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. Acetylcholineinduced vasorelaxation (EC 50 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 (EC 50 180 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. {Hypertension 1989;13:964-967)

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 < 0.001), whereas sensitivity was not significantly different between the two strains (EC50 171 + 21 and 102 + 19, respectively).3 In aortic rings, in constrast, 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.

No abstract

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.