INTRACELLULAR CA2-II AND ENDOTHELIN-1 IN CARDIOMYOCYTES AND FIBROBLASTS FROM HYPERTROPHIED HEARTS OF SPONTANEOUSLY HYPERTENSIVE RATS( MODULATION BY ANGIOTENSIN)

The vasoactive peptides angiotensin II (Ang II) and endothelin-1 (ET-1 ) have been implicated in cardiac hypertrophy. This study investigates Ang II and ET-1 effects on intracellular free calcium concentration a nd the receptor subtype through which agonist-induced calcium response s are mediated in isolated cardiomyocytes and fibroblasts from hypertr ophied hearts of spontaneously hypertensive rats (SKR). We measured in tracellular free calcium concentration by fura 2 methodology and deter mined receptor status by radioligand binding assays. Ang II (10(-12) t o 10(-7) mol/L) had no effect on cardiomyocyte calcium levels in contr ol Wistar-Kyoto rats but-significantly increased (P < .01) intracellul ar free calcium concentration in a dose-dependent manner in cardiomyoc ytes from SHR. Ang II total and specific binding were increased (P < . 05) in SHR cardiomyocytes. Calcium responses elicited by 10(-7) to 10( -5) mol/L Ang II were significantly reduced (P < .01) in SHR fibroblas ts despite no significant change in Ang II receptor density. The angio tensin type 1 receptor blocker losartan (1 mu mol/L) blocked Ang II-st imulated calcium transients, whereas the angiotensin type 2 receptor b locker PD 123319 had no effect. ET-1- and sarafotoxin S6c-induced calc ium responses in cardiomyocytes and fibroblasts were not different bet ween hypertensive and control groups. In conclusion, Ang II and ET-1 e licit distinct and differential responses in a cell-specific manner in cardiomyocytes and fibroblasts from hypertrophied hearts of SHR. Wher eas Ang II-mediated effects, which are elicited via angiotensin type 1 receptors, are detectable in cardiomyocytes from SHR, responses to An g II are blunted in fibroblasts from SHR, and ET-1-related actions are similar in cells from both rat groups. Stimulation of cardiomyocytes by Ang II in hypertrophied hearts associated with pressure overload in genetic hypertension suggests that Ang II could modulate the function of cardiomyocytes of SHR but not those of Wistar-Kyoto rats, whereas cardiac actions of ET-1 do not change with the development of hyperten sion.