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

A sustained Ca2+ influx via L-type Ca2+ channels has been shown in the resting state of dog cerebral arteries. Sarcoplasmic reticulum is now recognized to serve as a buffer barrier to Ca2+ entry in vascular smooth muscle cells. To clarify whether sarcoplasmic reticulum of the cerebral arteries can buffer the sustained Ca2+ influx, effects of cyclopiazonic acid (CPA), an inhibitor of sarcoplasmic reticulum Ca2+-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 microM) 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)-pyr idine-5-carboxylate] (100 nM) to produce an increase in Ca2+ influx via L-type Ca2+ channels. We conclude that, in the resting state of dog cerebral arteries, (1) the greater part of the sustained Ca2+ influx is buffered by Ca2+ uptake into the sarcoplasmic reticulum, (2) therefore, the inhibition of sarcoplasmic reticulum Ca2+-ATPase by CPA causes a potent contraction, and (3) the maintenance of basal tone suggests that some Ca2+ that entered via L-type Ca2+ channels always reaches the myofilaments in the resting state.