Modulation of atrial contraction by PKAand PKC during the compensated phase ofeccentric cardiac hypertrophy

Abstract. Calcium homeostasis is intimately regulated by protein kinasephosphorylation cascades that are also involved in the induction and maintenanceof cardiac hypertrophy. In addition, the development of cardiachypertrophy has been associated with alteration in the activation of theadrenergic system. Therefore, we investigated the specific role of proteinkinase A (PKA) and C (PKC) on cardiac muscle contractile activity in thepresence and absence of adrenergic stimulation. Isolated left atrial preparationsfrom sham– and volume overload–induced cardiac hypertrophied ratswere superfused with Tyrode and electrically stimulated at 0.75 Hz. Contractionwas assessed in the basal and pre–stimulated (norepinephrine, 10^–9M)states. Specific inhibitors, KT 5720 for PKA and Ro-32-0432 for PKC, wereused. Peak tension development in left atria from sham–operated rats wasmore sensitive to PKC– than PKA–inhibition, whereas this differential sensitivitywas abolished in the hypertrophied hearts. This difference was mainlydue to an increase in the role of PKA in the contractile response. Developedpeak tension by left atria from shunt rats was higher than that from sham rats,but when expressed to relative tissue mass, hypertrophied muscle showedweaker contraction than that from the sham group. In addition, the left atrialvelocity of contraction in the sham is PKA–sensitive, while that of the shuntis PKC–sensitive. Furthermore, the velocity of relaxation shows dependencyon both protein kinases, with PKC having a greater effect than PKA in thehypertrophied group. NE increased the PTD and the velocity of contraction(+dT/dt) through PKA and PKC dependent mechanisms, without affectingthe velocity of relaxation (–dT/dt) in atrial muscle from sham rats. In contrast,during eccentric hypertrophy NE effectively reduced PTD as well as the–dT/dt through a PKC–dependent mechanism. The present study demonstratesthat during early development of moderate eccentric cardiac hypertrophythere is: (1) a reduced specific peak tension developed due to an imbalancein the PKA and PKC activation; (2) a change in the protein kinasedependence of the velocity of contraction and relaxation from PKA to PKCwith atrial hypertrophy; and (3) a negative inotropic response to adrenergicreceptor stimulation. These functional responses may play a critical role inthe cardiac performance during the progression of eccentric cardiac hypertrophyinto the decompensated phase and heart failure.