Synthesis and secretion of natriuretic peptides in the hypertensive TGR(mREN-2)27 transgenic rat.
To examine the pathophysiological mechanisms in transgenic rats carrying the murine Ren-2d renin gene, we studied atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression and secretion in 12-week-old hypertensive TGR(mREN-2)27 and normotensive Sprague-Dawley rats. Hypertension and marked left ventricular hypertrophy in TGR(mREN-2)27 rats were associated with high baseline plasma levels of 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 versus 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 normotensive rats. There were no statistically significant differences between atrial and ventricular BNP mRNA levels, but left ventricular immunoreactive BNP concentrations were twofold higher in hypertensive TGR(mREN-2)27 than in normotensive rats. Infusion of [Arg8]-vasopressin (0.05 microgram/kg per minute IV, for 2 hours) in normotensive rats produced rapid increases (twofold, P < .05 to .01) in left ventricular BNP mRNA and immunoreactive BNP levels, whereas ventricular BNP mRNA and peptide levels did not change significantly in hypertensive rats. The increase in left atrial BNP mRNA levels in response to acute pressure overload was also significantly smaller in the hypertensive than normotensive rats (3.5-fold versus 5.2-fold, P < .01). Furthermore, the proportional but not absolute (in picomoles per liter) increase in plasma immunoreactive ANP was smaller in transgenic rats in response to acute saline and [Arg8]-vasopressin infusions (0.9% NaCl: 1.9-fold increase versus 4.4-fold increase in normotensive rats, P < .001; [Arg8]-vasopressin: 2.2-fold versus 4.8-fold increase, P < .001). These results show that baseline and cardiac overload-induced increases in BNP synthesis are markedly attenuated in transgenic rats carrying the murine Ren-2d renin gene. In addition, acute volume and pressure overload produced a smaller proportional increase in ANP secretion in hypertensive rats than normotensive rats. These alterations in the natriuretic peptide system may contribute to the pathogenesis of hypertension and cardiovascular complications in the TGR(mREN-2)27 rat.
Marttila
M
M
Department of Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, Finland.
Vuolteenaho
O
O
Ganten
D
D
Nakao
K
K
Ruskoaho
H
H
D000818:Animals; D030801:Animals, Genetically Modified; D001127:Arginine Vasopressin / Q000008:administration & dosage / Q000494:pharmacology*; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D020097:Natriuretic Peptide, Brain; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D012076:Renal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013045:Species Specificity
D009419:Nerve Tissue Proteins; D012076:Renal Agents; D001127:Arginine Vasopressin; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor