LEFT-VENTRICULAR STRETCH STIMULATES ANGIOTENSIN-II-MEDIATED PHOSPHATIDYLINOSITOL HYDROLYSIS AND PROTEIN-KINASE-C EPSILON-ISOFORM TRANSLOCATION IN ADULT GUINEA-PIG HEARTS

Stretch of neonatal cardiomyocytes activates phospholipase C with prod uction of inositol trisphosphate and diacylglycerol in part by formati on of angiotensin II (Ang II). However, the response of this pathway t o physical stimuli in the adult heart is poorly understood. Thus, in i sovolumic perfused guinea pig hearts, we characterized stretch-mediate d phosphatidylinositol (PI) hydrolysis and protein kinase C (PKC) isof orm translocation using elevated diastolic pressure. Balloon dilatatio n (minimum diastolic pressure, 25 mm Hg) of the left ventricle (LV) st imulated PI hydrolysis. Pretreatment of stretched hearts with the spec ific angiotensin (AT(1)) receptor antagonist losartan abolished stretc h-mediated accumulation of inositol phosphates. To examine PKC isoform expression and activation under these conditions, whole-heart extract s were examined by immunoblot analysis. Ang II translocated PKC epsilo n to the particulate fraction. 4 beta-Phorbol 12-myristate 13-acetate but not an inactive congener translocated PKC epsilon to the particula te fraction and produced a decrease in myocardial contractile function . Mechanical stretch also translocated PKC epsilon to the particulate fraction; however, this was attenuated but not abolished by losartan. We conclude that in the adult heart, LV dilatation produced stretch-me diated activation of phospholipase C, which resulted in PI hydrolysis and PKC epsilon activation in part by stimulation of the local renin a ngiotensin system. In contrast to stretch-mediated inositol phosphate accumulation, PKC epsilon translocation is not prevented by AT(1) rece ptor blockade, indicating that this PKC isoform can be activated in re sponse to mechanical deformation by an Ang II-independent mechanism in the adult myocardium.