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Angiotensin-Converting Enzyme Inhibition and AT₁ Receptor Blockade Modify the Pressure-Natriuresis Relationship by Additive Mechanisms in Rats with Human Renin and Angiotensinogen Genes

EERO MERVAALA^*,,§, BASTIAN DEHMEL^*,, VOLKMAR GROSS^*,, ANDREA LIPPOLDT, JÜRGEN BOHLENDER^*,, ANNA FRANCA MILIA^*,||, DETLEV GANTEN^, and FRIEDRICH C. LUFT^*,

^* Franz Volhard Clinic, Universitätsklinikum-Charité, Humboldt University of Berlin, Berlin, Germany
Max Delbrück Center for Molecular Medicine, Berlin, Germany
Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin, Berlin, Germany
^§ Institute of Biomedicine, University of Helsinki, Helsinki, Finland
^|| Laboratorio Nazionale Biotechnologie e Biostructure, Sassari, Italy.

Correspondence to Dr. Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13125 Berlin, Germany. Phone: 49-30-9417-2202; Fax: 49-30-9417-2206; E-mail: luft{at}fvk-berlin.de

Abstract

Abstract. The intrarenal factors responsible for hypertension in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes are unclear. The pressure-natriuresis and -diuresis relationships in response to chronic angiotensin-converting enzyme (ACE) inhibition and AT₁ receptor blockade were evaluated. Renal renin-angiotensin and nitric oxide (NO) system gene 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-natriuresis relationships were maximally shifted rightward by approximately 70 to 80 mmHg, and both renal blood flow (RBF) and GFR were markedly decreased. Submaximal cilazapril and losartan dosages both decreased systolic BP by 30 mmHg and shifted the pressure-natriuresis curves leftward by 25 to 30 mmHg. Cilazapril increased RBF and GFR to values observed in normotensive control animals but did not significantly affect fractional sodium excretion (FENa) or fractional water excretion (FEH₂O) curves. In contrast, losartan had 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, only losartan shifted FENa and FEH₂O curves leftward. Human and rat renin and angiotensinogen genes were downregulated in dTGR and were increased by losartan and cilazapril treatments, whereas no changes in the expression of rat ACE and AT_1A receptor genes were observed. Endothelial NO synthase expression was increased by cilazapril but not by losartan. Neither inducible NO synthase nor neural NO synthase gene expression was affected by drug treatments. Therefore, submaximal ACE inhibition enhanced sodium excretion mainly by increasing RBF and GFR, whereas submaximal AT₁ receptor blockade decreased tubular sodium and water reabsorption. The combination of the two drugs produced an additive effect. The ACE inhibitor effects may involve increased endothelial NO synthase expression, perhaps related to the inhibition of bradykinin degradation.

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