Angiotensin II receptor antagonist blocks the expression of connexin43 induced by cyclical mechanical stretch in cultured neonatal rat cardiac myocytes

Mechanical forces have profound effects on cardiomyocytes. To test whether angiotensin IT is a potential mediator of stretch-induced effects on gap ju nctions, we used the angiotensin II (AT1) receptor antagonist, losartan, to investigate the cyclical stretch-induced expression of connexin43 (Cx43), the major cardiac muscle gap junction channel protein. Cultured neonatal ra t cardiomyocytes grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation, at 60 cycles/min. The levels of Cx43 protein began to increase as early as 2 h after stretch was applied, reached a max imum of six-ford over the control by 24 h and remained at this level anothe r 24 h (i.e. up to 45 h after stretch was applied). These increases of Cx43 protein at 24 h were largely (73%) and completely (100%) attenuated (P<0.0 01) by the addition (30 min before stretch) of 10 nM and 100 nM losartan, r espectively. Similarly, the Cx43 mRNA levels in stretched cardiomyocytes ro se 89% (P<0.01) above control (non-stretched cells) mRNA levels, This incre ase also was blocked by losartan, Cyclical stretch increased (and losartan decreased) the immunohistochemical labeling of Cx43 and significantly incre ased release of angiotensin II into the culture media from 7.5 +/-0.6 ng/ml to 23.8 +/-1.0ng/ml (P<0.01) after a Ih stretch. These findings indicate t hat cyclical mechanical stretch augments angiotensin II production and Cx43 gene expression in cultured cardiomyocytes, partially through mediation of the ATI receptors, and suggests interaction between the cardiomyocyte loca l rennin-angiotensin system and Cx43 in response to stretch, <(c)> 2001 Aca demic Press.