Oleg Osadchii

Aldosterone Receptor Blockade Prevents the Transition to Cardiac Pump Dysfunction Induced by β-Adrenoreceptor Activation

The transition from compensated to decompensated left ventricular hypertrophy (LVH) in hypertension involves excessive &bgr;-adrenoreceptor (&bgr;-AR) stimulation. To explore whether aldosterone receptor activation contributes toward &bgr;-AR–induced left ventricular (LV) decompensation in hypertensive LVH, the effect of spironolactone (SPIRO; 80 mg · kg−1 · day−1) on LV cavity dimensions, function, and chamber remodeling mechanisms was evaluated in spontaneously hypertensive rats (SHR) receiving a low dose of the &bgr;-AR agonist isoproterenol (ISO) at 0.02 to 0.04 mg · kg−1 · day for 4.5 months. ISO administered to SHR resulted in an increased 24-hour urinary aldosterone excretion and LV cavity dimensions, a right shift in LV diastolic pressure-volume relations, a decreased LV relative wall thickness, and increased total, noncross-linked, type I and type III myocardial collagen concentrations without further enhancing increased myocardial norepinephrine (NE) release. ISO reduced pump function without modifying intrinsic myocardial systolic function or inducing further myocyte necrosis or apoptosis. ISO only increased LV cavity volumes after prolonged periods of administration. SPIRO abolished ISO-induced chamber dilatation, wall thinning, and pump dysfunction and reduced total, noncross-linked, type I and type III myocardial collagen concentrations but failed to modify blood pressure, volume preloads, intrinsic myocardial systolic function, myocardial NE release, or the degree of necrosis or apoptosis. In conclusion, these results suggest that aldosterone receptor blockade, through load-independent effects, may be useful in preventing the transition from compensated LVH to dilatation and pump dysfunction mediated by chronic &bgr;-AR activation.

Contractile responses to selective phosphodiesterase inhibitors following chronic β-adrenoreceptor activation

Contractile responses to phosphodiesterase (PDE) inhibitors are attenuated in heart failure, an effect limiting the clinical value of these agents. In this study, we sought to determine whether abnormalities in the β-adrenoreceptor (β-AR)–cyclic adenosine monophosphate (cAMP) signal transduction are sufficient to account for downregulation of PDE inhibitor-induced inotropic responses following chronic sympathetic activation. Sustained β-AR activation produced by administration of isoproterenol (ISO) (50xa0μg kg−1 day−1 i.p. for 1xa0month) to rats resulted in cardiac hypertrophy, but did not affect baseline cardiac systolic function, as assessed in vivo by echocardiography and ex vivo under controlled loading conditions and heart rate (left ventricular systolic pressure–volume and stress–strain relations). Moreover, chronic ISO administration did not alter the baseline myocardial norepinephrine release or inotropic responses to incremental concentrations of Ca2+ in isolated, perfused heart preparations. However, left ventricular contractile responses to ISO, the PDE III inhibitor amrinone, and the PDE IV inhibitor rolipram were attenuated following chronic β-AR activation. Myocardial cAMP concentrations after stimulation with amrinone and rolipram were similar in ISO-treated and control rats. However, in ISO-treated rats, a marked decrease in contractile responsiveness to the cell-permeable, PDE-resistant cAMP analogue, 8-bromoadenosine cAMP, was noted. In conclusion, these data suggest that in cardiac disease, sustained β-AR activation, without producing ventricular systolic dysfunction or enhanced myocardial norepinephrine release, is sufficient to account for the downregulation of contractile responses to PDE inhibitors. This effect appears to be largely mediated through abnormalities in signal transduction between cAMP and Ca2+-induced Ca2+ release.

Temporal changes in myocardial adrenergic regulation with the progression to pump dysfunction after chronic β-adrenoreceptor activation in rats

We evaluated the relationship between myocardial norepinephrine release or inotropic responsiveness to adrenergic stimulation and intrinsic myocardial function after the progression to pump dysfunction induced by chronic β-adrenoreceptor activation (isoproterenol [ISO], 0.1xa0mg/kg/day for 1xa0month or 6xa0months) in rats. Left ventricular (LV) systolic chamber dysfunction occurred after 6xa0months, but not after 1xa0month of β-adrenoreceptor activation, as evidenced by reduced LV endocardial fractional shortening determined by echocardiography and a decrease in the slope of the LV systolic pressure–volume relations assessed in isolated, perfused heart preparations. A reduced pump function at 6xa0months of ISO administration was associated with chamber dilatation, while LV midwall fractional shortening (echocardiography) and the slope of the LV systolic stress–strain relations (isolated heart preparations), indices of intrinsic myocardial function, were unchanged. After 1xa0month of ISO administration, reduced β1- and β2-adrenoreceptor-mediated and sustained α-adrenoreceptor-mediated inotropic responses were noted. Nevertheless, increased inotropic potency of β-adrenoreceptor agonists and upregulation of α-adrenoreceptor-mediated contractile responses were noted after 6xa0months of ISO administration. Increased adrenergic–inotropic responsiveness after 6xa0months of ISO administration was associated with depleted LV norepinephrine stores, as evidenced by reduced desipramine-stimulated norepinephrine concentrations in the coronary effluent. In conclusion, in the progression from compensated cardiac hypertrophy to pump dysfunction after chronic sympathetic activation, a preserved intrinsic myocardial contractility is accounted for by paradoxical upregulation of adrenergic-mediated contractile responses.