ENDOTHELIN-1 IS INVOLVED IN STRETCH-INDUCED EARLY ACTIVATION OF B-TYPE NATRIURETIC PEPTIDE GENE-EXPRESSION IN ATRIAL BUT NOT IN VENTRICULARMYOCYTES - ACUTE EFFECTS OF MIXED ETA ETB AND AT(1) RECEPTOR ANTAGONISTS IN-VIVO AND IN-VITRO/

Background The precise role of paracrine and autocrine factors in mech anical 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 activat ion of cardiac B-type natriuretic peptide (BNP) gene expression in spo ntaneously hypertensive rats (SHRs) in vivo and on mechanical stretch- induced increase in atrial BNP gene expression it vitro. Methods and R esults Acute pressure overload produced in conscious SHRs by infusion of arginine(8)-vasopressin (0.05 mu g . kg(-1) . min(-1)) for 2 hours resulted in an increase in BNP mRNA levels in the left ventricle as we ll as in the atrium. Bolus injections of bosentan (mixed ETA/ETB recep tor antagonist, 10 mg/kg IV) but not losartan (AT(1) receptor antagoni st, 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 m RNA levels was similar (a 1.9-fold increase) in the left ventricles of vehicle-, losartan-, and bosentan-infused SHRs. In an isolated perfus ed rat heart preparation, infusion of bosentan (1 mu mol/L) for 2 hour s inhibited the mechanical stretch-induced increase in BNP mRNA levels in the right atria, whereas an AT(1) receptor antagonist, CV-11974 (1 0 nmol/L), had no effect. Conclusions The findings of the present stud y demonstrate that Ang II and ET-1 are not obligatorily required for s tretch to trigger the increased BNP gene expression in ventricular myo cytes invivo. In contrast, mechanical load on the atrial myocytes did initiate an ET-1-dependent expression of BNP gene showing that endogen ous ET-1 production differentially regulates BNP gene expression in at rial and ventricular myocytes.