DOWN-REGULATION OF beta1-ADRENOCEPTORS IN RAPID PACING-INDUCED HEART FAILURE IN DOGS WITH LEFT VENTRICULAR HYPERTROPHY

Abstract

Introduction: Experimental left ventricular hypertrophy (LVH) induced by aortic valve stenosis over a 6-month period has been shown to maintain myocardial functions and beta-adrenergic responsiveness, despite a decrease in the density of ventricular beta-adrenoceptors [1]. We studied the underlying mechanism of myocardial decompensation induced by rapid pacing in dogs with LVH. Methods: Pressure overload LVH was created using aortic valve plication in dogs over a 6-month period. Five months after aortic valve plication, congestive heart faiulre (LVH+CHF) was induced by rapid pacing at 240 bpm for 4 weeks. In 5 control, 5 LVH and 5 LVH+CHF anesthetized open-chest dogs, EKG, LV and aortic pressures, segmental length and force were continuously monitored. Isoproterenol was infused into LAD artery over 10 min (0.1 [micro sign]g/kg/min). Partially purified membrane was prepared from a transmural sample from the circumflex region. beta1-adrenoceptors binding studies were carried out using [(125) I] iodocyanopindolol (1.6 - 100 rho M) for total binding and beta1-specific antagonist, esmolol (50 [micro sign]M), for nonspecific binding. The density and affinity of the receptors were determined using Scatchard analysis. ANOVA was used. A value of p<0.05 was accepted as significant. Data were presented as Mean +/- S.E.M. Results: In control and LVH dogs, all baseline hemodynamics and regional mechanimics were similar, except that LVH dogs had a higher LV systolic pressure (167 +/- 11 mm Hg) when compared with controls (119 +/- 9). In LVH+CHF dogs, most baseline hemodynamics were lower than control and LVH dogs, except that LV diastolic pressure (14 +/- 1 mm Hg) was significantly higher than those of control (5 +/- 0) and LVH (5 +/- 1) dogs. Isoproterenol infusion into LAD caused significant increases in LV dP/dt (mm Hg/sec) and regional peak force (g) in control dogs (2839 +/- 481 to 5809 +/- 910; 11.1 +/- 1.4 to 16.9 +/- 2.6) and LVH dogs (3235 +/- 403 to 6010 +/- 607; 8.6 +/- 1.5 to 13.7 +/- 2.3). On the other hand, isoproterenol did not cause significant changes in these parameters in LVH+CHF dogs (1082 +/- 230 to 1480 +/- 210; 12.2 +/- 1.1 to 11 +/- 1.8). The density of myocardial beta1-adrenoceptors (fmol/mg membrane protein; fmol/gm wet tissue) was significantly lower in LVH+CHF dogs (170 +/- 23; 646 +/- 83) when compared to those of control (329 +/- 64; 1601 +/- 216) and LVH (295 +/- 46; 1615 +/- 158) dogs. The receptor affinities were not significantly different among all 3 groups. Discussion: Down-regulation of beta1-adrenoceptors appears to be responsible for the decreased myocardial functions and responses to beta-adrenergic stimulation in the decompensated hypertrophic hearts induced by rapid pacing. Other defects in the receptor-signal transduction pathway may also contribute to cardiac failure.