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

Abstract

Abstract-The transition from compensated to decompensated left ventricular hypertrophy (LVH) in hypertension involvesexcessive ␤-adrenoreceptor (␤-AR) stimulation. To explore whether aldosterone receptor activation contributes toward ␤-AR-induced left ventricular (LV) decompensation in hypertensive LVH, the effect of spironolactone (SPIRO; 80 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) on LV cavity dimensions, function, and chamber remodeling mechanisms was evaluated in spontaneously hypertensive rats (SHR) receiving a low dose of the ␤-AR agonist isoproterenol (ISO) at 0.02 to 0.04 mg ⅐ kg Ϫ1 ⅐ 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 loadindependent effects, may be useful in preventing the transition from compensated LVH to dilatation and pump dysfunction mediated by chronic ␤-AR activation. Key Words: remodeling Ⅲ collagen Ⅲ sympathetic nervous system Ⅲ aldosterone T here is substantial evidence to indicate that in hypertension, the transition from compensated left ventricular hypertrophy (LVH) to heart failure involves chronic ␤-adrenoreceptor (␤-AR) activation. Indeed, in LVH, increased circulating norepinephrine (NE) concentrations 1,2 as well as myocardial NE release 3 precede heart failure. Moreover, in hypertensive LVH, prolonged ␤-AR agonist administration 4 or genetically enhanced sympathetic effects 5 increase the susceptibility to decompensation without blood pressure (BP) changes. Despite data to support a notion that ␤-AR activation induces the transition to heart failure in hypertensive LVH, whether the renin-angiotensin-aldosterone system (RAAS) mediates this effect is unknown. This question arises because ␤-AR stimulation provokes the RAAS, ␤-AR blockers inhibit the RAAS in hypertension, 6 and aldosterone receptor antagonists attenuate left ventricular (LV) dilatation. 7-9 Because ␤-AR blockers have a limited impact on LVH 10 and increase the chance of new onset diabetes mellitus, 11 identification of downstream targets from ␤-ARs responsible for LV decompensation that modify LVH but not metabolic pathways is desirable. Therefore, in the present stud...

Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic β-adrenoreceptor activation

“…LV FS end and FSmid were used as load-dependent indexes of LV chamber and intrinsic myocardial function, respectively. Systolic blood pressure was measured using a tail-cuff technique as previously described (35).…”

“…Samples of coronary effluent were collected for 1 min from hearts of control and Iso-treated rats while perfused at a constant flow rate. Since norepinephrine release decreases when measured at incremental LV filling volumes (35), all measurements were performed at filling volumes of 0.19 ml. For the collection of coronary effluent samples, preparations were paced at the same rate as described in Isolated, perfused heart preparations (330 beats/min).…”

“…However, as cardiac chamber dilatation usually coexists with myocardial damage and dysfunction, the extent to which pump dysfunction in a dilated chamber reflects the impact of chamber dilatation or the degree of underlying myocardial systolic failure is uncertain. Recent evidence obtained by our group suggests that the presence of cardiac dilatation and pump dysfunction may be independent of the degree of underlying intrinsic myocardial systolic dysfunction (3,23,35). Nevertheless, these studies were conducted in pressure-overload states where, even without pump failure, intrinsic myocardial systolic dysfunction may still occur (23).…”

Spironolactone Modulates Expressions of Cardiac Mineralocorticoid Receptor and 11.BETA.-Hydroxysteroid Dehydrogenase 2 and Prevents Ventricular Remodeling in Post-Infarct Rat Hearts

“…In sham and MI rats without spironolactone treatment, saline dissolved in DMSO was also orally administered as a vehicle. The dose of spironolactone (100 mg/kg per day) was determined from previous studies ( 22 ).…”

Kinetics of cardiac and vascular remodeling by spontaneously hypertensive rats after discontinuation of long-term captopril treatment

“…Moreover, it is well known that SHR have increased sympathetic activity (24). Veliotes et al (25) reported that cardiac hypertrophy and dysfunction induced by chronic β-adrenergic stimulation are mediated by the activation of the local renin-angiotensin-aldosterone system in the heart, a fact previously observed in rats treated with isoproterenol (26). Thus, the activation of the local renin-angiotensin-aldosterone system in the heart may accelerate the development of cardiac hypertrophy before the rise in blood pressure.…”