ABSTRACT
OBJECTIVE: To evaluate potential in vitro relaxant actions of sildenafil on human isolated bladder neck smooth muscle. METHODS: Bladder neck strips were sampled from patients (aged 55-77 years) submitted to prostatic surgery (6 adenomectomies and 1 radical prostatectomy). These were carefully dissected into 1-2 x 0.5-cm pieces and suspended in an organ bath containing 30 mL of a modified Krebs Henseleit solution, bubbled with 95% O(2)/5% CO(2). After tissue stabilization and viability test with KCl, the tissue was precontracted with phenylephrine, and a concentration-response relaxant curve to sildenafil was constructed. The effect of sildenafil was also assessed in tissues treated with N(omega)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) (inhibitors of nitric oxide synthase and guanylyl cyclase, respectively). RESULT: Sildenafil induced significant bladder neck relaxation at all concentrations tested. The maximum relaxation was 86.97% +/- 6.69%, obtained with a high concentration of sildenafil (5.1 x 10(-4) M). Both L-NAME and ODQ significantly reduced sildenafil-induced relaxation. CONCLUSIONS: Sildenafil was effective in inducing bladder neck smooth muscle relaxation in vitro. This effect was almost abolished by L-NAME and ODQ, clearly demonstrating a dependence of the nitric oxide-cyclic guanosine monophosphate pathway. Our in-vitro results suggest that sildenafil might be useful in improving lower urinary tract symptoms due to benign prostatic hyperplasia.
Subject(s)
Muscle Relaxation/drug effects , Phosphodiesterase Inhibitors/pharmacology , Piperazines/pharmacology , Sulfones/pharmacology , Urinary Bladder/drug effects , Urinary Bladder/physiology , Aged , Humans , In Vitro Techniques , Male , Middle Aged , Purines/pharmacology , Sildenafil CitrateABSTRACT
OBJECTIVE: To investigate the effects of sildenafil on noradrenaline- and potassium-induced contractions of isolated human seminal vesicles (SVs), as premature ejaculation is a relatively common male sexual dysfunction that currently lacks an adequate therapy, and recent in vitro tests showed that sildenafil induces relaxation of rodent isolated SVs, but it is not known whether it also inhibits isolated human SV. MATERIAL AND METHODS: Isolated strips of human SVs were suspended in an organ bath and cumulative concentration-response curves to either noradrenaline or KCl were constructed in the presence and absence of sildenafil to evaluate its inhibitory actions. RESULTS: Sildenafil (25-100 microm) induced concentration-dependent inhibitory effects on the human SV contracted by either noradrenaline or KCl. These actions of sildenafil do not therefore appear to be mediated via a competitive antagonism of alpha-adrenoceptors and are consistent with its recognized ability to inhibit phosphodiesterase-5. CONCLUSIONS: The present results show an important inhibitory action of sildenafil in the isolated human SV, supporting the therapeutic indication of this drug for treating premature ejaculation.
