This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hershberger, R. E. Articles by Bristow, M. R. Search for Related Content PubMed PubMed Citation Articles by Hershberger, R. E. Articles by Bristow, M. R.

Circulation, Vol 83, 1343-1351, Copyright © 1991 by American Heart Association

ARTICLES

A1-adenosine receptor inhibition of adenylate cyclase in failing and nonfailing human ventricular myocardium

RE Hershberger, AM Feldman and MR Bristow
Department of Medicine, University of Utah School of Medicine, Salt Lake City.

BACKGROUND. Receptors that couple via the stimulatory G protein, Gs, to adenylate cyclase and to a positive inotropic response have been extensively investigated in falling human heart. In contrast, much less is known about receptors, such as the A1-adenosine receptor, that couple to adenylate cyclase via the inhibitory G protein, Gi, to give a negative inotropic response. Activation of such Gi-coupled receptors might worsen heart failure. Furthermore, alpha Gi is increased in failing human ventricular myocardium, which may enhance inhibitory receptor coupling to adenylate cyclase. METHODS AND RESULTS. A1- Adenosine receptor inhibition of adenylate cyclase was examined in crude particulate preparations derived from 12 nonfailing and 12 failing human left ventricles. Experimental conditions were designed for maximal inhibitory responses. Dose-response curves were performed with the selective A1-adenosine receptor agonist R-phenylisopropyl- adenosine (R-PIA). No differences in nonfailing versus failing heart were observed for basal adenylate cyclase activity (49.0 +/- 4.1 versus 45.7 +/- 2.6 pmol cyclic AMP/min/mg), maximal R-PIA-mediated inhibition (31.1 +/- 2.6 versus 30.2 +/- 1.6 pmol cyclic AMP/min/mg), ED50 (R-PIA x 10(-7) 1.28 +/- 0.10 versus 1.36 +/- 0.08), or slope (1.06 +/- 0.06 versus 1.03 +/- 0.10), respectively. Furthermore, fluoride, forskolin, and manganese adenylate cyclase activation were not different in failing heart, which is consistent with no change in the catalytic unit of adenylate cyclase. The inhibitory G protein alpha Gi, as quantitated by pertussis toxin-catalyzed ADP-ribosylation, was increased in failing heart (105.7 +/- 5.8 versus 132.7 +/- 3.4 optical density units, p less than 0.003). Basal adenylate cyclase activity was reduced in failing heart (7.8 +/- 0.8 versus 4.5 +/- 0.4 pmol cyclic AMP/min/mg, p less than 0.005) with assay conditions designed to assess G protein effects. CONCLUSIONS. The A1-adenosine receptor pathway exerts a major inhibitory effect on human myocardial adenylate cyclase activity. Although alpha Gi was increased in failing heart, A1-adenosine receptor inhibition of adenylate cyclase was not altered in preparations of failing versus nonfailing human ventricular myocardium.

This article has been cited by other articles:

				S. Lutz, R. Mura, D. Baltus, M. Movsesian, W. Kubler, and F. Niroomand Increased activity of membrane-associated nucleoside diphosphate kinase and inhibition of cAMP synthesis in failing human myocardium Cardiovasc Res, January 1, 2001; 49(1): 48 - 55. [Abstract] [Full Text] [PDF]

				M. M Borst, P. Szalai, N. Herzog, W. Kubler, and R. H Strasser Transregulation of adenylyl-cyclase-coupled inhibitory receptors in heart failure enhances anti-adrenergic effects on adult rat cardiomyocytes Cardiovasc Res, October 1, 1999; 44(1): 113 - 120. [Abstract] [Full Text] [PDF]

				D. E. Vatner, N. Sato, J. B. Galper, and S. F. Vatner Physiological and Biochemical Evidence for Coordinate Increases in Muscarinic Receptors and Gi During Pacing-Induced Heart Failure Circulation, July 1, 1996; 94(1): 102 - 107. [Abstract] [Full Text]

				M. Bohm, C. Grabel, M. Flesch, A. Knorr, and E. Erdmann Treatment in Hypertensive Cardiac Hypertrophy, II : Postreceptor Events Hypertension, May 1, 1995; 25(5): 962 - 970. [Abstract] [Full Text]