Modulation by the endothelium of the inhibitory effects of pinacidil and nimodipine on endothelin-induced contraction in cerebral arteries.
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 N omega-nitro-L-arginine (0.1 mM) also increased the sensitivity to endothelin-1 (0.6 log units) in basilar arteries with endothelium, whereas N omega-nitro-D-arginine (0.1 mM) and indomethacin (3 microM) 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 microM) 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 microM) 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.
Petersson
J
J
Department of Neurology, Malmö University Hospital, Sweden.
Andersson
K E
KE
Brandt
L
L
Högestätt
E D
ED
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000187:drug effects*; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology*; D009553:Nimodipine / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D020110:Pinacidil; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D006146:Guanidines; D014665:Vasodilator Agents; D019335:Nitroarginine; D009553:Nimodipine; D020110:Pinacidil; D019001:Nitric Oxide Synthase; D002118:Calcium