Inhibition by nickel of endothelin-1-induced tension and associated 45Ca movements in rabbit aorta.
Contractions induced by 10 nM endothelin-1 (ET) in the rabbit aortic media intimal layer were inhibited by prior exposure to 100 microM Ni++ (33.1%) or to a Ca(++)-free buffer (80.2%) but were unaffected by pretreatment with 0.1 microM nifedipine. Contractions elicited by phenylephrine (1 nM-100 microM) or K+ (10-50 mM) were not inhibited by 100 microM Ni++ but those induced by ET in tissues submaximally precontracted with 20 mM K+ were selectively antagonized by the divalent cation. The mechanism for the inhibitory action of Ni++ was ascertained by an examination of the effects of the cation on ET-induced alterations in the cellular distribution and mobilization of Ca++. Efflux of 45Ca from the muscle into a solution without added Ca++ was not altered by ET. Total or cellular 45Ca uptake (uptake after exposure to La and low temperature), at either low- or high-affinity sites in resting muscles was also not affected by the peptide. However, low-affinity cellular 45Ca retention in muscles depolarized with high K+ levels (160 mM) was significantly enhanced (45.1%) by ET. Ni++ did not alter 45Ca retention in control and K(+)-treated muscles but it blocked the additional incremental 45Ca uptake associated with ET (in the presence of high K+). Thus, Ni++ produced a selective blockade of an ET-activated Ca++ influx pathway, distinct from the dihydropyridine-sensitive L-type Ca++ channels, in rabbit aortic smooth muscle. This action by Ni++ apparently inhibits subsequent contractile responses of the muscle to ET.
Shetty
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SS
Research Department, Ciba-Geigy Corporation, Summit, New Jersey.
DelGrande
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D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D009532:Nickel / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects*
D016232:Endothelins; D009532:Nickel; D011188:Potassium; D002118:Calcium