Inhibition by nickel of endothelin-1-induced tension and associated 45Ca movements in rabbit aorta

SS Shetty and D DelGrande

Research Department, Ciba-Geigy Corporation, Summit, New Jersey.

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.

Volume 271, Issue 3, pp. 1223-1227, 12/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

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