MYOCARDIAL FIBROSIS ASSOCIATED WITH ALDOSTERONE OR ANGIOTENSIN-II ADMINISTRATION - ATTENUATION BY CALCIUM-CHANNEL BLOCKADE

Chronic administration of either angiotensin IT (Ang II) or aldosteron e (ALDO) leads to myocardial fibrosis. Myofibroblasts (myoFb) play a m ajor role in collagen accumulation at sites of tissue repair. Pathophy siologic bases of cardiac fibrosis in such chronic primary or secondar y hyperaldosteronism are under investigation. In vitro studies have sh own that Ang II and ALDO each increase intracellular calcium and this second messenger is involved in altered fibroblast collagen turnover a nd growth. In the present study, we tested our hypothesis that calcium channel blockade would attenuate myocardial fibrosis that accompanies administration of either circulating Ang II or ALDO. Five animal grou ps were studied: (1) untreated age-and sex-matched control rats: (2) i ntact rats receiving Ang II (75 ng/min) for 2 weeks; (3) rats receivin g Ang II, plus mibefradil (30 mg/kg/day p.o.), a calcium channel block er, for 2 weeks; (4) uninephrectomized rats receiving ALDO (0.75 mu g/ h) together with a high salt diet for 6 weeks; and (5) uninephrectomiz ed rats receiving ALDO and high salt diet plus mibefradil. Myocardial fibrosis was assessed by hydroxyproline concentration and interstitial and perivascular collagen volume fraction examined by videodensitomet ry on heart sections stained with collagen-specific picrosirius red. M yoFb were identified by immunohistochemical alpha-smooth muscle actin (SMA)) labeling. ACE binding was determined by in vitro quantitative a utoradiography. Compared to controls, in rats receiving either Ang II or ALDO we found: (1) myocardial fibrosis, expressed as microscopic sc ars, and perivascular fibrosis in both right and left ventricles with increased (P<0.05) hydroxyproline concentration and collagen volume fr action: (2) myoFb at sites of fibrosis, where high ACE binding density was also present; and (3) hydroxyproline concentration and collagen v olume fraction were significantly (P<0.05) attenuated and the extent o f alpha-SMA labeling and ACE binding density were each markedly (P<0.0 1) reduced in rats receiving either hormone plus mibefradil. This stud y therefore suggests calcium may modulate fibrous tissue formation in rat models of hyperaldosteronism by altering MyoFb collagen turnover a nd cell growth. It further is our contention that these findings impli cate calcium as a signal used by effector hormones of the RAAS to prom ote tissue repair and that calcium channel blockade may offer advantag e as a cardioprotective strategy in this setting. (C) 1998 Academic Pr ess Limited.