ATRIAL STRETCH INDUCES RAPID INCREASE IN BRAIN NATRIURETIC PEPTIDE BUT NOT IN ATRIAL-NATRIURETIC-PEPTIDE GENE-EXPRESSION IN-VITRO

Pressure and volume overload in vivo is characterized by induction of the expression of two cardiac hormones, atrial natriuretic peptide (AN P) and brain natriuretic peptide (BNP), but whether stretch directly o r other pathophysiological factors associated with cardiac overload ca use the activation of these genes is not known. In the present study w e examined the effect of short-term (from 30 min to 2 h) direct myocar dial stretch on atrial ANP and BNP synthesis and release in modified p erfused rat heart preparation that enabled the stepwise distension of the right atrium by pressures approximating those found in vivo. The i ncrease in right atrial pressure by 3.6 mm Hg for 2 h resulted in a 3. 3- (p<0.00 1) and 1. 7-fold (p<0.02) increase in the rate of IR-ANP an d IR-BNP release, respectively, into the perfusate. The maximal increa se in both ANP and BNP release was seen after 20 min distension. There after the perfusate IR-ANP and IR-BNP concentration gradually decrease d, reaching control values within 2 hours. Chromatographic analysis sh owed that the hearts primarily release the active, processed 28- and 4 5-amino acid ANP- and BNP-like peptides, respectively, both before and during atrial stretch. Atrial stretch induced rapid stimulation of BN P gene expression: 1.9- (p<0.001) and 4.5-fold (p<0.001) increase in r ight auricular BNP mRNA levels after 1.0 and 2. 0 hours' stretching, r espectively, was found on Northern blot analysis, while no change was seen after 30 min distension. In contrast, stretching for up to 2 h di d not change auricular ANP mRNA, IR-ANP or IR-BNP levels. Our results show for the first time that atrial stretch induces rapid stimulation of both synthesis and secretion of BNP. The induction of BNP gene expr ession in the very early stages of cardiac overload mimics the inducti on of protooncogenes and occurred without involvement of humoral or ne ural factors. The lack of response of atrial ANP mRNA levels demonstra tes that the regulation of BNP gene expression differs from that of AN P.