Myocardial function in the working mouse heart overexpressing cardiac A1 adenosine receptors.
Adenosine, acting via A1 receptors, modulates heart rate and contractility, and provides myocardial protection during times of stress. A transgenic model of cardiac A1 overexpression was produced and it demonstrated cardiac protection from ischemia. Since A1 receptor stimulation can inhibit contractility under some conditions, the present study was undertaken to determine the effects of transgenic A1 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 A1 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 A1 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.
Gauthier
N S
NS
Department of Pediatrics, University of Virginia, USA.
Headrick
J P
JP
Matherne
G P
GP
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D015870:Gene Expression; D006321:Heart / Q000502:physiology*; D006439:Hemodynamics; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000502:physiology*
D002316:Cardiotonic Agents; D018047:Receptors, Purinergic P1; D007545:Isoproterenol