Cyclopiazonic acid is a sarcoplasmic reticulum Ca(2+)-pump inhibitor of rat aortic muscle

The effects of a mycotoxin, cyclopiazonic acid (CPA), on the contractile function of rat aortic smooth muscle rings were investigated to test the hypothesis that CPA selectively inhibits the sarcoplasmic reticulum Ca(2+)-pump. This hypothesis was tested by two types of experimental approaches. First, we compared the ability of the vascular muscle rings to relax upon washout of the agonists following the contraction induced by high concentration of depolarizing KCl (60 mmol.L-1) and supramaximal concentration of phenylephrine (Phe; 10(-5) mol.L-1). In this case, we found that CPA treatment resulted in slowing the rate of relaxation to both stimuli. In the second approach, the status of Phe-sensitive intracellular Ca2+ pool was assessed by the ability of Phe to elicit sequential responses in Ca(2+)-free medium with loading of Ca2+ by reintroduction of extracellular Ca2+ in the presence and absence of CPA following the first response to Phe 10(-5) mol.L-1 and the washout of the agonist. We found that effective Ca2+ loading resulted in total restoration of the second response to Phe, while CPA treatment caused ineffective loading leading to ultimate prevention of the second response to Phe. Our finding are consistent with the hypothesis that CPA acts by inhibiting the SR Ca(2+)-pump, thus interfering an effective refilling of the agonist-sensitive intracellular Ca2+ stores.