Publications by authors named "Giovanni Romussi"

17 Publications

  • Page 1 of 1

Anti-inflammatory and analgesic activity of carnosol and carnosic acid in vivo and in vitro and in silico analysis of their target interactions.

Br J Pharmacol 2017 06 8;174(11):1497-1508. Epub 2016 Aug 8.

Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.

Background And Purpose: The diterpenoids carnosol (CS) and carnosic acid (CA) from Salvia spp. exert prominent anti-inflammatory activities but their molecular mechanisms remained unclear. Here we investigated the effectiveness of CS and CA in inflammatory pain and the cellular interference with their putative molecular targets.

Experimental Approach: The effects of CS and CA in different models of inflammatory pain were investigated. The inhibition of key enzymes in eicosanoid biosynthesis, namely microsomal prostaglandin E synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) was confirmed by CS and CA, and we determined the consequence on the eicosanoid network in activated human primary monocytes and neutrophils. Molecular interactions and binding modes of CS and CA to target enzymes were analyzed by docking studies.

Key Results: CS and CA displayed significant and dose-dependent anti-inflammatory and anti-nociceptive effects in carrageenan-induced mouse hyperalgesia 4 h post injection of the stimuli, and also inhibited the analgesic response in the late phase of the formalin test. Moreover, both compounds potently inhibited cell-free mPGES-1 and 5-LO activity and preferentially suppressed the formation of mPGES-1 and 5-LO-derived products in cellular studies. Our in silico analysis for mPGES-1 and 5-LO supports that CS and CA are dual 5-LO/mPGES-1 inhibitors.

Conclusion And Implications: In summary, we propose that the combined inhibition of mPGES-1 and 5-LO by CS and CA essentially contributes to the bioactivity of these diterpenoids. Our findings pave the way for a rational use of Salvia spp., traditionally used as anti-inflammatory remedy, in the continuous expanding context of nutraceuticals.

Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.
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http://dx.doi.org/10.1111/bph.13545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429324PMC
June 2017

Antibacterial compounds from Salvia adenophora Fernald (Lamiaceae).

Phytochemistry 2015 Feb 27;110:120-32. Epub 2014 Nov 27.

Dipartimento di Farmacia, Università di Salerno, Via Giovanni Paolo II 132, 84084 Salerno, Italy.

From the aerial parts of Salvia adenophora Fernald four derivatives of 12-oxo-phytodienoic acid (1-4) together with five clerodane diterpenoids (5, 6, 8-10), and one known diterpene (7) have been isolated. Compounds 1-6 and 8-10 are described for the first time. The structures were established by extensive 1D, 2D NMR and HRESI-TOFMS spectroscopic methods. Finally, the absolute configuration has been established by comparing of experimental and quantum chemical calculation of ECD spectra. Despite a total lack of antimicrobial activity of the plant extract, hinting to the existence of antagonistic interactions in the crude material, three oxylipins (2-4) displayed a promising inhibition on Gram-positive multidrug-resistant clinical strains including Staphylococcus aureus, Streptococcus agalactiae and, particularly, Staphylococcus epidermidis, while the compounds 9 and 10 revealed a specific and strain-dependent activity against S. epidermidis. Interestingly, the inhibition provided by these compounds was independent of the resistance patterns of these pathogens to classic antibiotics. No action was reported on Gram-negative strains nor on Candida albicans. These results confirm that clerodanes and, particularly, prostaglandin-like compounds can be considered as interesting antimicrobial agents deserving further study.
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http://dx.doi.org/10.1016/j.phytochem.2014.10.033DOI Listing
February 2015

Effects of the neoclerodane Hardwickiic acid on the presynaptic opioid receptors which modulate noradrenaline and dopamine release in mouse central nervous system.

Neurochem Int 2013 Mar 26;62(4):354-9. Epub 2013 Jan 26.

Department of Pharmacy, Pharmacology and Toxicology Section, University of Genoa, Italy.

