Role of protein kinase C in mediating alpha-1-adrenoceptor-induced negative inotropic response in rat ventricles

Abstract

The aim of this study was to determine the effect of protein kinase C (PKC) activation on intracellular Ca(2+) transient and its relation to alpha(1)-adrenoceptor (alpha(1)-AR)-stimulated negative inotropic response in rat ventricles. The electromechanical responses to phenylephrine (PE) in rat ventricular muscles were concomitantly examined using the conventional microelectrode method. The responses of intracellular Ca(2+) transient and cell contractions to PE in the absence of certain pharmacological interventions were ascertained in fura-2-loaded myocytes. The influence of PE on L-type Ca(2+) current (I(Ca,L)) was also examined using a voltage clamp in a whole-cell configuration. PE did not alter the action potential parameters during the negative inotropic phase. The negative inotropic effect (NIE) was inhibited by prazosin, chloroethylclonidine (CEC) and staurosporine, but was insensitive to pertussis toxin. Desensitization of PKC after prolonged pretreatment of rat ventricles with PDBu also abolished the NIE of PE. Caffeine modulated the NIE, but thapsigargin did not. The evoked intracellular Ca(2+) transient and cell contraction were initially decreased by PE, while I(Ca,L) was not altered. Prazosin and staurosporine significantly inhibited the responses. Our data indicated that alpha(1)AR-mediated NIE in rat ventricular muscles was due to the decrease of intracellular Ca(2+) transients by the modulation of PKC on Ca(2+)-releasing channels signaling through a CEC-sensitive alpha(1)AR subtype.

Biomedical Vignette

“…Chen and Su [5] further reported that ␣ 1 -adrenoceptors also mediate negative inotropism in rat ventricular muscles and myocytes, and are due to the activation of PKC. This leads to inhibition of ryanodine-sensitive Ca 2+ -releasing channels [6] and a decrease in the intracellular Ca 2+ transient [14].…”

Biomedical Vignette

“…Chen and Su [5] further reported that ␣ 1 -adrenoceptors also mediate negative inotropism in rat ventricular muscles and myocytes, and are due to the activation of PKC. This leads to inhibition of ryanodine-sensitive Ca 2+ -releasing channels [6] and a decrease in the intracellular Ca 2+ transient [14].…”