Comparative relaxant effects of YC-1 and DETA/NO on spontaneous contractions and the levels of cGMP of isolated pregnant rat myometrium.

This study was designed to compare the effects of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole), a nitric oxide (NO)-independent soluble guanylate cyclase activator, and diethylenetriamine-NONOate (DETA/NO), a NO donor, on spontaneous contractions and the levels of cyclic GMP (cGMP) of myometrial strips isolated from timed-pregnant rats. Myometrial strips were obtained from timed-pregnant Wistar albino rats (n=10) and were mounted in organ baths and tested for changes in isometric tension in response to YC-1 and DETA/NO. We also evaluated the effect of YC-1 and DETA/NO on the levels of cGMP in myometrial strips obtained from timed-pregnant rat uterine horns (n=20). YC-1 (10(-9)-3x10(-5) M) and DETA/NO (10(-7)-10(-4) M) concentration-dependently decreased the amplitude and frequency of spontaneous contractions of myometrial strips isolated from term-pregnant rats. The inhibitions of the amplitude and frequency of spontaneous contractions by YC-1 and DETA/NO were antagonized with methylene-blue (10(-5) M). Antagonistic effect of methylene-blue (10(-5) M) was more on DETA/NO responses than that of YC-1 (P<0.05). In addition, YC-1-stimulated myometrial strips showed more elevation in myometrial cGMP than that of DETA/NO (P<0.05). We demonstrated that YC-1 and DETA/NO induce relaxations in the amplitude and frequency of spontaneous contractions of myometrial strips with different potencies. We also found that YC-1 and DETA/NO-induced relaxations are associated with significant increases in cGMP. These results might suggest that the relaxant effects of YC-1 and DETA/NO on the rat myometrium could be due to the stimulation of the soluble guanylate cyclase and cGMP may play a role for the maintenance of uterine quiescence during pregnancy.

Effects of nimesulide and pentoxifylline on decreased contractile responses in rat ileum with peritonitis.

The aim of this study was to determine the effects of nimesulide and pentoxifylline on the contractile effects of KCl, carbachol and substance P in the longitudinal muscle of rat ileum during peritonitis. Peritonitis was induced in rat ileum by cecal ligation and puncture. Thirty rats were operated on to induce peritonitis, 10 of which received nimesulide (5 mg/kg, subcutaneously) and 10 of which received pentoxifylline (25 mg/kg, subcutaneously) before the operation; 10 other rats underwent a sham operation and acted as controls. Twenty-four hours after the operation, ileum segments were transferred to isolated organ baths and responses to KCl, carbachol and substance P were recorded. Emax values of KCl, carbachol and substance P were markedly lower (P<0.05), with no change in the pD2 values, in the peritonitis group than in the controls. Peritonitis-induced changes in the KCl, carbachol and substance P responses of ileum were significantly restored by nimesulide (P<0.05), but not by pentoxifylline. The improved contractile responses following nimesulide treatment indicate that products of cyclooxygenase-II may be, at least in part, responsible for the decreased contractile responses to KCl, carbachol and substance P in peritonitis.

Comparison of effects of cyclooxygenase inhibitors on myometrial contraction and constriction of ductus arteriosus in rats.

The aim of this study was to compare the tocolytic effect of a selective cyclooxygenase-2 inhibitor, DFU (5,5-dimethyl-3(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone), indomethacin and nimesulide on myometrial strips isolated from rats in both lipopolysaccharide-induced preterm labour and term labour. We also compared the constrictor effects of DFU and indomethacin on the fetal ductus arteriosus. Myometrial strips were obtained from preterm and term labour Wistar albino rats and were mounted in organ baths for the recording of isometric tension. DFU, nimesulide and indomethacin significantly inhibited KCl-, oxytocin-, prostaglandin E(2)- and prostaglandin F(2 alpha)-stimulated contractions of myometrial strips isolated from rats in preterm and term labour. The E(max) value of indomethacin was significantly lower than those for DFU and nimesulide (P<0.05), with no change-log (10) EC(50) values. There was no significant difference between in -log (10) EC(50) and E(max) values of DFU and nimesulide for any of the tissues (P>0.05). In addition, there was no significant difference between -log (10) EC(50) and E(max) values for each of these three agents in myometrial tissues isolated from rats in preterm and term labour (P>0.05). Fetal ductus arteriosus was significantly constricted by DFU (10 or 100 mg/kg) in preterm and term rats, although DFU (10 or 100 mg/kg)-induced constriction ratios were significantly lower than those for indomethacin (P<0.05). These data demonstrate that DFU, a specific cyclooxygenase-2 inhibitor, could be considered as a new therapeutic agent for preterm labour. However, careful attention should be given to constriction of the fetal ductus arteriosus.