We have comparatively investigated the effects of Hardwickiic acid and Salvinorin A on the K(+)-evoked overflow of [(3)H]noradrenaline ([(3)H]NA) and [(3)H]dopamine ([(3)H]DA) from mouse hippocampal and striatal nerve terminals, respectively. The K(+)-evoked overflow of [(3)H]DA was inhibited in presence of Salvinorin A (100 nM) but not in presence of Hardwickiic acid (100 nM). Hardwickiic acid (100 nM) mimicked Salvinorin A (100 nM) in facilitating K(+)-evoked hippocampal [(3)H]NA overflow and the two compounds were almost equipotent. Facilitation of [(3)H]NA overflow caused by 100 nM Hardwickiic acid was prevented by the κ-opioid receptor (KOR) antagonist norbinaltorphimine (norBNI, 100 nM) and by the selective δ-opioid receptor (DOR) antagonist naltrindole (100 nM), but was not altered by 100 nM D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), a selective μ-opioid receptor (MOR) antagonist. We conclude that Hardwickiic acid modulates hippocampal [(3)H]NA overflow evoked by a mild depolarizing stimulus by acting at presynaptic opioid receptor subtypes.
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http://dx.doi.org/10.1016/j.neuint.2013.01.016DOI Listing
March 2013

Total phenolic content and antioxidant activity of Salvia spp. exudates.

Nat Prod Commun 2012 Feb;7(2):201-2

Dipartimento di Scienze della Terra, della Vitae dell'Ambiente (DiSTeVA) - Sez. Biologia Vegetale-Università degli Studi di Urbino "Carlo Bo", Via Bramante 28 - 61029, Urbino (PU), Italy.

The total phenolic content and antioxidant activity of 6 Salvia spp. exudates were measured to find new potential sources of natural antioxidants. Total phenolic content was assessed by a modified Prussian blue method, and the antioxidant activity by two methods: 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging capacity assay and lipoxygenase inhibitory assay. The total phenolic content ranged between 1.3 microg/mg DW (S. fallax) and 74.0 microg/mg DW (S. cacaliaefolia). In the DPPH test, S. cacaliaefolia was more effective than BHT, while in the inhibition of lipid peroxidation all the extracts presented good antioxidant capacity.
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February 2012

Phytotoxic clerodane diterpenes from Salvia miniata Fernald (Lamiaceae).

Phytochemistry 2011 Feb 2;72(2-3):265-75. Epub 2010 Dec 2.

Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari, Università di Genova, Genova, Italy.

Our ongoing research to identify natural growth inhibitors with diterpene and triterpene skeletons exuding from the surface of the aerial parts of Salvia species led us to study Salvia miniata Fernald. Ten clerodane diterpenoids were found, along with three known diterpenes. Most of the isolated compounds from S. miniata inhibited the germination of Papaver rhoeas L. and Avena sativa L. in Petri dish experiments. Parallel results have been obtained in experiments carried out to evaluate the subsequent growth of the seedlings of the target species in the presence of the tested compounds.
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http://dx.doi.org/10.1016/j.phytochem.2010.11.011DOI Listing
February 2011

Demethyl fruticulin A (SCO-1) causes apoptosis by inducing reactive oxygen species in mitochondria.

J Cell Biochem 2010 Dec;111(5):1149-59

Centro Biotecnologie Avanzate, Genova, Italy.

