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Vascular effects of endothelin-1 in humans and influence of calcium channel blockade.

AIM
To investigate the effects of brachial artery infusions of endothelin-1 on forearm blood flow in normal healthy volunteers.


METHODS
Brachial artery cannulation was used for a direct assessment of blood pressure and for intra-arterial regional drug infusions. Drug-induced forearm blood flow changes were measured by venous occlusion plethysmography.


RESULTS
Low-dose endothelin-1 infusions resulted in a significant 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, followed by dose-dependent and long-lasting vasoconstriction. In the human forearm the vasoconstrictor potency of endothelin-1 was approximately 10-15 times greater than that of norepinephrine. Maximal cyclic GMP-dependent vascular muscle relaxation, after muscarinergic stimulation by acetylcholine (endothelium-dependent) or after infusion of sodium nitroprusside (endothelium-independent), did not prevent endothelin-1 induced vasoconstriction. However, calcium channel blockade by brachial artery infusions of maximally vasodilating doses of either verapamil or nifedipine not only abolished the endothelin-induced vasoconstriction 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 concentrations estimated to be in the therapeutic range.


CONCLUSIONS
These results demonstrate a dual action of luminally applied endothelin-1 in human resistance vessels in vivo, consisting of transient initial vasodilation followed by pronounced vasoconstriction, and suggest that blockade of voltage-operated calcium channels can effectively counter the vasoconstrictor effects of endothelin-1.