A1-adenosine receptor inhibition of adenylate cyclase in failing and nonfailing human ventricular myocardium.
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.
- Copyright © 1991 by American Heart Association