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

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 mu M) 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. (C) 1998 Elsevier Science B.V. All rights reserved.