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(Hypertension. 2001;37:84.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Endothelin-1–Independent and Angiotensin II–Independent Induction of Adrenomedullin Gene Expression

Hannu Romppanen; Jutta Puhakka; Gábor Földes; István Szokodi; Olli Vuolteenaho; Heikki Tokola; Miklós Tóth; Heikki Ruskoaho

From the Departments of Pharmacology and Toxicology (H.R., J.P., I.S., H.T., H.R.) and Physiology (O.V.), Biocenter Oulu, University of Oulu (Finland); and the First Department of Medicine (G.F., M.T.), Semmelweis University, Budapest, Hungary.

Correspondence to Heikki Ruskoaho, MD, PhD, Department of Pharmacology and Toxicology, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 University of Oulu, Finland. E-mail heikki.ruskoaho{at}oulu.fi

Abstract—Adrenomedullin (AM) may function as an autocrine and/or paracrine factor in the heart, but the exact mechanisms regulating cardiac AM gene expression are unknown. The aim of the present study was to characterize the precise time course of induction of atrial and ventricular AM gene expression during pressure overload and to study whether endothelin-1 or angiotensin II plays a causal role in the activation of cardiac AM gene expression. The pressure overload was produced by arginine-vasopressin (AVP, 0.05 µg/kg per minute IV) infusion for 15 minutes, 30 minutes, 1 hour, 2 hours, or 4 hours in conscious rats. A significant increase in left ventricular AM mRNA levels was seen after 2 hours of pressure overload in the left ventricle and after 30 minutes in the left atrium. The left atrial immunoreactive AM (ir-AM) levels decreased significantly after 2 hours of pressure overload. Plasma ir-AM levels increased slightly in response to 4 hours of AVP infusion. Bolus injections of bosentan (mixed ET_A/ET_B receptor antagonist, 10 mg/kg IV), losartan (AT₁ receptor antagonist, 10 mg/kg IV), and their combination had no effect on the increase of cardiac AM mRNA and ir-AM levels produced by 2 hours of pressure overload. In addition, losartan, bosentan, and their combination did not affect plasma ir-AM levels in the vehicle-infused and AVP-infused animals. The present study indicates that cardiac AM gene expression is rapidly upregulated in response to pressure. The induction of ventricular and atrial AM gene expression by pressure overload is angiotensin II–independent and endothelin-1–independent.

Key Words: adrenomedullin • gene expression • angiotensin II • endothelin