VASCULAR EFFECTS OF ENDOTHELIN-1 IN HUMANS AND INFLUENCE OF CALCIUM-CHANNEL BLOCKADE

Aim: To investigate the effects of brachial artery infusions of endoth elin-1 on forearm blood flow in normal healthy volunteers. Methods: Br achial artery cannulation was used for a direct assessment of blood pr essure and for intra-arterial regional drug infusions. Drug-induced fo rearm blood flow changes were measured by venous occlusion plethysmogr aphy. Results: Low-dose endothelin-1 infusions resulted in a significa nt increase in forearm blood flow, indicating vasodilation, which was significantly attenuated by cyclo-oxygenase inhibition using aspirin. High-dose endothelin-1 infusions resulted in transient vasodilation, f ollowed by dose-dependent and long-lasting vasoconstriction. In the hu man forearm the vasoconstrictor potency of endothelin-1 was approximat ely 10-15 times greater than that of norepinephrine. Maximal cyclic CM P-dependent vascular muscle relaxation, after muscarinergic stimulatio n by acetylcholine (endothelium-dependent) or after infusion of sodium nitroprusside (endothelium-independent), did not prevent endothelin-1 induced vasoconstriction. However, calcium channel blockade by brachi al artery infusions of maximally vasodilating doses of either verapami l or nifedipine not only abolished the endothelin-induced vasoconstric tion but also unmasked the vasodilator potency of high-dose endothelin -1 infusions. The infusion of lower doses of nifedipine indicated that endothelin-1 induced vasoconstriction was reversed by plasma concentr ations estimated to be in the therapeutic range. Conclusions: These re sults demonstrate a dual action of luminally applied endothelin-1 in h uman resistance vessels in vivo, consisting of transient initial vasod ilation followed by pronounced vasoconstriction, and suggest that bloc kade of voltage-operated calcium channels can effectively counter the vasoconstrictor effects of endothelin-1.