Demethyl fruticulin A (SCO-1) is a compound found in Salvia corrugata leaves. SCO-1 was reported to induce anoikis in cell lines via the membrane scavenging receptor CD36. However, experiments performed with cells lacking CD36 showed that SCO-1 was able to induce apoptosis also via alternative pathways. To gain some insight into the biological processes elicited by this compound, we undertook an unbiased genomic approach. Upon exposure of glioblastoma tumor initiating cells (GBM TICs) to SCO-1 for 24 h, we observed a deregulation of the genes belonging to the glutathione metabolism pathway and of those belonging to the biological processes related to the response to stress and to chemical stimulus. On this basis, we hypothesized that the SCO-1 killing effect could result from the induction of reactive oxygen species (ROS) in the mitochondria. This hypothesis was confirmed by flow cytometry using MitoSOX, a mitochondria-selective fluorescent reporter of ROS, and by the ability of N-acetyl cysteine (NAC) to inhibit apoptosis when co-administered with SOC-1 to the GBM TICs. We further show that NAC also protects other cell types such as HeLa, MG-63, and COS-7 from apoptosis. We therefore propose that ROS production is the major molecular mechanism responsible for the pro-apoptotic effect induced by SCO-1. Consequently, SCO-1 may have a potential therapeutic value, which deserves further investigation in animal models.
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http://dx.doi.org/10.1002/jcb.22801DOI Listing
December 2010

Phytotoxic activity of Salvia x jamensis.

Nat Prod Commun 2009 Dec;4(12):1621-30

Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari, University of Genoa, Genoa, Italy.

A study has been carried out on the surface exudate of Salvia x jamensis, which showed a significant phytotoxic activity against Papaver rhoeas L. and Avena sativa L.. Bioguided separation of the exudate yielded active fractions from which 3 beta-hydroxy-isopimaric acid (1), hautriwaic acid (2), betulinic acid (3), 7,8 beta-dihydrosalviacoccin (4), isopimaric acid (5), 14 alpha-hydroxy-isopimaric acid (7), 15,16-epoxy-7 alpha, 10 beta-dihydroxy-clerod-3,13(16),14-trien-17,12;18,19-diolide (8), cirsiliol (5,3',4'-trihydroxy-6,7-dimethoxyflavone, 9) and two new neoclerodane diterpenes (6 and 10) were isolated. The structures of 6 and 10 were identified as 15,16-epoxy-10 beta-hydroxy-clerod-3,13(16),14-trien-17,12;18,19-diolide and 15,16-epoxy-7 alpha,10-dihydroxy-clerod-2,13(16),14-trien-17,12;18,19-diolide respectively on the basis of spectroscopic data analysis. All compounds, but 7, 8 and 10, were active in inhibiting the germination of the tested species.
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December 2009

The administration of demethyl fruticulin A from Salvia corrugata to mammalian cells lines induces "anoikis", a special form of apoptosis.

Phytomedicine 2010 May 13;17(6):449-56. Epub 2009 Aug 13.

Stem Cell Laboratory, Advanced Biotechnology Center, Largo R. Benzi 10, 16132 Genova, Italy.

Recently demethyl fruticulin A was identified as the major diterpenoid component of the exudates produced by the trichomes of Salvia corrugata leafs. Given the documented apoptotic effects of some of the other known components of the exudates from Salvia species, we assessed if demethyl fruticulin A, once administered to mammalian cells, was involved in the onset of apoptosis and if its biological effects were exerted through the participation of a scavenger membrane receptor, CD36. Three model cell lines were chosen, one of which lacking CD36 expression. Functional availability of the receptor, or its transcriptional rate, were blocked/reduced with a specific antibody or by the administration of vitamin E. Immunodetection of cell cytoskeletal components and tunel analysis revealed that demethyl fruticulin A triggers the onset of anoikis, a special form of apoptosis induced by cell detachment from the substrate. Impairment of CD36 availability/transcription confirmed the receptor partial involvement in the intake of the substance and in anoikis, as also sustained by FACS analysis and by the downregulation of p95, a marker of anoikis, upon blockade of CD36 transcription. However, experiments with CD36-deficient cells suggested that alternate pathways, still to be determined, may take part in the biological effects exerted by demethyl fruticulin A.
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http://dx.doi.org/10.1016/j.phymed.2009.07.007DOI Listing
May 2010

Salvinorin A exerts opposite presynaptic controls on neurotransmitter exocytosis from mouse brain nerve terminals.

Neuropharmacology 2009 Oct-Nov;57(5-6):523-30. Epub 2009 Jul 21.

