CHANGES IN CYCLIC-AMP-DEPENDENT PROTEIN-KINASE AND ACTIVE STIFFNESS IN THE RAT VOLUME OVERLOAD MODEL OF HEART HYPERTROPHY

Objective: The aim was to clarify the role of cyclic AMP dependent protein kinase (PKA) and changes in mechanical heart function during development of cardiac hypertrophy induced by volume overload. Methods: Protein and DNA contents, PKA activity, and peak systolic stress-strain relationships in hearts from animals submitted to aortocaval shunt were assessed as a function of time. Sham operated (control) rats were used as controls. Results: Heart weight to body weight ratio and cardiac protein content per heart increased from d 7 (p<0.005 and p<0.01, respectively) reaching their highest values by d 56; the same occurred with cardiac DNA content. PKA activity.g-1 tissue in soluble extracts of hearts from rats with aortocaval shunt increased by 2.7-fold on d 2 (p<0.005), reached a ninefold peak increase by d 7 (p<0.0001) and declined to fourfold by d 56 with respect to control values. The end peak systolic stress-strain relation slopes were: control, 368(SEM 14) g.cm-2 (n=16); aortocaval shunt values: 2 d, 514(28) g.cm-2 (n=6); 7 d, 579(10) g.cm-2 (n=7); and 56 d, 554(28) g.cm-2 (n=7). The force generating capacity at 0% strain was also significantly higher in the shunt groups as compared to sham operated controls (p<0.01). Early activation of PKA was also confirmed through endogenous cardiac protein phosphorylation. SDS-PAGE gel electrophoretogram and autoradiography showed more heavily phosphorylated bands in aortocaval shunt hearts than in the control group. Conclusions: PKA activity and the slope of systolic stress-strain regression line followed a similar trend throughout the study, with an early increase in both variables by d 2 in the shunt group, reaching a peak at d 7, and decreasing thereafter but remaining higher than in controls. PKA activity appears to be related to increased force generating capacity rather than to hypertrophy or increased cardiac protein content. Thus PKA activation is an early biochemical event after aortocaval shunt, followed later by cardiac hypertrophy. Changes in PKA activity showed a similar trend to mechanical heart function over time. These findings help to explain the changes in the mechanical properties of the heart preceding the development of cardiac hypertrophy in the rat model of volume overload.