Endothelin‐I—mediated vasoconstriction: Specific blockade by verapamil

The capacity of three vasodilators that act by distinct mechanisms to reverse endothelin‐I—mediated vasoconstriction was studied in 11 healthy nonsmoking male subjects (mean age ± SEM, 26 ± 2 years; mean weight ± SEM, 74 ± 2 kg) by use of brachial artery infusion and forearm strain‐gauge plethysmography. Isoproterenol (cyclic adenosine monophosphate–mediated vasodilation), sodium nitroprusside (cyclic guanosine monophosphate–mediated vasodilation), and verapamil (L‐type calcium channel blocker) were compared for capacity to reverse endothelin‐I–mediated increase in forearm vascular resistance (FVR). Endothelin‐I infusion increased FVR 1.9‐fold in the control state. Isoproterenol infusion decreased FVR with or without concurrent endothelin‐I infusion; however, at comparable isoproterenol infusion rates, endothelin‐I increased FVR similar to the control state (for 5 ng/min isoproterenol, endothelin‐I increased FVR 1.85‐fold; for 12.5 ng/min isoproterenol, endothelin‐I increased FVR 2.03‐fold). Similarly, sodium nitroprusside infusion decreased FVR with or without concurrent endothelin‐I infusion; however, at comparable sodium nitroprusside infusion rates the endothelin‐I increase in FVR was similar to control (for 0.48 µg/min sodium nitroprusside, endothelin‐I increased FVR 1.89‐fold; for 0.96 µg/min sodium nitroprusside, endothelin‐I increased FVR 2.36‐fold). In contrast, verapamil infusion decreased FVR with or without endothelin‐I infusion. At a verapamil infusion rate of 19.1 µg/min, endothelin‐I increase in FVR was comparable to control (for 19.1 µg/min verapamil, endothelin‐I increased FVR 1.36‐fold, less than the 1.9‐fold increase in the control state; p < 0.05). Isoproterenol and sodium nitroprusside decreased FVR during concurrent endothelin‐I infusion but did not reverse the endothelin‐I effect. In contrast, verapamil reversed endothelin‐I‐induced vasoconstriction to control FVR, suggesting a specific antagonism of endothelin‐I—mediated increase in FVR. Clinical Pharmacology and Therapeutics (1992) 52, 583–589; doi: