3-4 months old, weighing 300-400 g, was isolated and mounted in organ baths for functional experiments. The results indicated that the neuronally evoked contraction of the testicular capsule was affected by histamine (10(-10) to 10(-8) M) with participation of inhibitory (H3 receptors) and excitatory (H1 receptors) receptors. Histamine (10(-7) to 10(-4) M) modulated the field-stimulated vas deferens by excitatory (H2 receptors) and inhibitory (H1 receptors) receptors. Histamine was able to decrease the tonic response for noradrenaline-induced contractions with participation of H1 receptors (testicular capsule) and H3 receptors (vas deferens) followed by nitric oxide generation. At high concentration, histamine exerts contractile effects in both tissues. In the testicular capsule, the histamine-induced contractions were related to H1 receptor activation followed by release of prostaglandins. In contrast, the contractile effects of histamine in the vas deferens were related to H2 receptor activation followed by release of catecholamines from sympathetic nerve endings. Therefore, our results indicate that histamine induced several effects on the sympathetic neurotransmission of rat testicular capsule and vas deferens. These effects are dependent on the concentration used and with participation of multiple histamine receptors.
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http://dx.doi.org/10.1007/s00210-014-0979-zDOI Listing
August 2014

Effects of clonidine in the isolated rat testicular capsule.

Eur J Pharmacol 2014 Mar;726:16-26

The testicular capsule contracts in response to noradrenaline and adrenaline, but the effects of adrenoceptor agonists, as for instance clonidine, had not yet been thoroughly evaluated. The testicular capsule from adult male Wistar rats was isolated and mounted in organ bath and cumulative concentration curves were performed for clonidine and other adrenergic agonists in the absence or presence of α-adrenoceptors antagonists. The order of potency for agonists (pD2) was clonidine=adrenaline>UK 14,304>noradrenaline>phenylephrine>methoxamine. The consecutive curves for clonidine showed desensitization with 3-fold rightward shift and Emax reduction of 40%. The noradrenaline curves were 4.5, 19 and 190-fold less potent after clonidine pretreatment at 10−5, 10−4 or 10−3 M for 10 min, respectively, added to Emax decrease by about 20%. Clonidine (10−5 M for 10 min) was unable to alter the noradrenaline curves if the treatment was made in the presence of idazoxan (α2-adrenoceptor antagonist) whereas prazosin (α1-adrenoceptor antagonist) was ineffective. The effect of idazoxan 3×10−7 M on noradrenaline curves was decreased by 50% after clonidine pretreatment, as reflected by the concentration ratio of 5.2±1.2 (treated tissue) and 10.1±1.0 (untreated tissue). However, the concentration ratio for prazosin 3×10−8 M was unchanged. After phenoxybenzamine (irreversible antagonist of α1-adrenoceptor) pretreatment, the residual noradrenaline contraction was antagonized by idazoxan or prazosin with pKB values of 7.8 and 5.1, respectively. The results indicate the presence of α2-adrenoceptors in testicular capsule. Furthermore, these receptors may be desensitized by clonidine, causing a decreased potency of noradrenaline.
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http://dx.doi.org/10.1016/j.ejphar.2014.01.027DOI Listing
March 2014

Functional characterization of acetylcholine receptors and calcium signaling in rat testicular capsule contraction.

Eur J Pharmacol 2013 Aug 16;714(1-3):405-13. Epub 2013 Jul 16.

Department of Pharmacology, Federal University of São Paulo-Escola Paulista de Medicina, 04044-020 São Paulo-SP, Brazil.

The motor activity of mammalian testicular capsule (TC) contributes to male fertility and infertility, but the acetylcholine receptors related to the contractions induced by cholinergic drugs are poorly known. Indeed to characterize the acetylcholine receptors and cellular signaling by Ca(2+) involved in TC motor activity of rats, the potency of agonists (pD₂) and antagonists (pA₂) of acetylcholine receptors, and effects of Ca(2+) cellular transport blockers on the cholinergic contractions were evaluated. pD₂ values of acetylcholine (5.98) were ten-fold higher than that of carbachol (4.99). Efficacy (Emax) of acetylcholine and carbachol to induce contractions corresponded to 95% and 97% of Emax for KCl, but Emax for nicotine was very low (8% of Emax for KCl). Further, physostigmine did not affect the acetylcholine potency. Contractions induced by acetylcholine or carbachol were antagonized by muscarinic but not nicotinic antagonist. The order of pA₂ values obtained for muscarinic antagonists, namely atropine>4-DAMP>AF-DX116>pirenzepine, corresponded to a typical profile of M3 receptors. Contractions induced by acetylcholine or carbachol were inhibited by blockers of Ca(2+) influx through voltage-dependent calcium channels (nifedipine and Ni(2+)), Ca(2+) reuptake by sarco-endoplasmic reticulum (cyclopiazonic acid) and mitochondria (FCCP). The protein kinase C (PKC) inhibitor chelerythrine only affected the acetylcholine-induced contraction. These results suggest that TC motor activity of rats are mediated mainly by M₃ receptors followed by the increase of cytosolic Ca(2+) concentration regulated by voltage-dependent calcium channels, sarco-endoplasmic reticulum and mitochondria. Furthermore, the differential effects of chelerythrine in the acetylcholine or carbachol-induced contractions are discussed.
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http://dx.doi.org/10.1016/j.ejphar.2013.07.007DOI Listing
August 2013

