Relaxation of rat thoracic aorta induced by the Ca2+‐ATPase inhibitor, cyclopiazonic acid, possibly through nitric oxide formation

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Abstract
1 The effect of the Ca2+-ATPase inhibitor, cyclopiazonic acid (CPA), was studied on rat thoracic aortic ring preparations. 2 At concentrations above 0.3 μm, CPA induced relaxation in the arteries precontracted with phenylephrine. Removal of the endothelium abolished CPA-induced relaxation. 3 The nitric oxide (NO) synthase inhibitor NG-nitro l-arginine (3–300 μm), the free radical scavenger haemoglobin (0.1–3 μm), the soluble guanylate cyclase inhibitor, LY83583 (0.1–10 μm), each inhibited the endothelium-dependent relaxation to CPA. The potassium channel blocker, glibenclamide (10 μm) and cyclo-oxygenase inhibitor, indomethacin (100 μm for 60 min and then washed out) did not alter the action of CPA. 4 The calmodulin inhibitors calmidazolium (3–10 μm) and W-7 (100 μm) also abolished CPA-induced relaxation. 5 CPA (10 μm) increased guanosine 3′:5′-cyclic monophosphate (cyclic GMP) levels in arteries with an intact endothelium, without affecting adenosine 3′:5′-cyclic monophosphate (cyclic AMP) levels. 6 The inhibitors of NO synthesis and actions, the calmodulin inhibitor and removal of the endothelium abolished the CPA-stimulated increase in the levels of cyclic GMP. 7 In Ca2+-free solution, CPA failed to induce relaxation or to stimulate cyclic GMP production. Relaxation to nitroprusside was not affected under these conditions. 8 These results suggest that CPA can stimulate NO synthesis, possibly by inhibiting a Ca2+-ATPase, which replenishes Ca2+ in the intracellular storage sites in endothelial cells. Depletion of the Ca2+ store in the endothelium may then trigger influx of extracellular Ca2+, contributing to an increase in free Ca2+ in the endothelial cells, which activates NO synthase and NO formation.