Diazepam reduces action potential duration in guinea-pig papillary muscle by a cAMP-dependent mechanism.

In this study, we have analyzed the role of cyclic AMP (cAMP) as the mediator of the decrease in action potential duration induced by diazepam. Diazepam (1-100 microM) reduced, in a dose-dependent manner, the duration of intracellular action potential recorded in the papillary muscle obtained from the right ventricle of the guinea pig heart. This effect was mimicked by the analog of cyclic AMP, 8-Br-cAMP (100 microM), but not by gamma-amino-butyric acid (GABA). Also, the selective antagonist of the benzodiazepine receptors, flumazenil did not modify the effect of diazepam. The diazepam-induced shortening of action potential duration was partially antagonized by the inhibitor of cAMP synthesis carbachol (1 microM) or the blocker of the cAMP-dependent protein kinase A, Rp-cAMP[S] (1 microM). These results indicate that cyclic AMP is involved in the diazepam-induced shortening of the action potential duration of the guinea pig papillary muscle.

Effect of endothelin blockade on pressure natriuresis in nitric oxide-deficient hypertensive rats.

OBJECTIVE: Chronic inhibition of nitric oxide synthesis has been shown to cause arterial hypertension and an important blunting of the pressure diuresis and natriuresis response. The mechanisms mediating these abnormalities are not completely established. We therefore studied the effects of endothelin on these alterations. MATERIALS AND METHODS: Pressure diuretic and natriuretic relationships were evaluated in rats treated chronically (3 weeks) with the nitric oxide synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg per day), alone or in combination with bosentan sodium salt (acute treatment: 10 mg/kg, intravenously; chronic treatment: 10 mg/kg per day). RESULTS: Chronic treatment with L-NAME significantly elevated mean arterial pressure (143.7 +/- 2.8 mmHg versus 102.8 +/- 1.6 in controls), reduced the glomerular filtration rate and renal blood flow and shifted the pressure diuretic and natriuretic responses to the right. Treatment with bosentan, either acute or chronically, did not attenuate the arterial hypertension of the L-NAME-treated rats but normalized the glomerular filtration rate and renal blood flow. In spite of the normalization of renal hemodynamics, the pressure diuretic and natriuretic responses of the bosentan-treated groups were not normalized, although chronic bosentan significantly improved the pressure natriuretic response. CONCLUSIONS: These results indicate that endothelin participates in the renal hemodynamic and excretory alterations that follow chronic inhibition of nitric oxide synthesis. However, the arterial hypertension is not mediated by endothelin activation.

Mediation of serotonin-induced hyperventilation via 5-HT3-receptor in European eel Anguilla anguilla.

The effects of serotonin (5-hydroxytryptamine) on ventilation were investigated by continuous measurements of intrabuccal pressure in unrestrained eel. Intravenous administration of 5-hydroxytryptamine (30 micrograms.kg-1) caused a large increase in ventilatory frequency (+ 100%) and amplitude (+ 140%). The 5-hydroxytryptamine-induced hyperventilation was blocked by the 5-HT3-receptor antagonists metoclopramide (1.0 mg.kg-1) or MDL72222 (1.0 mg.kg-1), and was insensitive to the 5-HT1/2-receptor antagonist methysergide (3.0 mg.kg-1) and to the 5-HT4-receptor antagonist DAU 6285 CL (3.0 mg.kg-1). The hyperventilatory response to 5-hydroxytryptamine could be mimicked by the 5-HT3 receptor agonist 1-phenylbiguanide (300 micrograms.kg-1). These results strongly implicate the 5-HT3-receptor as the mediator of the 5-hydroxytryptamine-induced hyperventilation in eel.

Effects of serotonin on the cardio-circulatory system of the European eel (Anguilla anguilla) in vivo.

The effects of serotonin on continuously recorded cardiac parameters (heart rate, cardiac output, cardiac stroke volume), ventral and dorsal aortic blood pressures, branchial and systemic vascular resistances were investigated in the European eel in vivo. Intravenous administration of serotonin (30 micrograms.kg-1) caused a marked bradycardia (45%) and a simultaneous decrease in cardiac output (50%), ventral (35%) and dorsal (50%) aortic blood pressures. Branchial resistance was markedly increased (60%) and systemic resistance decreased (30%). Cardiac stroke volume remained unchanged. The effects of serotonin on cardiac parameters were suppressed either by methysergide or a bilateral section of the cardiac vagus. Bradycardia could then be regarded as the consequence of a vagal mechanism triggered by serotonin action on central methysergide-sensitive serotonergic receptors. No inotropic effect of serotonin was observed. This lack of myocardiac contractility modification is discussed. The serotonin-mediated branchial vasoconstriction was attenuated by vagotomy, whereas the residual increase in branchial resistance (40%) was suppressed by methysergide. The serotonin-mediated branchial vasoconstriction could be the consequence of both a passive mechanism (compliance) caused by the decrease in cardiac output and an active mechanism involving methysergide-sensitive serotonergic receptors of the branchial vasculature. A possible involvement of this vasomotor effect in gill oxygen uptake is discussed. The serotonin-induced systemic vasodilation was insensitive either to cardiac vagotomy or to 5-HT1/2, 5-HT3 and 5-HT4 receptor antagonists, suggesting the involvement of a local mechanism which remains to be assessed.