Regional Desensitization of -Adrenergic Receptor Signaling in Swine With Chronic Hibernating Myocardium

Contractile reserve during submaximal -adrenergic stimulation is attenuated in patients and swine with hibernating myocardium. We tested the hypothesis that this arises as a regional adaptive response in -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). -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 2/Gs 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 -receptor adenylyl cyclase signaling in hibernating myocardium. This blunts the local contractile response to -adrenergic stimulation and may serve to protect against a myocardial supply/demand imbalance when external determinants of myocardial workload increase during sympathetic activation. (Circ Res. 2005;97:789-795.)