Possible mechanism underlying the potent vasoconstrictor actions of cyclopiazonic acid on dog cerebral arteries

Abstract

A sustained Ca 2+ influx via L-type Ca 2+ channels has been shown in the resting state of dog cerebral arteries. Sarcoplasmic reticulum is now recognized to serve as a buffer barrier to Ca 2+ entry in vascular smooth muscle cells. To clarify whether sarcoplasmic reticulum of the cerebral arteries can buffer the sustained Ca 2+ influx, effects of cyclopiazonic acid (CPA), an inhibitor of sarcoplasmic reticulum Ca 2+-ATPase, were determined in endothelium-denuded strips of the cerebral (basilar, posterior communicating, middle cerebral), mesenteric and coronary arteries of the dog. The addition of CPA (0.1–10 μM) during the resting state of the strips caused a concentration-dependent contraction in the three cerebral arteries. The CPA-induced contraction was extremely small in the mesenteric or coronary artery. The CPA-induced contractions in the cerebral arteries were inhibited concentration-dependently by nifedipine (1–100 nM). Nifedipine itself induced relaxation from the resting state of cerebral arteries, suggesting a maintenance of basal tone. The CPA-induced potent contraction seen in the cerebral arteries could be mimicked in the mesenteric artery by elevating the extracellular K + concentration (14.9 mM) or adding Bay k 8644 [methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate] (100 nM) to produce an increase in Ca 2+ influx via L-type Ca 2+ channels. We conclude that, in the resting state of dog cerebral arteries, (1) the greater part of the sustained Ca 2+ influx is buffered by Ca 2+ uptake into the sarcoplasmic reticulum, (2) therefore, the inhibition of sarcoplasmic reticulum Ca 2+-ATPase by CPA causes a potent contraction, and (3) the maintenance of basal tone suggests that some Ca 2+ that entered via L-type Ca 2+ channels always reaches the myofilaments in the resting state.