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(Circulation. 1997;96:3053-3062.)
© 1997 American Heart Association, Inc.

Articles

Endothelin-1 Is Involved in Stretch-Induced Early Activation of B-Type Natriuretic Peptide Gene Expression in Atrial but Not in Ventricular Myocytes

Acute Effects of Mixed ET_A/ET_B and AT₁ Receptor Antagonists In Vivo and In Vitro

Jarkko Magga, MD; Olli Vuolteenaho, MD, PhD; Minna Marttila, MD; ; Heikki Ruskoaho, MD, PhD

From the Department of Pharmacology and Toxicology and the Department of Physiology (O.V.), Biocenter Oulu, University of Oulu, Finland.

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

Background The precise role of paracrine and autocrine factors in mechanical load–induced activation of cardiac gene expression is unknown. Here we report the effects of endothelin-1 (ET-1) and angiotensin II (Ang II) receptor antagonism on acute pressure overload–induced activation of cardiac B-type natriuretic peptide (BNP) gene expression in spontaneously hypertensive rats (SHRs) in vivo and on mechanical stretch–induced increase in atrial BNP gene expression in vitro.

Methods and Results Acute pressure overload produced in conscious SHRs by infusion of arginine⁸-vasopressin (0.05 µg · kg^-1 · min^-1) for 2 hours resulted in an increase in BNP mRNA levels in the left ventricle as well as in the atrium. Bolus injections of bosentan (mixed ET_A/ET_B receptor antagonist, 10 mg/kg IV) but not losartan (AT₁ receptor antagonist, 10 mg/kg IV) blocked the increase of the BNP mRNA levels produced by pressure overload in the left atria, whereas the elevation of BNP mRNA levels was similar (a 1.9-fold increase) in the left ventricles of vehicle-, losartan-, and bosentan-infused SHRs. In an isolated perfused rat heart preparation, infusion of bosentan (1 µmol/L) for 2 hours inhibited the mechanical stretch–induced increase in BNP mRNA levels in the right atria, whereas an AT₁ receptor antagonist, CV-11974 (10 nmol/L), had no effect.

Conclusions The findings of the present study demonstrate that Ang II and ET-1 are not obligatorily required for stretch to trigger the increased BNP gene expression in ventricular myocytes in vivo. In contrast, mechanical load on the atrial myocytes did initiate an ET-1–dependent expression of BNP gene showing that endogenous ET-1 production differentially regulates BNP gene expression in atrial and ventricular myocytes.

Key Words: pressure • natriuretic peptides • endothelin • angiotensin • hypertrophy

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