Dawn Deftereos

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.

Neurotensin-induced myocardial noradrenergic effects in spontaneously hypertensive rats

Although increases in myocardial synaptic norepinephrine concentrations contribute toward the progression to heart failure in hypertension, the stimuli for norepinephrine release are unclear. In this study we explored whether neurotensin, a neuropeptide found in heart tissue, could modify myocardial norepinephrine release in spontaneously hypertensive rats (SHR). Prior to the development of cardiac decompensation, baseline coronary effluent norepinephrine concentrations were higher in isolated heart preparations of spontaneously hypertensive rats than in Wistar Kyoto (WKY) control rat hearts. Neurotensin increased coronary effluent norepinephrine concentrations and induced positive inotropic responses, effects that were enhanced in spontaneously hypertensive rats compared with Wistar Kyoto rats. Although the neurotensin receptor antagonist, SR 48692, did not modify either baseline coronary effluent norepinephrine concentrations or left ventricular systolic function in spontaneously hypertensive rats, it dose dependently abolished neurotensin-induced cardiac norepinephrine release and contractile responses. Neurotensin-mediated inotropic responses were also abolished by co-administration of the β-adrenoreceptor blockers, propranolol and atenolol. Inotropic responses to exogenous norepinephrine were similar in SHR and WKY rats. In summary, in the hypertensive heart there is an increased sensitivity to neurotensins actions on myocardial norepinephrine release and subsequent contractile changes. Therefore, neurotensin receptor blockade may represent a novel therapeutic target in preventing the progression to heart failure in hypertension.