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(Circulation Research. 1997;80:114-123.)
© 1997 American Heart Association, Inc.

Articles

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

Hanna Leskinen, Olli Vuolteenaho, Heikki Ruskoaho

the Departments of Physiology (H.L., O.V.) and Pharmacology and Toxicology (H.R.), Biocenter Oulu, University of Oulu (Finland).

Correspondence to Heikki Ruskoaho, MD, PhD, Department of Pharmacology and Toxicology, University of Oulu, Kajaanintie 52 D, FIN-90220 Oulu, Finland. E-mail heikki.ruskoaho@oulu.fi

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 (AT₁ 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 AT₁ 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 AT₁ 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 AT₁ receptors.

Key Words: volume load • atrial natriuretic peptide • N-terminal atrial natriuretic peptide • endothelin • angiotensin

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