CONVERTING-ENZYME INHIBITORS DIFFERENTIALLY AFFECT EXPRESSION OF GENES OF THE RENIN-ANGIOTENSIN SYSTEM

There is considerable evidence from clinical and experimental studies that blood pressure is lowered by converting enzyme inhibitors (CEIs) irrespective of whether the plasma renin-angiotensin system (RAS) is s timulated. New insights into the molecular biology of the RAS - in par ticular, the gene expression of renin and angiotensinogen in various t issues - support the view that the antihypertensive properties of CEIs may be mediated, at least in part, by interaction with tissue RAS. To investigate this possibility further, stroke-prone spontaneously hype rtensive male rats (SHRSP) were treated orally for 28 days with differ ent CEIs or a peripheral vasodilator to study the effects of the vario us drug treatments on the gene expression of the RAS in selected tissu es. Different effects of different CEIs on tissue gene expression sugg est localized action and some degree of organ specificity of the drugs . The experiments involved: (1) untreated controls; and rats treated w ith either (2) 50 mg/kg of captopril; (3) 10 mg/kg of lisinopril; (4) 10 mg/kg of cilazapril; (5) or 30 mg/kg of the vasodilator hydralazine with 10 rats/group. All of the study drugs reduced systolic blood pre ssure to normotension. Cardiac hypertrophy and the heart:body weight r atio were significantly decreased only in the CEI-treated animals, and kidney renin mRNA was increased by the CEIs whereas hydralazine had n o effect on heart weight or kidney renin mRNA. Plasma renin activity i ncreased in parallel with kidney renin mRNA levels. Liquid hybridizati on and Northern blotting assays revealed drug-specific regulation of t he angiotensinogen mRNA level in the adrenal gland, with cilazapril pr oducing the most marked stimulation of adrenal angiotensinogen gene ex pression. Both lisinopril and cilazapril suppressed hypothalamic angio tensinogen mRNA. There were no significant changes in angiotensinogen gene expression observed in the kidney or liver with any of the CEIs. In conclusion, these data show that CEIs interact differentially and d rug-specifically with tissue RAS, and have class-specific effects on c ardiac hypertrophy.