Department of Experimental Medicine, Pharmacology and Toxicology Section, University of Genoa, 16148 Genova, Italy.

We investigated the effects of salvinorin A on the basal and the 12 mM K(+)-evoked release of preloaded [(3)H]noradenaline ([(3)H]NA) and [(3)H]serotonin ([(3)H]5-HT) from mouse hippocampal nerve terminals (synaptosomes), as well as on the basal and 12mM K(+)-evoked release of preloaded [(3)H]dopamine ([(3)H]DA) from mouse striatal and prefrontal cortex (PFc) synaptosomes. Salvinorin A (0.1-1000 nM) failed to affect the basal release of amines, but inhibited the 12 mM K(+)-evoked, Ca(2+)-dependent, exocytotic-like release of [(3)H]5-HT and [(3)H]DA. At the same concentration, salvinorin A facilitated the 12 mM K(+)-evoked, Ca(2+)-dependent, exocytotic-like release of [(3)H]NA. These effects could not be observed in pertussis toxin (PTx) entrapped synaptosomes. The broad spectrum kappa-opioid receptor (KOR) antagonist norbinaltorphimine (norBNI, 1-100 nM) antagonized the inhibition of [(3)H]5-HT and [(3)H]DA exocytosis as well as the facilitation of [(3)H]NA overflow induced by 100 nM salvinorin A. The KOR agonist U69593 (1-100 nM) mimicked salvinorin A in inhibiting [(3)H]5-HT and of [(3)H]DA exocytosis, its effect being prevented by norBNI, but leaving unchanged the K(+)-evoked release of [(3)H]NA. The effects of Salvinorin A on neurotransmitter exocytosis were not prevented by the selective mu opioid (MOR) receptor antagonist CTAP (10-100 nM), whereas facilitation of [(3)H]NA exocytosis, but not inhibition of [(3)H]5-HT and [(3)H]DA K(+)-evoked release, was counteracted by the delta opioid receptor (DOR) antagonist naltrindole (1-100 nM). We conclude that salvinorin A presynaptically modulates central NA, 5-HT, and DA exocytosis evoked by a mild depolarizing stimulus by acting at presynaptic opioid receptors having different pharmacological profiles.
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http://dx.doi.org/10.1016/j.neuropharm.2009.07.023DOI Listing
December 2009

First evidence for an anxiolytic effect of a diterpenoid from Salvia cinnabarina.

Nat Prod Commun 2009 Apr;4(4):469-72

Department of Experimental Pharmacology, University of Naples Federico II, via Domenico Montesano 49, 80131 Naples, Italy.

The potential anxiolytic and anti-depressive activity of CMP1 was studied in the elevated plus-maze test and in the forced swimming test. Furthermore, CMP1 sedative activity was evaluated in pentobarbital treated animals; the effect of CMP1 on spontaneous motor activity (total locomotion) was also evaluated. Our data show that CMP1, at doses that did not affect locomotion, was able to induce anxiolytic and sedative, but not anti-depressive effects. In conclusion, our results represent first evidence for an anxiolytic activity of this diterpenoid from Salvia cinnabarina.
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April 2009

Antimicrobial activity of the ornamental species Salvia corrugata, a potential new crop for extractive purposes.

J Agric Food Chem 2008 Nov;56(22):10468-72

Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari, Universita di Genova, Genova, Italy.

As a part of our search for biologically active compounds from cultivated Salvia spp. we investigated Salvia corrugata Vahl. The activity of two isolated icetaxane diterpene quinones, fruticuline A and demethylfruticuline A, was assessed against 46 bacterial pathogens, mostly resistant to several primary antibiotics. The MIC for all the inhibited Gram-positive pathogens tested showed a very narrow distribution and ranged from 32 to 64 mg/L, regardless of their resistance patterns to other antibiotics. Demethylfruticuline A was shown to be highly bactericidal (>3 log(10) CFU decrease within 24 h) against Staphylococcus aureus and S. epidermidis and bacteriostatic against Enterococcus faecalis and E. faecium. Fruticuline A manifested bacteriostatic activity against all tested strains. S. corrugata can be viewed as an interesting source for these diterpenes, which, if well tolerated in vivo, may represent new medical agents useful for the treatment of serious infections caused by resistant Gram-positive pathogens.
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http://dx.doi.org/10.1021/jf802200xDOI Listing
November 2008

Relative stereochemistry of a diterpene from Salvia cinnabarina.

