Chronic blockade of angiotensin II AT1-receptors increased cell-to-cell communication, reduced fibrosis and improved impulse propagation in the failing heart

Abstract

PaperAbstract I In nt tr ro od du uc ct ti io on n. . The influence of chronic administration of losartan on gap junction conductance (gj), conduction velocity and interstitial fibrosis was investigated in the failing heart of 4-month-old cardiomyopathic hamsters (TO-2).After two months of administration of losartan (25 mg/kg/day/po) the number of cell pairs showing very low values of gj (2-8 nS) was significantly reduced whereas the group of cell pairs with larger values of gj (18-45 nS) was significantly increased.The conduction velocity measured with intracellular microelectrodes in the wall of the left ventricle was enhanced from 38 + 2.3 cm/s (n=25) (control) to 49 + 2 cm/s (n=24) (p<0.05) after losartan administration. Moreover, the number of ventricular fibres showing non-propagated action potentials was significantly decreased (p<0.05) by losartan.The % area of interstitial fibrosis measured in the wall of the left ventricle was reduced from 22 + 1.4% (n=18) to 14 + 1.3% (n=18) (p<0.05) after losartan administration. C Co on nc cl lu us si io on n. . Chronic blockade of angiotensin II type 1 receptors increased gj in the failing heart. Moreover, the conduction velocity was enhanced in part by the increase of gj and in part by the decrease of interstitial fibrosis and structural remodelling. IntroductionEvidence has been presented that the activation of the plasma and cardiac renin angiotensin systems during the process of heart failure is largely responsible for the ventricular remodelling, changes in intercellular communication, impulse propagation and the generation of cardiac arrhythmias.

Enhanced Angiotensin II-Induced Cardiac and Aortic Remodeling in ACE2 Knockout Mice

“…In addition, AT 1 receptor activation mediates a growth response in several cell types, in particular, endothelial cells and cardiomyocytes (de Gasparo, Catt, Inagami, Wright, & Unger, 2000). Moreover, AT 1 receptor blockers are effective in decreasing interstitial cardiac fibrosis in the failing heart (De Mello & Specht, 2006). A study of the effects of Ang II in adult rats showed myocyte hypertrophy and midmyocardial interstitial fibrosis (Grobe et al, 2007).…”

Potential Therapeutic Targets for Cardiac Fibrosis

“…Angiotensin receptor inhibitors such as losartan appear to be effective in reducing cardiac fibrosis in a variety of models in animals and in humans. 36,37 Thus, compared to generally antagonizing TGF␤ signaling, angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists may be useful approaches to control fibrotic disease. …”

Na+–H+exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies

“…The contribution of the RAS to HF was further supported by evidence that the density of AT 1 receptors increased in the ventricles of cardiomyopathic hamsters early during the development of the disease before apparent myocardial damage (Lambert et al 1995). In fact, it was shown that blockade of the AT 1 receptor has beneficial effects on the cardiac structure and performance in UM-X7.1 hamsters (Nakamura et al 1994) and decreased cardiac remodeling in Bio TO-2 cardiomyopathic hamsters (De Mello and Specht 2006;Shimizu et al 2006). This may again justify therapeutic targeting of the angiotensin II system in the treatment of DMD.…”