Subject(s)
Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Phosphodiesterase Inhibitors/pharmacology , Piperazines/pharmacology , Seminal Vesicles/drug effects , Sulfones/pharmacology , Aged , Case-Control Studies , Humans , Male , Middle Aged , Muscle Contraction/physiology , Muscle, Smooth/physiology , Norepinephrine/metabolism , Potassium Chloride/metabolism , Purines/pharmacology , Seminal Vesicles/physiology , Sildenafil CitrateABSTRACT
The mechanisms involved in the cardioprotector effect of red wine have not yet been completely elucidated but probably an endothelium-dependent vasodilator action may play a significant role in this effect. Experiments were undertaken to determine whether a Brazilian red wine (BRW) induces vasodilation in the mesenteric vascular bed (MVB) and an antihypertensive effect was also assessed in rats with NO-deficient hypertension. In MVB precontracted with norepinephrine, BRW (alcohol-free lyophilized) induces a long-lasting endothelium-dependent vasodilation that is not reduced by indomethacin. Inhibition of NO-synthase by NG-nitro-L-arginine methyl ester (L-NAME) and guanylyl cyclase by 1H-[1,2,3] oxadiazolo [4,4-a]quinoxalin-1-one (ODQ) reduces the vasodilator effect of BRW. In vessels precontracted with norepinephrine and depolarized with KCl (25 Mm) or treated with Ca-dependent K channel blockers charybdotoxin (ChTx) plus apamin, the effect of BRW was significantly reduced. However, this effect is not affected by ATP-dependent K (KATP) channel blocker (glibenclamide). The residual vasodilator effect of BRW observed in vessels pretreated with ChTx plus apamin is completely abolished by ChTx plus apamin plus L-NAME. Concentrations of atropine, pyrilamine, yohimbine, and HOE 140 that significantly reduced the vasodilator effect of acetylcholine, histamine, clonidine, and bradykinin, respectively did not change the vasodilator effect of BRW. Chronic oral administration of BRW induced a significant reduction in systolic, mean and diastolic arterial pressure in rats with L-NAME hypertension. The present results demonstrated that vasodilator effect of BRW is dependent on endothelium-derived hyperpolarizing factor (EDHF) in combination with nitric oxide (NO). The antihypertensive effect of red wine demonstrated in the present study may play a significant role on the cardioprotective action of chronic red wine consumption.
Subject(s)
Alcohol Drinking/adverse effects , Bradykinin/analogs & derivatives , Endothelium, Vascular/physiology , Hypertension/prevention & control , Vasodilation/physiology , Acetylcholine/antagonists & inhibitors , Acetylcholine/pharmacology , Administration, Oral , Animals , Apamin/pharmacology , Atropine/pharmacology , Blood Pressure/drug effects , Bradykinin/pharmacology , Brazil , Charybdotoxin/pharmacology , Clonidine/antagonists & inhibitors , Clonidine/pharmacology , Deoxycholic Acid/pharmacology , Drug Therapy, Combination , Flavonoids/analysis , Flavonoids/antagonists & inhibitors , Flavonoids/pharmacology , Glyburide/pharmacology , Guanylate Cyclase/antagonists & inhibitors , Hypertension/chemically induced , Indomethacin/pharmacology , Male , Mesenteric Arteries/drug effects , Muscle, Smooth, Vascular/drug effects , NG-Nitroarginine Methyl Ester/adverse effects , Nitric Oxide Synthase/antagonists & inhibitors , Nitroglycerin/pharmacology , Norepinephrine/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Perfusion , Phenols/analysis , Phenols/antagonists & inhibitors , Phenols/pharmacology , Polyphenols , Potassium Chloride/pharmacology , Pressure , Pyrilamine/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Quinoxalines/pharmacology , Rats , Rats, Wistar , Vasoconstriction/drug effects , Vasodilation/drug effects , Wine/adverse effects , Yohimbine/pharmacologyABSTRACT
The mechanism underlying the analgesic effect of clonidine, an alpha(2)-adrenoceptor agonist, remains uncertain. Activation of alpha(2)-adrenoceptor induces the release of nitric oxide (NO) from endothelial cells, which has led us to test the hypothesis that the observed antinociceptive effect induced by the systemic administration of clonidine depends on the NO-cGMP pathway. The possible involvement of an opioid link in the antinociceptive effect of clonidine was also evaluated. The antinociceptive effect induced by systemic administration (intravenous or intraperitoneal) of clonidine was evaluated using the rat paw formalin, mice tail-flick and writhing tests. Clonidine (3-120 microg/kg) induces a dose-dependent antinociceptive effect in the formalin, tail-flick and writhing tests. The antinociceptive effect of clonidine in a dose that had no sedative effect assessed by rota rod test, was significantly reduced by NO-synthase and guanylyl cyclase inhibition. The antinociceptive effect of morphine, but not clonidine, was inhibited by naloxone. Our current results suggest that the antinociceptive effect of systemic clonidine does not involve the opioid receptor and is modulated by the NO-cGMP pathway.
