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

Contractile reserve during submaximal β-adrenergic stimulation is attenuated in patients and swine with hibernating myocardium. We tested the hypothesis that this arises as a regional adaptive response in β-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). β-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 Giα₂/Gsα 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 β-receptor adenylyl cyclase signaling in hibernating myocardium. This blunts the local contractile response to β-adrenergic stimulation and may serve to protect against a myocardial supply/demand imbalance when external determinants of myocardial workload increase during sympathetic activation.