Molecules 2007 Oct 10;12(10):2279-87. Epub 2007 Oct 10.

Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari, Università di Genova, Via Brigata Salerno, Genova, Italy.

The relative stereochemistry of 3,4-secoisopimara-4(18),7,15-triene-3-oic acid, a diterpenoid with antispasmodic, hypotensive and antibacterial activities isolated from Salvia cinnabarina, was determined by an X-ray diffraction analysis of a single crystal of a suitable crystalline derivative.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149099PMC
http://dx.doi.org/10.3390/12102279DOI Listing
October 2007

Effect of a diterpenoid from Salvia cinnabarina on arterial blood pressure in rats.

Phytother Res 2007 Jul;21(7):690-2

Dipartimento di Farmacologia Sperimentale, University of Naples Federico II, via D. Montesano 49, 80131 Napoli, Italy.

The effect of a diterpenoid isolated from Salvia cinnabarina, 3,4-seicosopimar-4(18),7,15-triene-3-oic acid (SCB), on arterial blood pressure was evaluated in anaesthetized rats. Male Wistar rats, anaesthetized with urethane (sol. 10% p/v; 10 mL/kg), underwent surgery for continuous monitoring of arterial blood pressure. After preliminary experiments to evaluate the dose response (3, 10 and 30 mg/kg i.v.) of SCB, a dose of 3 mg/kg was chosen for all successive experiments. On different groups of rats treated with the ganglion-blocking agent chlorisondamine (2.5 mg/kg i.p.) the effect of SCB (3 mg/kg i.v.) was evaluated before and following an infusion of the nitric oxide synthase inhibitor L-NAME (0.3 mg/kg/min i.v.). Intravenous administration of SCB at doses of 3, 10 and 30 mg/kg led to a fall in mean arterial blood pressure (MABP) of 14.75 +/- 1.44 mmHg, 36.60 +/- 31.40 mmHg and 31.40 +/- 6.28 mmHg, respectively (n = 4-5), that was not modified by treatment of the rat with chlorisondamine nor with L-NAME. The results demonstrate a hypotensive effect of SCB - due to a peripheral mechanism but independent of endothelial nitric oxide release.
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http://dx.doi.org/10.1002/ptr.2128DOI Listing
July 2007

Diterpenoids from Salvia wagneriana.

Planta Med 2004 May;70(5):452-7

Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari, Università di Genova, Genova, Italy.

From the surface exudate of the aerial parts of Salvia wagneriana, three new clerodane diterpenoids, the known hardwickiic acid and 1,10-didehydrosalviarin, were obtained. Two were bis-diterpenoids. Their structures were established by 1D- and 2D-NMR spectroscopic techniques.
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http://dx.doi.org/10.1055/s-2004-818975DOI Listing
May 2004

A diterpenoid from Salvia cinnabarina inhibits mouse intestinal motility in vivo.

Planta Med 2004 Apr;70(4):375-7

Department of Experimental Pharmacology, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy.

This study was aimed to investigate the effect of 3,4 secoisopimara-4(18),7,15-trien-3-oic acid (compound 1) isolated from the aerial parts of Salvia cinnabarina, on upper gastrointestinal transit in mice in vivo. Compound 1 (10 - 100 mg/kg, i. p.) dose-dependently delayed gastrointestinal motility. Pretreatment ( i. p.) of mice with hexamethonium (10 mg/kg), naloxone (2 mg/kg), N(G)-nitro- L-arginine-methyl ester ( L-NAME) (25 mg/kg) or yohimbine (1 mg/kg) did not modify the inhibitory effect of compound 1 (50 mg/kg). However, the L-type Ca (2+) channel verapamil (5 mg/kg, i. p.) significantly reduced the antimotility effect of compound 1 (50 mg/kg). These results suggest that compound 1 inhibits gastrointestinal motility in mice. The effect could involve, at least in part, L-type Ca (2+) channels.
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http://dx.doi.org/10.1055/s-2004-818954DOI Listing
April 2004

New compounds from an extract of Vernonia colorata leaves with anti-inflammatory activity.

