Endothelin-1-independent and angiotensin II-independent induction of adrenomedullin gene expression

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 t ime course of induction of atrial and ventricular AM gene expression during pressure overload and to study whether endothelin-1 or angiotensin II play s a causal role in the activation of cardiac AM gene expression. The pressu re overload was produced by arginine-vasopressin (AVP, 0.05 mug/kg per minu te 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 w as 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) le vels 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 ETA/ETB receptor antagonist, 10 mg/kg IV), lo sartan (AT(1) 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 com bination did not affect plasma ir-AM levels in the vehicle-infused and AVP- infused animals. The present study indicates that cardiac AM gene expressio n is rapidly upregulated in response to pressure. The induction of ventricu lar and atrial AM gene expression by pressure overload is angiotensin II-in dependent and endothelin-1-independent.