Effects of 5-nitro-2-(3-phenylpropylamino) benzoic acid, anthracene-9-carboxylate, and zaprinast on endothelin-1-induced contractions of pregnant rat myometrium.

OBJECTIVE: The effects of 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), anthracene-9-carboxylate (9-AC) (chloride channel blockers) and zaprinast (an inhibitor of phosphodiesterase-5) on endothelin-1 (ET-1) induced contractions of pregnant rat myometrium were investigated in vitro. METHODS: Isolated myometrial strips were obtained from pregnant rats, and the strips were mounted in organ baths for recording of isometric tension (n=8). The effects of 10(-7) to 10(-4)M NPPB, 10(-7) to 10(-4)M 9-AC, and 10(-7) to 10(-4)M zaprinast on 10(-8)M ET-1-induced contractions of pregnant rat myometrial smooth muscle were recorded. RESULTS: NPPB and 9-AC increased the amplitude of ET-1-induced myometrial contractions, while decreasing the frequency, in a concentration-dependent manner. The amplitude of myometrial contractions were significantly increased by NPPB and 9-AC beginning from the concentration of 10(-6)M. The frequency of myometrial contractions were significantly decreased by NPPB and 9-AC beginning from the concentration of 10(-6)M. Zaprinast inhibited the amplitude and frequency of ET-1-induced myometrial contractions in a concentration-dependent manner. Zaprinast-induced decreases in amplitude and frequency of myometrial contractions reached statistical significance beginning from the concentrations of 10(-7)M and 10(-5)M, respectively. CONCLUSION: These data provide evidence that the ET-1-induced contractions of pregnant rat myometrial strips may be modulated by chloride channels. In addition, zaprinast effectively inhibited ET-1-induced contractions in pregnant rat myometrium.

High-concentration tramadol-induced vasodilation in rabbit aorta is mediated by both endothelium-dependent and -independent mechanisms.

AIM: The mechanism of tramadol-induced vasodilation was investigated using isolated rabbit thoracic aortic rings. METHODS: Aortic rings from 8 rabbits were placed in organ bath and precontracted with phenylephrine (10(-5) mol/L) before addition of tramadol. Relaxation responses by tramadol were evaluated in the presence and absence of endothelium, indomethacin (an inhibitor of cyclooxygenase), NG-nitro-L-arginine methyl ester (L-NAME, a specific inhibitor of nitric oxide synthase), glibenclamide (an inhibitor of ATP-sensitive potassium channels), tetraethylammonium chloride (TEA, an inhibitor of calcium-sensitive potassium channels), and naloxone (an antagonist of opioid receptors). RESULTS: Tramadol (10(-4) mol/L and 3 x 10(-4) mol/L) caused significant vasodilation in endothelium-intact and endothelium-denuded aortic rings (P<0.05). The relaxation response to tramadol was significantly greater in endothelium-intact rings than in endothelium-denuded rings. Pretreatment of aortic rings with indomethacin (10(-5) mol/L), glibenclamide (10(-5) mol/L), TEA (10(-3) mol/L), and naloxone (10(-4) mol/L) had no effect on the tramadol-induced relaxation. In endothelium-intact rings, L-NAME (10(-4) mol/L) pretreatment caused marked inhibition of the relaxation induced by tramadol, but not endothelium-denuded rings. CONCLUSION: In the rabbit aorta, vascular relaxation induced by tramadol is due to both nitric oxide production from endothelium and a direct effect on smooth muscle.