Myocardial function in the working mouse heart overexpressing cardiac A1 adenosine receptors

Adenosine, acting via A, receptors, modulates heart rate and contractility, and provides myocardial protection during times of stress. A transgenic model of cardiac A, overexpression was produced and it demonstrated cardiac protection from ischemia. Since A, receptor stimulation can inhibit contractility under some conditions, the present study was undertaken to determine the effects of transgenic A, overexpression on intrinsic contractility and the response to catecholamine stimulation. Isolated working mouse hearts were subjected to volume-and pressure-loading protocols to assess intrinsic contractility, and isoproterenol infusions to assess catecholamine response. Basal heart rates were lower in transgenic (Trans) hearts than controls (Ctrl), but with pacing baseline cardiac function and contractility (as measured by +dP/dt) were similar. Volume and pressure loading of Ctrl and Trans hearts were also similar along the entire range tested, No differences were seen in the sensitivity to isoproterenol infusion, but at maximal doses there was a decrease in maximum + dP/dt in Trans hearts compared to Ctrl (maximum +dP/dt 152+/-6% baseline for Ctrl, 131+/-2% baseline for Trans, P<0.05). In summary, overexpression of A, receptors does not produce untoward effects on ventricular function or sensitivity to catecholamine stimulation, but does dampen the contractile response at high doses of catecholamines. These data suggest that even with 1000-fold overexpression of A, adenosine receptors, adenosine plays little or no role in regulating intrinsic myocardial contractility in the sympathectomized isolated working heart, only modulating contractility as the heart becomes stressed during exposure to higher catecholamine levels. (C) 1998 Academic Press Limited.