Colforsin or imidazolidione potentiates cAMP elevation caused by endothelin-1 in rat aorta.
Endothelin-1 (ET-1) caused slow-developing and stable vasoconstrictions in isolated rings of rat thoracic aortae with a pD2 value of 7.55 +/- 0.10 compared to pD2 values of 9.30 +/- 0.10 and 8.36 +/- 0.30 for angiotensin II and norepinephrine, respectively. Although the potency of ET-1 was somewhat lower than those of norepinephrine and angiotensin II, the maximal tension generated by ET-1 was comparable to that of norepinephrine and considerably greater than that of angiotensin II. Incubation of aortic rings in the absence of extracellular Ca2+ or in the presence of the Ca2+ channel blocker nifedipine (100 nmol.L-1) greatly attenuated ET-1-induced vasoconstriction. ET-1 (20 nmol.L-1, approximately the ED50 for vasoconstrictions) also caused elevation of cAMP levels in aortic rings after 15 and 25 min of exposure. The cAMP phosphodiesterase inhibitor imidazolidione (Imi, Ro 20-1724, 100 mumol.L-1) potentiated the cAMP responses to ET-1. Rings incubated for 25 min with ET-1 (20 nmol.L-1) showed much larger cAMP elevations caused by colforsin (Col, forskolin 1 mumol.L-1), a direct adenylate cyclase activator and potentiator, than with Col or ET-1 alone. Therefore, ET-1 may utilize at least 2 signal transduction mechanisms, one involving the opening of nifedipine-sensitive Ca2+ channels and the other involving the elevation of cAMP levels, to produce the unusually slow-developing and stable vasoconstrictions in rat aortae.
Zhou
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HL
Department of Physiology, Loyola University Medical Center, Maywood IL 60153.
Fiscus
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D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002415:Cats; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D016232:Endothelins / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects
D016232:Endothelins; D010726:Phosphodiesterase Inhibitors; D005576:Colforsin; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D000242:Cyclic AMP; D009543:Nifedipine; D002118:Calcium