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 pro tein kinase (PKA) and changes in mechanical heart function during deve lopment of cardiac hypertrophy induced by volume overload. Methods: Pr otein and DNA contents, PKA activity, and peak systolic stress-strain relationships in hearts from animals submitted to aortocaval shunt wer e assessed as a function of time. Sham operated (control) rats were us ed 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, res pectively) reaching their highest values by d 56; the same occurred wi th 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 decli ned to fourfold by d 56 with respect to control values. The end peak s ystolic 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 generatin g capacity at 0% strain was also significantly higher in the shunt gro ups as compared to sham operated controls (p<0.01). Early activation o f PKA was also confirmed through endogenous cardiac protein phosphoryl ation. SDS-PAGE gel electrophoretogram and autoradiography showed more heavily phosphorylated bands in aortocaval shunt hearts than in the c ontrol group. Conclusions: PKA activity and the slope of systolic stre ss-strain regression line followed a similar trend throughout the stud y, 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 highe r than in controls. PKA activity appears to be related to increased fo rce generating capacity rather than to hypertrophy or increased cardia c protein content. Thus PKA activation is an early biochemical event a fter aortocaval shunt, followed later by cardiac hypertrophy. Changes in PKA activity showed a similar trend to mechanical heart function ov er time. These findings help to explain the changes in the mechanical properties of the heart preceding the development of cardiac hypertrop hy in the rat model of volume overload.