Comparison of the Electromechanical Responsiveness of Alpha-1-Adrenoceptor Stimulation in Ventricles of Normal and Cardiomyopathic Hamsters

Abstract

Alterations in α₁-adrenoceptor (α₁AR) density and related signal transduction proteins were reported in cardiomyopathic hearts in the failing stage. The electromechanical modification of α₁-adrenergic stimulation in the failing heart is unclear. The present study compares the α₁AR-stimulated electromechanical response in failing ventricles of genetically cardiomyopathic BIO 14.6 hamsters (280–320 days old) with that in age-matched normal Syrian hamsters. The action potential was recorded with a conventional microelectrode technique, and twitch force was measured with a transducer. In the presence of propranolol, phenylephrine increased the contraction and prolonged the action potential duration (APD) to similar values in ventricles of both strains, despite a prolonged basal APD in cardiomyopathic ventricles. The positive inotropism stimulated by phenylephrine was inhibited by staurosporine, and was potentiated by 4β-phorbol-12,13-dibutyrate (PDBu) in both strains. The maximum positive inotropic effect of phenylephrine in PDBu-treated ventricles of normal hamsters was significantly greater than that in BIO 14.6 hamsters. The effects of phenylephrine on the ventricular force-frequency relationship and on the mechanical restitution in both normal and BIO 14.6 strain hamsters were examined. The uniform negative force-frequency relationship and the altered mechanical restitution reveal a defect of intracellular Ca²⁺ handling in cardiomyopathic BIO 14.6 hamsters. α₁-Adrenergic modulation cannot convert the defective properties in the model of the failing heart. Nevertheless, phenylephrine decreased postrest potentiation in short rest periods, and enhanced postrest decay after longer resting periods. The results indicate that α₁-adrenergic action enhances a gradual loss of Ca²⁺ from the sarcoplasmic reticulum, although its action in prolonging the APD can indirectly increase the influx of Ca²⁺.