Acute ischemic heart disease is associated with alterations in the cardiac adenylate cyclase system response, although the specificity and mechanism of these events are unknown. We studied the characteristics of inhibitory (G,) and stimulatory (Gs) GTP-binding regulatory proteins (G proteins) of adenylate cyclase in erythrocyte membranes of patients (n=16) with nonacute ischemic heart disease resulting from coronary atherosclerosis. Gswas measured by reconstitution with the resolved catalytic unit of adenylate cyclase and by cholera toxin-catalyzed ADP-ribosylation of a 42 -kD protein; G, was tested as a 41-kD substrate of pertussis toxin-catalyzed ADP-ribosylation. G s activity was decreased by 27 ±2% in the cholate extract and by 25±3% in the supernatant of guanosine 5′-(y-thio)triphosphate-treated membranes. The amount of cholera toxin substrate was decreased by 33 ±3%, and the pertussis toxin substrate was increased by 27±5% compared with healthy subjects (n=10). All changes in G-protein characteristics appear to be specific relative to other erythrocyte membrane proteins and hemoglobin. Those patients who have a decreased Gs possess approximately normal G, and those with increased G, showed no change in Gs. Patients with increased G, (normal Gs) exhibited more severe deterioration of their coronary arteries than did patients with decreased G s (normal Gj) (p<.05), but these two groups did not differ significantly in serum lipids, hormones, drug therapy, historical data, or baseline assessment (i><0.05).