Reduced lymphocyte stimulatory guanine nucleotide regulatory protein and β-adrenergic receptors in congestive heart failure and reversal with angiotensin converting enzyme inhibitor therapy

Abstract

Adrenergic hyporesponsiveness in congestive heart failure has been understood previously in terms of a reduction in β-adrenergic receptors. We have examined another hypothesis, one that states the stimulatory guanine nucleotide regulatory protein (G(s)) that couples the β-adrenergic receptor to adenylate cyclase activity is also decreased in congestive heart failure. In addition to the 40% decrease in lymphocyte β-adrenergic receptors in patients in congestive heart failure (5.9 ± 0.7 vs. 9.7 ± 1.4 fmol/mg, p < 0.05), we found an 80% decrease in levels of G(s) compared with age- and sex-matched healthy control subjects (72.5 ± 19 vs. 376 ± 73 fmol/mg, p < 0.05). Myocardial G(s) levels correlated significantly with lymphocyte G(s) levels. We also assessed the hypothesis that reductions in β-adrenergic receptors and in G(s) are reversible after successful therapy with angiotensin converting enzyme inhibitors. Treatment with either captopril or lisinopril was associated with clinical improvement, an increase in β-adrenergic receptor density (from 5.5 ± 0.7 to 8.7 ± 1.5 fmol/mg), and a twofold increase in G(s) levels (p < 0.05). Thus, the data are compatible with G(s) serving as an adaptable and reversible regulator of the adrenergic response in congestive heart failure. In view of the fact that G(s) is a transducing element common to all hormones that stimulate cyclic adenosine 5'-monophosphate production, the observations could extend to other abnormal neurohumoral mechanisms in congestive heart failure.