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Relaxation of rat thoracic aorta induced by the Ca 2+ ‐ATPase inhibitor, cyclopiazonic acid, possibly through nitric oxide formation
Author(s) -
Moritoki Hideki,
Hisayama Tetsuhiro,
Takeuchi Shougo,
Kondoh Wataru,
Imagawa Masayuki
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb14788.x
Subject(s) - cyclopiazonic acid , nitric oxide , calmodulin , chemistry , phenylephrine , nitric oxide synthase , cyclic guanosine monophosphate , extracellular , endothelium , glibenclamide , guanosine , medicine , endocrinology , biochemistry , biophysics , intracellular , biology , enzyme , diabetes mellitus , blood pressure
1 The effect of the Ca 2+ ‐ATPase inhibitor, cyclopiazonic acid (CPA), was studied on rat thoracic aortic ring preparations. 2 At concentrations above 0.3 μ m , CPA induced relaxation in the arteries precontracted with phenylephrine. Removal of the endothelium abolished CPA‐induced relaxation. 3 The nitric oxide (NO) synthase inhibitor N G ‐nitro l ‐arginine (3–300 μ m ), the free radical scavenger haemoglobin (0.1–3 μ m ), the soluble guanylate cyclase inhibitor, LY83583 (0.1–10 μ m ), each inhibited the endothelium‐dependent relaxation to CPA. The potassium channel blocker, glibenclamide (10 μ m ) and cyclo‐oxygenase inhibitor, indomethacin (100 μ m for 60 min and then washed out) did not alter the action of CPA. 4 The calmodulin inhibitors calmidazolium (3–10 μ m ) and W‐7 (100 μ m ) also abolished CPA‐induced relaxation. 5 CPA (10 μ m ) 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 Ca 2+ ‐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 Ca 2+ ‐ATPase, which replenishes Ca 2+ in the intracellular storage sites in endothelial cells. Depletion of the Ca 2+ store in the endothelium may then trigger influx of extracellular Ca 2+ , contributing to an increase in free Ca 2+ in the endothelial cells, which activates NO synthase and NO formation.