Reactivity and sensitivity of mesenteric vascular beds and aortic rings of spontaneously hypertensive rats to endothelin: effects of calcium entry blockers.

1. The vasoconstrictor effects of endothelin-1 were studied in perfused mesenteric vascular beds (MVB) and aortic rings of 14-16 week-old spontaneously hypertensive rats (SHR) and age-matched Wistar Kyoto rats (WKY). 2. Reactivity to endothelin-1 was increased in MVBs of SHR, as indicated by the maximum perfusion pressure obtained (264 +/- 8 and 141 +/- 9 mmHg respectively) (P less than 0.001), whereas sensitivity was not significantly different between the two strains (EC50 171 +/- 21 and 102 +/- 19, respectively). 3. In aortic rings, in contrast, reactivity to endothelin-1 was reduced in SHR as compared to WKY, whereas sensitivity was similar (EC50 0.78 +/- 0.08 and 0.87 +/- 0.09 nM). 4. As with endothelin-1, reactivity to noradrenaline and potassium chloride was increased in MVBs, but not in aortic rings of SHR. Endothelin-1 was 30 times more potent than noradrenaline in MVBs of SHR, and 15 times more potent than noradrenaline in aortic rings. 5. In both strains, nifedipine and nitrendipine almost completely blocked potassium-induced contractions in MVB and aortic rings, respectively, whereas contractions induced by endothelin-1 or noradrenaline were only partially inhibited. 6. It is concluded that calcium influx via the voltage-operated calcium channel is only partially responsible for the vasoconstrictor action of endothelin-1 in MVBs and aortic rings of SHR and WKY rats. The increased reactivity of the MVB of SHR to endothelin-1 at this stage of the hypertensive process is most likely to be the result of a change in vascular structure rather than due to a primary hypertensive mechanism.

Alcohol suppresses endothelium-dependent relaxation in rat mesenteric vascular beds.

The effects of prolonged infusions of ethanol on endothelium-dependent vasorelaxation induced by acetylcholine and adenosine triphosphate (ATP) and on endothelium-independent relaxation induced by papaverine were studied and compared in isolated perfused rat mesenteric artery preparations. Infusion of ethanol over 60 minutes at concentrations of 1.6, 4.7, 6.3, and 7.9 mg/ml caused concentration-related inhibition of norepinephrine-induced vasoconstriction. In preparations infused with 6.3 and 7.9 mg/ml, this effect reached a maximum after 10-20 minutes but had vanished by the end of the infusion; 1 hour after the end of the infusion, the effects of norepinephrine were potentiated by 71% and 108%, respectively. Acetylcholine-induced vasorelaxation (EC50 3.0 ng/ml in controls) was significantly reduced after 6.3 mg/ml ethanol infusion and totally abolished after 7.9 mg/ml ethanol infusion. ATP-induced vasorelaxation (EC50 180 ng/ml in controls) was also abolished after 7.9 mg/ml of ethanol infusion. By contrast, the vasorelaxant effects of papaverine were not affected by 7.9 mg/ml ethanol infusion. Light-microscopic examination revealed that the endothelial cells were present in ethanol-treated and in control mesenteric arterial beds. These observations indicate that ethanol suppresses endothelium-dependent vasorelaxation without apparent removal of the endothelial cells. The compromised relaxant capacity of the endothelium after ethanol and the resultant intensification of the vasoconstrictor response to norepinephrine may contribute to the development of vascular diseases such as hypertension and stroke.

Systemic and regional hemodynamic effects of atriopeptin II in anesthetized rats.

The hemodynamic and renal effects of atriopeptin II were investigated in rats, using electromagnetic flowmeters and thermodilution and clearance techniques, and its direct cardiac effects were studied in isolated rat atria and ventricular muscle strips. Atriopeptin II had no effect on the rate or force of contraction of rat cardiac tissue in vitro. In anesthetized rats, i.v. injections of 1, 3, 5, and 7 micrograms/kg induced only transient hemodynamic effects: blood pressure (BP) was briefly reduced, and renal blood flow (RBF) but not mesenteric blood flow (MBF) increased. Infusions over 30 min at rates of 0.3, 1, 3, and 10 micrograms/kg/min caused a fall in BP, mediated by a reduction of cardiac output (CO); RBF and MBF were decreased in a dose-related manner, and systemic and regional vascular resistances rose. A reduction of RBF was also observed in clearance experiments, but glomerular filtration rate remained unchanged and the filtration fraction increased significantly. Natriuresis occurred at all rates of atriopeptin tested (0.3, 1, and 3 micrograms/kg/min i.v.) These results suggest that i.v. injection of atriopeptin II induces transient hypotensive and regional vasodilatory effects. Upon i.v. infusion, BP is lowered by way of a reduction in CO, which is accompanied by systemic and regional vasoconstriction. The decrease in CO cannot be ascribed to a direct cardiodepressant action, and the effects on regional blood flows are probably due to reflex activation. The natriuretic effects of atriopeptin II are independent of renal vasodilatation and may be attributable to changes in intrarenal hemodynamics or to direct tubular effects.

Absence of reflex sympathetic activation by the selective renal vasodilator CGP 22979A in the conscious rat.

The effects of the selective renal vasodilator prodrug CGP 22979A on mean arterial blood pressure (MAP), heart rate (HR) and sympathetic efferent splanchnic nerve activity (SpNA) were investigated in conscious normotensive rats, and compared with those of the active drug CGP 18137A, a hydrallazine-like systemic vasodilator. CGP 18137A (0.03 to 1mg/kg i.v.) produced a dose-dependent decrease in MAP, whereas HR and SpNA increased. CGP 22979A affected neither BP nor HR and SpNA at doses of 1 and 3mg/kg i.v. which induce a selective increase in renal blood flow. In contrast, a dose of 30mg/kg i.v., which produced systemic effects comparable to those of CGP 18137A, stimulated SpNA to the same extent as 18137A did. These results demonstrate that the rise in renal blood flow induced by low doses of CGP 22979A is not associated with an increase in efferent sympathetic nerve activity. They suggest also that selective renal vasodilatation can be accomplished without an activation of the sympathetic nervous system.