EVIDENCE FOR LOAD-DEPENDENT AND LOAD-INDEPENDENT DETERMINANTS OF CARDIAC NATRIURETIC PEPTIDE PRODUCTION

Background In hypertension with cardiac hypertrophy, the specific cont ributions to increased production of the cardiac natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BN P) by load and the hypertrophic process are not known. In the present work we determine ANF and BNP synthesis and secretion in the aortic-ba nded rat treated with dosage schedules of the ACE inhibitor ramipril t hat result in the prevention or regression of both hypertension and hy pertrophy (high dosage) or in the prevention or regression of hypertro phy alone with persistent hypertension (low dosage). Myosin heavy chai n (MHC) isoform switch was studied as an indicator of ventricular card iocyte hypertrophy as well as the levels of collagen III mRNA as a mea sure of changes in extracellular matrix. Methods and Results Ramipril was administered for 6 weeks just after suprarenal aortic banding, or rats were banded for 6 weeks, after which ramipril was administered du ring the following 6 weeks. Banding caused an increase in blood pressu re, left ventricular weight-to-body weight ratio, plasma and ventricul ar NP, ventricular NP mRNA, collagen III, and beta-MHC mRNA. Ramipril at 1 mg/kg normalized all these parameters while ramipril at 10 mu/kg normalized left ventricular weight-to-body weight ratio but not blood pressure. Plasma and ventricular NP content and mRNA levels were parti ally normalized by ramipril (10 mu g/kg). Ramipril (10 mu g/kg) preven ted increased collagen III mRNA levels but did not affect beta-MHC mRN A levels. Conclusions (1) NP production and secretion in aortic-banded rats are independently related to increased blood pressure and hypert rophy. (2) A load-dependent component is more important than a load-in dependent component in regulating left ventricular NP production. (3) ANF production is more sensitive than BNP production to the load-indep endent component. (4) Low-dose ramipril treatment reverses hypertrophy and the increased collagen III expression but does not reverse the in creased beta-MHC isoform expression, suggesting that these are indepen dently regulated processes. (5) Aortic banding and ACE inhibition do n ot affect atrial NP production and content.