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Inhibition of cyclic AMP accumulation by endothelin is pertussis toxin sensitive and calcium independent in isolated adult feline cardiac myocytes.

Abstract：

:The aims of this study were to determine whether endothelin-1 (ET-1), a positive inotropic agent, altered the production of cyclic AMP (cAMP) in adult feline cardiac myocytes and to characterize the effect with respect to G-protein-coupling and calcium regulation of adenylyl cyclase. ET-1 inhibited basal and/or stimulated cAMP accumulation in the intact cardiac myocyte and in membrane preparations in a dose-dependent manner. In intact cells, maximal inhibition of forskolin-stimulated cAMP accumulation was 90-95% with an EC50 of 5 x 10(-10) M. Inhibition of isoproterenol-stimulated cAMP was biphasic with maximal inhibition of 70% observed by 10(-11)M; at higher doses inhibition was not consistently observed. The inhibitory response to ET-1 occurred in the absence or presence of isobutylmethylxanthine suggesting that activation of cAMP phosphodiesterases was not the means for reducing cAMP levels. Prior exposure of cardiac myocytes to 100ng/ml pertussis toxin blocked the inhibitory action of ET-1, indicating that this response is mediated through the involvement of a pertussis toxin-sensitive G-protein such as Gi. Studies carried out in the absence of extracellular calcium and under conditions of cell-loading with the intracellular calcium chelator, 1,2-bis-(2-aminophenoxy)-ethane-N,N,N'N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM), suggest that the mechanism by which ET-1 inhibits cAMP accumulation is not calcium-dependent. Thus, inhibition of cAMP accumulation by ET-1 appears to be mediated through a pertussis toxin sensitive protein rather than by activation of phosphodiesterases or calcium inhibition of cardiac forms of adenylyl cyclase. Though unlikely to play a role in the positive inotropic effect of ET-1, transduction of ET-1 responses through Gi suggests another means for regulation of growth in these adult cardiac myocytes.

journal_name

Life Sci

journal_title

Life sciences

authors

Jones LG

doi

10.1016/0024-3205(95)02264-3

subject

Has Abstract

pub_date

1996-01-01 00:00:00

pages

115-23

issue

eissn

0024-3205

issn

1879-0631

pii

0024320595022643

journal_volume

pub_type

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Inhibition of cyclic AMP accumulation by endothelin is pertussis toxin sensitive and calcium independent in isolated adult feline cardiac myocytes.