Discoordinate re-expression of cardiac fetal genes in N-omega-nitro-L-arginine methyl ester (L-NAME) hypertension

Objective: Hypertension produced by chronic inhibition of nitric oxide (NO) synthase by N-w-nitro-L-arginine methyl ester (L-NAME) was used to determine the effect of severe pressure overload with or without left ventricular (LV) hypertrophy on the transcriptional activation of the cardiac fetal genes encoding for the natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP), and for beta-myosin heavy chain (MHC) in both atrial and ventricular muscle. A previously reported association of LV hypertrophy with the activation of cardiac renin and angiotensin-converting enzyme (ACE) in this hypertension model was also investigated. Methods: Male Sprague-Dawley rats received L-NAME (75 mg/kg/day) or were left untreated for 4 (n=12) or 8 (n=12) weeks. Results: L-NAME-treated rats became severely hypertensive in both treatment groups but only five out of 12 8-week treatment animals showed a significantly increased LV weight to body weight (BW) ratio (LVW/ BW). LV ANF mRNA, but not LV BNP mRNA, correlated significantly with LVW/BW only in animals showing LV hypertrophy. No changes were observed in atrial gene expression or plasma concentration of ANF or BNP A significant correlation was found between LVW/BW and LV renin mRNA and LV ACE activity in rats with LV hypertrophy. LV beta-MHC mRNA levels were significantly increased in the LV of rats with or without LV hypertrophy at both 4 and 8 weeks of treatment. Conclusions: It is concluded that pressure overload per se does not promote NP or cardiac renin-angiotensin system gene expression while increased beta-MHC expression is a marker of LV pressure overload even in the absence of LV hypertrophy. It is apparent that L-NAME causes a disruption in the coordinated transcriptional activation of cardiac fetal genes expected of hypertrophic stimuli acting on the LV. (C) 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.