Regional desensitization of β-adrenergic receptor signaling in swine with chronic hibernating myocardium

Contractile reserve during submaximal beta-adrenergic stimulation is attenuated in patients and swine with hibernating myocardium. We tested the hypothesis that this arises as a regional adaptive response in beta-adrenergic adenylyl cyclase coupling. Pigs ( n = 8) were studied 3 months after instrumentation with a left anterior descending artery ( LAD) stenosis when flow ( LAD, 0.7 +/- 0.2 versus 1.2 +/- 0.1 mL/min per gram in normal remote; P < 0.05) and wall thickening ( LAD, 5.5 +/- 3.2% versus 40.0 +/- 5.5% in remote; P < 0.05) were reduced in the absence of infarction. Whereas basal cAMP production was normal ( LAD, 87 +/- 18 versus 91 +/- 19 pmol/mg per minute; P = NS), responses to isoproterenol were blunted ( LAD, 83 +/- 6 versus 146 +/- 25 pmol/mg per minute in remote; P < 0.05). beta-receptor density and subtype were unchanged, but there was a reduction in the number of high-affinity binding sites ( LAD, 40 +/- 4% versus 53 +/- 7% in normal remote; P < 0.05). The Gi alpha(2)/Gs alpha ratio increased ( LAD, 1.8 +/- 0.3 versus 0.99 +/- 0.3 in remote myocardium; P < 0.05), although GppNHp- stimulated cAMP production was equivocally reduced. Forskolin responses were unchanged and similar to shams. These data indicate regional attenuation of beta-receptor adenylyl cyclase signaling in hibernating myocardium. This blunts the local contractile response to beta-adrenergic stimulation and may serve to protect against a myocardial supply/demand imbalance when external determinants of myocardial workload increase during sympathetic activation.