Changes of cytosolic calcium and contractility of young rat vas deferens by acute treatment with amphetamine, fluoxetine or sibutramine.

Eur J Pharmacol 2012 Sep 17;691(1-3):52-60. Epub 2012 Jul 17.

Department of Pharmacology, Federal University of São Paulo-UNIFESP, Rua 3 de Maio 100, 04044-020 São Paulo, SP, Brazil.

Previous studies conducted in our laboratory indicated that administration of amphetamine, fluoxetine or sibutramine affects the sympathetic nervous system of the rat vas deferens. Therefore, our goal was to verify the role of calcium in vasa deferentia from young rats pretreated with a single dose of these drugs. Young 40-day-old male Wistar rats were pretreated with amphetamine 3 mg/kg, fluoxetine 10 mg/kg or sibutramine 6 mg/kg for 4 h before the experiments. CaCl(2) (10 mM) was used to induce contraction through time-effect curves in calcium-free solution to measure phasic and tonic components. We also evaluated the calcium-induced fluorescence of vas deferens cut into thin slices. In rats pretreated with amphetamine, we found an increase of the tonic contraction component which was reduced by verapamil. The phasic and tonic responses were increased in the group treated with fluoxetine, but only the tonic response was more sensitive to the antagonism by verapamil. The group treated with sibutramine showed an increase of phasic response whereas the tonic component was decreased. In this group an increase of the affinity for verapamil antagonism was found. In the calcium fluorescence study it was observed that the group treated with amphetamine, fluoxetine or sibutramine showed higher basal Ca(2+) fluorescence after stimulus with KCl (70 mM), noradrenaline (10(-4)M) or acetylcholine (10(-4)M). In all pretreated groups the calcium fluorescence was diminished by nifedipine 10(-7)M. Therefore, the pretreatment with amphetamine, fluoxetine or sibutramine seems to affect the calcium contractility and homeostasis in young rat vas deferens.
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http://dx.doi.org/10.1016/j.ejphar.2012.07.027DOI Listing
September 2012

Alteration of purinergic neurotransmission in isolated atria of streptozotocin-induced diabetic rats.

J Cardiovasc Pharmacol 2012 Feb;59(2):158-64

Department of Pharmacology, Federal University of São Paulo, São Paulo, Brazil.

Cardiac dysfunctions are described in diabetes. However, the role of purinergic neurotransmission in diabetes-related cardiovascular diseases is unknown. The purpose of this study was to evaluate the purinergic neurotransmission in isolated atria from streptozotocin-induced diabetic rats. The animals were grouped as control and diabetic with 30 days (D30) and 60 days (D60) after streptozotocin-induced diabetes. The isolated left and right atria were used in functional experiments. The effects of adenosine triphosphate, uridine diphosphate, and adenosine were evaluated on atrial inotropism and chronotropism. The antagonists 8-cyclopentyl-1,3-dipropylxanthine and pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate were also used, as blockers of P1 and P2 receptors, respectively. A negative inotropic effect followed by a positive inotropic effect was induced by adenosine triphosphate in isolated atria. This negative inotropic effect was decreased by 25% in left atria of D30. Additionally, the apparent affinity for adenosine was diminished in left atria of D30, suggesting changes in P1 receptor function. No changes were found in the right atria of D30 stimulated by adenosine. The left atria and right atria stimulated by uridine diphosphate showed an increased inotropic effect of 92% and 17%, respectively. No changes were observed in left and right atria of D30 stimulated by uridine diphosphate. Our data showed the involvement of purinergic neurotransmission in diabetes-related cardiovascular changes.
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http://dx.doi.org/10.1097/FJC.0b013e31823a0f31DOI Listing
February 2012