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Myocardial fibrosis associated with aldosterone or angiotensin II administration: attenuation by calcium channel blockade.
J Mol Cell Cardiol. 1998 Mar; 30(3):475-83.JM

Abstract

Chronic administration of either angiotensin II (Ang II) or aldosterone (ALDO) leads to myocardial fibrosis. Myofibroblasts (myoFb) play a major role in collagen accumulation at sites of tissue repair. Pathophysiologic bases of cardiac fibrosis in such chronic primary or secondary hyperaldosteronism are under investigation. In vitro studies have shown that Ang II and ALDO each increase intracellular calcium and this second messenger is involved in altered fibroblast collagen turnover and 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 groups were studied: (1) untreated age- and sex-matched control rats; (2) intact rats receiving Ang II (75 ng/min) for 2 weeks; (3) rats receiving Ang II plus mibefradil (30 mg/kg/day p.o.), a calcium channel blocker, for 2 weeks; (4) uninephrectomized rats receiving ALDO (0.75 microgram/h) together with a high salt diet for 6 weeks; and (5) uninephrectomized 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 videodensitometry on heart sections stained with collagen-specific picrosirius red. MyoFb were identified by immunohistochemical alpha-smooth muscle actin (SMA) labeling. ACE binding was determined by in vitro quantitative autoradiography. Compared to controls, in rats receiving either Ang II or ALDO we found: (1) myocardial fibrosis, expressed as microscopic scars, and perivascular fibrosis in both right and left ventricles with increased (P<0.05) hydroxyproline concentration and collagen volume fraction; (2) myoFb at sites of fibrosis, where high ACE binding density was also present; and (3) hydroxyproline concentration and collagen volume fraction were significantly (P<0.05) attenuated and the extent of alpha-SMA labeling and ACE binding density were each markedly (P<0.01) reduced in rats receiving either hormone plus mibefradil. This study therefore suggests calcium may modulate fibrous tissue formation in rat models of hyperaldosteronism by altering MyoFb collagen turnover and cell growth. It further is our contention that these findings implicate calcium as a signal used by effector hormones of the RAAS to promote tissue repair and that calcium channel blockade may offer advantage as a cardioprotective strategy in this setting.

Authors+Show Affiliations

Division of Cardiology, Department of Internal Medicine, University of Missouri Health Sciences Center, Columbia, MO, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9515025

Citation

Ramires, F J., et al. "Myocardial Fibrosis Associated With Aldosterone or Angiotensin II Administration: Attenuation By Calcium Channel Blockade." Journal of Molecular and Cellular Cardiology, vol. 30, no. 3, 1998, pp. 475-83.
Ramires FJ, Sun Y, Weber KT. Myocardial fibrosis associated with aldosterone or angiotensin II administration: attenuation by calcium channel blockade. J Mol Cell Cardiol. 1998;30(3):475-83.
Ramires, F. J., Sun, Y., & Weber, K. T. (1998). Myocardial fibrosis associated with aldosterone or angiotensin II administration: attenuation by calcium channel blockade. Journal of Molecular and Cellular Cardiology, 30(3), 475-83.
Ramires FJ, Sun Y, Weber KT. Myocardial Fibrosis Associated With Aldosterone or Angiotensin II Administration: Attenuation By Calcium Channel Blockade. J Mol Cell Cardiol. 1998;30(3):475-83. PubMed PMID: 9515025.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Myocardial fibrosis associated with aldosterone or angiotensin II administration: attenuation by calcium channel blockade. AU - Ramires,F J, AU - Sun,Y, AU - Weber,K T, PY - 1998/5/9/pubmed PY - 1998/5/9/medline PY - 1998/5/9/entrez SP - 475 EP - 83 JF - Journal of molecular and cellular cardiology JO - J Mol Cell Cardiol VL - 30 IS - 3 N2 - Chronic administration of either angiotensin II (Ang II) or aldosterone (ALDO) leads to myocardial fibrosis. Myofibroblasts (myoFb) play a major role in collagen accumulation at sites of tissue repair. Pathophysiologic bases of cardiac fibrosis in such chronic primary or secondary hyperaldosteronism are under investigation. In vitro studies have shown that Ang II and ALDO each increase intracellular calcium and this second messenger is involved in altered fibroblast collagen turnover and 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 groups were studied: (1) untreated age- and sex-matched control rats; (2) intact rats receiving Ang II (75 ng/min) for 2 weeks; (3) rats receiving Ang II plus mibefradil (30 mg/kg/day p.o.), a calcium channel blocker, for 2 weeks; (4) uninephrectomized rats receiving ALDO (0.75 microgram/h) together with a high salt diet for 6 weeks; and (5) uninephrectomized 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 videodensitometry on heart sections stained with collagen-specific picrosirius red. MyoFb were identified by immunohistochemical alpha-smooth muscle actin (SMA) labeling. ACE binding was determined by in vitro quantitative autoradiography. Compared to controls, in rats receiving either Ang II or ALDO we found: (1) myocardial fibrosis, expressed as microscopic scars, and perivascular fibrosis in both right and left ventricles with increased (P<0.05) hydroxyproline concentration and collagen volume fraction; (2) myoFb at sites of fibrosis, where high ACE binding density was also present; and (3) hydroxyproline concentration and collagen volume fraction were significantly (P<0.05) attenuated and the extent of alpha-SMA labeling and ACE binding density were each markedly (P<0.01) reduced in rats receiving either hormone plus mibefradil. This study therefore suggests calcium may modulate fibrous tissue formation in rat models of hyperaldosteronism by altering MyoFb collagen turnover and cell growth. It further is our contention that these findings implicate calcium as a signal used by effector hormones of the RAAS to promote tissue repair and that calcium channel blockade may offer advantage as a cardioprotective strategy in this setting. SN - 0022-2828 UR - https://www.unboundmedicine.com/medline/citation/9515025/Myocardial_fibrosis_associated_with_aldosterone_or_angiotensin_II_administration:_attenuation_by_calcium_channel_blockade_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2828(97)90612-X DB - PRIME DP - Unbound Medicine ER -