SYNTHESIS AND SECRETION OF NATRIURETIC PEPTIDES IN THE HYPERTENSIVE TGR(MREN-2)27 TRANSGENIC RAT

To examine the pathophysiological mechanisms in transgenic rats carryi ng the murine Ren-2(d) renin gene, we studied atrial natriuretic pepti de (ANP) and brain natriuretic peptide (BNP) gene expression and secre tion in 12-week-old hypertensive TGR(mREN-2)27 and normotensive Spragu e-Dawley rats. Hypertension and marked left ventricular hypertrophy in TGR(mREN-2)27 rats were associated with high baseline plasma levels o f immunoreactive ANP (148 +/- 18 versus 34 +/- 3 pmol/L, hypertensive Versus normotensive rats; P < .001), whereas plasma immunoreactive BNP levels did not differ significantly between the strains (19 +/- 4 Ver sus 12 +/- 3 pmol/L, P = .06). ANP mRNA and immunoreactive ANP levels in the left ventricular endocardial and epicardial layers in TGR(mREN- 2)27 rats were about 20 to 40 times higher (P < .001) than those in no rmotensive rats. There were no statistically significant differences b etween atrial and ventricular BNP mRNA levels, but left ventricular im munoreactive BNP concentrations were twofold higher in hypertensive TG R(mREN-2)27 than in normotensive rats. Infusion of [Arg(8)]-vasopressi n (0.05 mu g/kg per minute IV, for 2 hours) in normotensive rats produ ced rapid increases (twofold, P < .05 to .01) in left Ventricular BNP mRNA and immunoreactive BNP levels, whereas Ventricular BNP mRNA and p eptide levels did not change significantly in hypertensive rats: The i ncrease in left atrial BNP mRNA levels in response to acute pressure o verload was also significantly smaller in the hypertensive than normot ensive rats (3.5-fold versus 5.2-fold, P < .01). Furthermore, the prop ortional but not absolute (in picomoles per liter) increase in plasma immunoreactive ANP was smaller in transgenic-rats in response to acute saline and [Arg(8)]-vasopressin infusions (0.9% NaCl: 1.9-fold increa se versus 4.4-fold increase in normotensive rats, P < .001; [Arg(8)]-v asopressin: 2.2-fold versus 4.8-fold increase, P < .001). These result s show that baseline and cardiac overload-induced increases in BNP syn thesis are markedly attenuated in transgenic rats carrying the murine Ren-2(d) renin gene. In addition, acute Volume and pressure overload p roduced a smaller proportional increase in ANP secretion in hypertensi ve rats than normotensive rats. These alterations in the natriuretic p eptide system may contribute to the pathogenesis of hypertension and c ardiovascular complications in the TGR(mREN-2)27 rat.