J Nat Prod 2004 Mar;67(3):389-94

Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy.

Bioassay-directed fractionation of an anti-inflammatory CHCl(3)-MeOH (9:1) extract of leaves of Vernonia colorata, using a carrageenan-induced rat paw model, led to the isolation of six new compounds (1-6). These were assigned as two new androst-8-en glycosides, 3-O-[beta-d-galactopyranosyl-(1-2)-[beta-d-glucopyranosyl-(1-->6)]-beta-d-glucopyranoside]-5alpha,14alpha-androst-8-ene (1) and 3-O-[beta-d-glucopyranosyl-(1-->6)-beta-d-glucopyranoside]-5alpha,14alpha-androst-8-ene (2), two new stigmastane-type glycosides, 3beta,21,24-trihydroxy-21,23;22,28;26,28-triepoxy-5alpha-stigmasta-8(9),14(15)-dien-3-O-beta-d-galactopyranosyl-(1-->2)-beta-d-glucopyranoside (3) and 3beta,21,24-trihydroxy-21,23;22,28;26,28-triepoxy-5alpha-stigmasta-8(9),14(15)-dien-3-O-beta-d-galactopyranosyl-(1-->2)-beta-d-(6-acetyl)glucopyranoside (4), and two new stigmastane-type steroids, 3beta,25,29-trihydroxy-5alpha-stigmasta-8(9),14(15),24Z(28)-triene (5) and 3beta,23,25-trihydroxy-24,28-epoxy-5alpha-stigmasta-8(9),14(15)-diene (6). The structures of 1-6 were elucidated by spectral and chemical studies. Compounds 1-6 were tested for the anti-inflammatory activity, but all were inactive or weakly inactive as anti-inflammatory agents.
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http://dx.doi.org/10.1021/np030337pDOI Listing
March 2004

A secoisopimarane diterpenoid from Salvia cinnabarina inhibits rat urinary bladder contractility in vitro.

Planta Med 2004 Feb;70(2):185-8

Department of Experimental Pharmacology, University of Naples "Federico II", Naples, Italy.

We have evaluated the effect of 3,4-secoisopimar-4(18),7,15-triene-3-oic acid (compound 1), isolated from the aerial parts of Salvia cinnabarina, on the contractile response elicited by electrical field stimulation (EFS) in the rat isolated urinary bladder. Compound 1 (10 ( - 7) - 10 ( - 4) M) produced a concentration-dependent inhibition of the EFS contractile response without modifying the contractions produced by exogenous acetylcholine (10 ( - 6) M). A number of antagonists/inhibitors including a combination of atropine (10 ( - 6) M), phentolamine (10 ( - 6) M), propranolol (10 ( - 6) M) and hexamethonium (10 ( - 4) M), the NK (1) receptor antagonist SR140333 (10 ( - 7) M) plus the NK (2) receptor antagonist SR48968 (10 ( - 6) M), naloxone (10 ( - 6) M), verapamil (10 ( - 7) M), capsazepine (10 ( - 5) M) and the CB (1) receptor antagonist SR141716A (10 ( - 6) M) did not modify the inhibitory effect of compound 1. However, the nitric oxide (NO) synthase inhibitor L-NAME (3 x 10 ( - 4) M), significantly reduced the inhibitory effect of compound 1. It is concluded that compound 1 inhibits rat bladder contractility with a mechanism involving, at least in part, NO production.
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http://dx.doi.org/10.1055/s-2004-815501DOI Listing
February 2004