Volume overload cardiac hypertrophy exhibits decreased expression of G(s)alpha and not of G(i)alpha in heart

We have recently reported enhanced levels of G(i)alpha proteins in genetic and other experimentally induced models of hypertension, whereas the levels of G(s)alpha were decreased in hypertensive rats expressing cardiac hypert rophy. The present studies were undertaken to investigate whether the decre ased levels of G(s)alpha are associated with cardiac hypertrophy per se and used an aortocaval fistula (AV shunt; volume overload) rat model that excl usively expresses cardiac hypertrophy. Cardiac hypertrophy in Sprague-Dawle y rats (200-250 g) was induced under anesthesia, and, after a period of 10 days, the hearts were used for adenylyl cyclase activity determination, pro tein quantification, and mRNA level determination. A temporal relationship between the expression of G(s)alpha proteins and cardiac hypertrophy was al so examined on days 2, 3, 7, and 10 after induction of AV shunt in the rat. The heart-to-body-weight ratio (mg/g) was significantly increased in AV sh unt rats after 3, 7, and 10 days of induction of AV shunt compared with sha m-operated controls, whereas arterial blood pressure was not different betw een the two groups. Guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) stimu lated adenylyl cyclase activity in a concentration-dependent manner in hear t membranes from both groups; however, the degree of stimulation was signif icantly decreased in AV shunt rats. In addition, the stimulatory effects of isoproterenol were also diminished in AV shunt rats compared with control rats, whereas glucagon-stimulated adenylyl cyclase activity was not differe nt in the two groups. The inhibitory effects of oxotremorine (receptor-depe ndent G(i) functions) and low concentrations of GTP gamma S on forskolin-st imulated adenylyl cyclase activity (receptor-independent G(i) functions) we re not different in the two groups. In addition forskolin and NaF also stim ulated adenylyl cyclase activity to a lesser degree in AV shunt rats compar ed with control rats. The levels of G(i)alpha-2 and G(i)alpha-3 proteins an d mRNA, as determined by immunoblotting and Northern blotting, respectively , were not different in both groups; however, the levels of G(s)alpha(45) a nd G(s)alpha(47), and not of G(s)alpha(52), proteins were significantly dec reased in AV shunt rats by days 7 and 10 compared with control rats, wherea s no change was observed on days 2 and 3 after induction of AV shunt. These results suggest that the decreased expression of G(s)alpha proteins may no t be the cause but the effect of hypertrophy and that the diminished respon siveness of adenylyl cyclase to GTP gamma S, isoproterenol, NaF, and forsko lin in hearts from AV shunt rats may partly be due to the decreased express ion of G(s)alpha. It can be concluded from these studies that the decreased expression of G(s)alpha may be associated with cardiac hypertrophy and not with arterial hypertension.