Beta-adrenergic receptor sensitivity and guanine nucleotide regulatory proteins in transplanted human hearts and autotransplanted baboons
Receptors, Adrenergic, beta
This study was conducted in human subjects and in baboons to assess elements of the beta-adrenergic receptor complex in vivo and in vitro following cardiac transplantation. In human subjects, the concentration at which administered isoproterenol increased heart rate by 25 beats per min was within the normal range (mean, 3.2 +/- 0.4 micrograms). Myocardial biopsies and lymphocytes were obtained from 14 transplant recipients undergoing routine right heart catheterization. The stimulatory guanine nucleotide regulatory protein, Gs, was significantly greater in the lymphocyte than in right ventricular myocardium (5.8 +/- 1.7 vs. 2.0 +/- 0.5 relative to standard rat heart membrane preparation, P less than 0.05). In contrast, Gi was significantly greater in the myocardium than in the lymphocyte (4.2 +/- 1.3 vs. 1.1 +/- 0.3, P less than 0.025). There was no correlation between lymphocyte and cardiac G protein determinations. In the autotransplanted baboon heart, beta-receptors were increased (73 +/- 4 vs. 36 +/- 10 fmol/mg, P less than 0.05). Gs was not significantly different in denervated myocardial tissue vs. control cardiac tissue (1.1 +/- 0.2 vs. 0.8 +/- 0.2, P greater than 0.05). However, the inhibitory G protein, Gi, was significantly greater in transplanted animals (0.4 +/- 0.1 vs. 0.2 +/- 0.04, P less than 0.05). Relative enrichment of a Gi-like protein in the autotransplanted baboon heart was associated with a non-statistically significant trend towards a uniform reduction in basal and Gs-mediated adrenergic effects on adenylate cyclase activity. Despite the lack of biochemical evidence of enhanced beta-adrenergic receptor-mediated adenylate cyclase coupling, denervation in the autotransplanted baboon was associated with in vitro evidence of chronotropic and inotropic supersensitivity to isoproterenol. The results call into question the notion of adrenergic hypersensitivity in human subjects following cardiac transplantation, indicate the potential role for guanine nucleotide regulatory proteins in mediating responses of the denervated heart, and distinguish between several characteristics of the chronically denervated, transplanted human heart compared with the acutely auto-denervated of the baboon heart.