Angiotensin-converting enzyme inhibition and AT(1) receptor blockade modify the pressure-natriuresis relationship by additive mechanisms in rats withhuman renin and angiotensinogen genes

The intrarenal factors responsible for hypertension in double-transgenic ra ts (dTGR) harboring human renin and human angiotensinogen genes are unclear . The pressure-natriuresis and -diuresis relationships in response to chron ic angiotensin-converting enzyme (ACE) inhibition and AT(1) receptor blocka de were evaluated. Renal renin-angiotensin and nitric oxide (NO) system gen e expression was also investigated. Six-week-old dTGR were treated for 3 wk with submaximal doses of cilazapril (10 mg/kg, orally) or losartan (10 mg/ kg, orally) or with the drug combination. In untreated dTGR, pressure-natri uresis relationships were maximally shifted rightward by approximately 70 t o 80 mmHg, and both renal blood flow (RBF) and GFR were markedly decreased. Submaximal cilazapril and losartan dosages both decreased systolic BP by 3 0 mmHg and shifted the pressure-natriuresis curves leftward by 25 to 30 mmH g. Cilazapril increased RBF and GFR to values observed in normotensive cont rol animals but did not significantly affect fractional sodium excretion (F ENa) or fractional water excretion (FEH2O) curves. In contrast, losartan ha d no significant effect on RBF or GFR but shifted the FENa and FEH2O curves leftward. The cilazapril and losartan combination completely normalized BP and shifted the pressure-natriuresis curves leftward more than did either drug alone. When cilazapril and losartan were administered at higher doses (30 mg/kg, orally), the two drugs equally shifted the pressure-natriuresis curves leftward, by 50 mmHg, Both drugs increased RBF and GFR; however, onl y losartan shifted FENa and FEH2O curves leftward. Human and rat renin and angiotensinogen genes were downregulated in dTGR and were increased by losa rtan and cilazapril treatments, whereas no changes in the expression of rat ACE and AT(1A) receptor genes were observed. Endothelial NO synthase expre ssion was increased by cilazapril but not by losartan, Neither inducible NO synthase nor neural NO synthase gene expression was affected by drug treat ments. Therefore, submaximal ACE inhibition enhanced sodium excretion mainl y by increasing RBF and GFR, whereas submaximal AT(1) receptor blockade dec reased tubular sodium and water reabsorption. The combination of the two dr ugs produced an additive effect. The ACE inhibitor effects may involve incr eased endothelial NO synthase expression, perhaps related to the inhibition of bradykinin degradation.