Mechanisms of preserved baseline cardiac systolic function in rats with adrenergic inotropic downregulation.

Abstract

Despite reductions in beta-adrenoreceptor (beta-AR)-mediated inotropic effects induced by sustained sympathetic activation in cardiac disease, whether these changes necessarily result in reductions in systolic function under resting conditions (baseline function) is not clear. Moreover, possible compensatory mechanisms which might contribute to maintaining the baseline systolic function despite reductions in beta-AR-mediated inotropic effects have not been systematically sought. In the present study, 1 month of daily administration of the beta-AR agonist, isoproterenol (0.05 mg/kg/day, i.p.), to rats resulted in an attenuation of left ventricular inotropic responses to isoproterenol over a wide range of concentrations (10(-8)-10(-4) M), whereas a decline of inotropic responses to norepinephrine, an endogenous inotrope, occurred only at high concentrations (10(-5)-10(-4) M). However, chronic isoproterenol administration failed to modify baseline systolic chamber and myocardial function, as determined in vivo using echocardiography (endocardial and midwall fractional shortening), and in isolated, perfused heart preparations (end-systolic chamber and myocardial elastance) Sustained baseline chamber function despite profound beta-AR-mediated inotropic downregulation was not attributed to alterations in cardiac loading conditions, resting heart rate, chamber remodeling, increased myocardial norepinephrine release, or enhanced contractile responses to alternative receptor/signal transduction pathways mediating positive inotropy (as assessed from histamine, serotonin, forskolin, angiotensin II or phenylephrine responsiveness). These findings indicate that baseline cardiac contractile function might be unaltered despite a profound impairment of beta-AR-induced responsiveness, an effect related to a preserved stimulatory influence of low physiological concentrations of endogenous norepinephrine constituting adrenergic tone at rest.