Myocyte response to β-adrenergic stimulation is preserved in the noninfarcted myocardium of globally dysfunctional rat hearts after myocardial infarction

Abstract

Background - Cellular mechanisms underlying the diminished inotropic response of remodeled hearts after myocardial infarction (MI) remain unclear. Methods and Results - Left ventricular (LV) remodeling and function were assessed by 2D echocardiography and isolated perfused heart studies in 6-week post-MI and sham-operated rats. LV myocytes from sham and noninfarcted MI hearts were used for morphometric and functional studies. β-Adrenergic receptor (β-AR) agonist isoproterenol (ISO)-induced contractile response was measured in isolated hearts. The effects of ISO and forskolin on contractile function and calcium transients of isolated myocytes were recorded. ISO-induced cAMP generation was compared in sham and MI myocytes. β-AR density was measured by radioligand binding. MI hearts were remodeled (LV diameter 8.5±0.3 versus 5.7±0.3 mm, P<0.001) and showed global (% fractional shortening 19.1±2.5 versus 55.3±2.2, P<0.01) and regional contractile dysfunction of noninfarcted myocardium (% systolic posterior wall thickening 37±4 versus 62±10, P<0.01). Isolated heart function (LV developed pressure 58±2 versus 72±3 mm Hg, P=0.004) and ISO concentration response were reduced in MI hearts. Myocytes from the noninfarcted LV were structurally remodeled (32% longer and 18% wider), but their contractile response and intracellular calcium kinetics to ISO and forskolin were not diminished. β-AR receptor density (B(max) 24±1.5 versus 22.4±1.6 fmol/mg protein) and β-AR agonist-stimulated cAMP were similar in both groups. Conclusions - Isolated myocytes from the remodeled and dysfunctional myocardium are structurally modified but contract normally under basal conditions and in response to β-AR stimulation. β-AR density is preserved in remodeled myocytes. Nonmyocyte factors may be more important in the genesis of contractile dysfunction in the remodeled rat heart up to 6 weeks after MI.