Combined Inhibition of Endothelin and Angiotensin II Receptors Blocks Volume Load–Induced Cardiac Hormone Release

Abstract

Volume expansion has been shown to increase plasma atrial natriuretic peptide (ANP) levels, but the precise role of paracrine and autocrine factors in stretch-induced cardiac hormone release is not clear. In the present study, we report the effects of endothelin (ET) and angiotensin receptor (AT receptor) antagonists on baseline and atrial stretch–induced immunoreactive ANP (IR-ANP) and immunoreactive N-terminal ANP (IR-NT-ANP) release in vivo by using BQ-123 (ET A receptor antagonist), bosentan (ET A and ET B receptor antagonist), and losartan (AT 1 receptor antagonist). Intravenous administration of BQ-123 had no significant effect on baseline hemodynamics in conscious rats, whereas bosentan (10 mg/kg) and losartan (10 mg/kg) decreased slightly (4 to 7 mm Hg, P <.05 to .001) the mean arterial pressure. Both the ET A receptor antagonist BQ-123 and ET A /ET B receptor antagonist bosentan decreased plasma ANP and NT-ANP responses to volume load ( P <.05 to .001), whereas the AT 1 receptor antagonist losartan had no significant effect on this response. The relative increase in plasma IR-ANP corresponding to a 3 mm Hg increase in right atrial pressure was 2.7-fold in the vehicle-treated group. BQ-123 (0.3 and 1.0 mg/kg) decreased this response 2.5- and 2.1-fold ( P <.05); bosentan (3 and 10 mg/kg), 1.7-fold ( P <.001) and 1.9-fold ( P <.05); and bosentan (10 mg/kg)+losartan (10 mg/kg), 1.6-fold ( P <.001). The responses in plasma IR-NT-ANP decreased simultaneously. These results indicate that combined inhibition of ET A/B and AT 1 receptors almost completely blocks ANP response to acute volume load. Therefore, our study shows that endogenous paracrine and/or autocrine factors liberated in response to atrial wall stretch rather than myocyte stretch itself are responsible for the activation of ANP peptide secretion in response to acute volume load. Our results also show that ET A receptors are more important in the regulation of mechanical stretch–induced changes in cardiac hormone secretion than AT 1 receptors.