INHIBITION BY NICKEL OF ENDOTHELIN-1-INDUCED TENSION AND ASSOCIATED CA-45 MOVEMENTS IN RABBIT AORTA

Contractions induced by 10 nM endothelin-1 (ET) in the rabbit aortic m edia intimal layer were inhibited by prior exposure to 100 mu M Ni++ ( 33.1%) or to a Ca++-free buffer (80.2%) but were unaffected by pretrea tment with 0.1 mu M nifedipine. Contractions elicited by phenylephrine (1 nM-100 mu M) or K+ (10-50 mM) were not inhibited by 100 mu M Ni+but those induced by ET in tissues submaximally precontracted with 20 mM K+ were selectively antagonized by the divalent cation. The mechani sm for the inhibitory action of Ni++ was ascertained by an examination of the effects of the cation on ET-induced alterations in the cellula r distribution and mobilization of Ca++. Efflux of Ca-45 from the musc le into a solution without added Ca++ was not altered by ET. Total or cellular Ca-45 uptake (uptake after exposure to La+++ and low temperat ure), at either low- or high-affinity sites in resting muscles was als o not affected by the peptide. However, low-affinity cellular Ca-45 re tention in muscles depolarized with high K+ levels (160 mM) was signif icantly enhanced (45.1%) by ET. Ni++ did not alter Ca-45 retention in control and K+-treated muscles but it blocked the additional increment al Ca-45 uptake associated with ET (in the presence of high K+), Thus, Ni++ produced a selective blockade of an ET-activated Ca++ influx pat hway, distinct from the dihydropyridine-sensitive L-type Ca++ channels , in rabbit aortic smooth muscle. This action by Ni++ apparently inhib its subsequent contractile responses of the muscle to ET.