Open AccessModulation by the Endothelium of the Inhibitory Effects of Pinacidil and Nimodipine on Endothelin‐Induced Contraction in Cerebral Arteries
Author(s) -
Petersson Jesper,
Andersson KarlErik,
Brandt Lennart,
Högestätt Edward D.
Publication year - 1997
Publication title -
pharmacology & toxicology
Language(s) - English
Resource type - Journals
eISSN - 1600-0773
pISSN - 0901-9928
DOI - 10.1111/j.1600-0773.1997.tb00280.x
Subject(s) - nimodipine , endothelium , contraction (grammar) , basilar artery , endothelin receptor , cerebral arteries , nitric oxide , endocrinology , medicine , pinacidil , endothelins , nitroarginine , endothelin 1 , papaverine , vasodilation , calcium , nitric oxide synthase , receptor , diabetes mellitus , glibenclamide
The effects of pinacidil and nimodipine on endothelin‐1‐induced contractions in isolated cerebral arteries with and without endothelium were compared. The sensitivity to endothelin‐1 was increased (0.5 log units) in the rabbit basilar artery after removal of the endothelium. The nitric oxide synthase inhibitor Nω‐nitro‐L‐arginine (0.1 mM) also increased the sensitivity to endothelin‐1 (0.6 log units) in basilar arteries with endothelium, whereas Nω‐nitro‐D‐arginine (0.1 mM) and indomethacin (3 μM) had no effect, indicating that withdrawal of endothelium‐derived nitric oxide may account for the enhancement of the endothelin‐1‐induced contraction after endothelial denudation. Pinacidil (1 μM) shifted the concentration‐response curve for endothelin‐1 to the right without affecting the maximal response in arteries without endothelium, but had no effect on the endothelin‐1‐induced contraction in vessels with endothelium. Nimodipine (1 μM) reduced the maximal endothelin‐1‐induced contraction by approximately 50% in both the presence and absence of endothelium, whereas the sensitivity to endothelin‐1 was reduced only in vessels without endothelium. Incubation in "calcium‐free" medium reduced the maximal endothelin‐1‐induced contraction by 69% and 80% in vessels with and without endothelium, respectively. In human pial arteries with endothelium, pinacidil did not affect the endothelin‐1‐induced contraction, whereas nimodipine and exposure to "calcium‐free" solution reduced the maximal response by 31% and 74%, respectively. The results show that, in the rabbit, pinacidil and to a lesser extent nimodipine preferentially act on cerebral arteries with disrupted endothelium, indicating that vasoactive factors liberated from the endothelium may modify the effect of a vasodilator.