Aldosterone receptor antagonism alleviates proteinuria, but not malignant hypertension, in Cyp1a1-Ren2 transgenic rats.

Abstract

The contribution of elevated aldosterone to the pathogenesis of malignant, ANG II-dependent hypertension remains uncertain. Therefore, we examined whether chronic mineralocorticoid receptor blockade attenuates the development of malignant hypertension in transgenic rats (TGRs) with inducible expression of the Ren2 gene [TGR(Cyp1a1Ren2)]. Systolic blood pressure (SBP) was measured by radiotelemetry in male TGRs in three groups: 1) control (n = 9), 2) hypertensives (HT; n = 8), and 3) hypertensives + spironolactone (11 mg.kg(-1).day(-1) sc; HTS; n = 8). Malignant hypertension was induced with dietary indole-3-carbinol (0.3%) for 10 days. Metabolic measurements were taken at the beginning of the study and at days 2 and 9. HT exhibited elevated SBP (125 +/- 3 vs. 187 +/- 5 mmHg), plasma renin activity (5 +/- 1 vs. 29 +/- 10 ng ANG I.ml(-1).h(-1)), plasma ANG II (175 +/- 39 vs. 611 +/- 74 fmol/ml), and plasma aldosterone (0.31 +/- 0.04 vs. 5.42 +/- 1.02 nmol/l). Urinary aldosterone excretion increased 5.5-fold by day 2 and an additional 90% by day 9. HT was associated with a 1.8-fold increase in proteinuria by day 9 that was alleviated by treatment with spironolactone (25 +/- 5 vs. 13 +/- 3 mg/day), suggesting that aldosterone contributes to the renal damage observed in malignant hypertension. Urinary Na+ excretion was decreased 76% on day 2, despite a sixfold increase in urinary aldosterone excretion. Decrease in urinary Na+ excretion on day 2 in HT suggests that Na+ reabsorption was increased in response to the increase in aldosterone; however, the lack of a change in SBP between HT and HTS suggests that mechanisms independent of aldosterone stimulation make a greater contribution to the maintenance of elevated arterial pressure in malignant hypertension in Cyp1a1-Ren2 transgenic rats.

• Authors: Rudy M Ortiz, Miguel L Graciano, John J Mullins, Kenneth D Mitchell
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 293 Issue 5 Pg. F1584-91 (Nov 2007) ISSN: 1931-857X [Print] United States
• PMID: 17715265 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Mineralocorticoid Receptor Antagonists
• Angiotensin II
• Spironolactone
• Aldosterone
• Sodium
• Cytochrome P-450 CYP1A1
• Renin

Topics

• Adrenal Glands (metabolism, pathology)
• Aldosterone (metabolism, urine)
• Angiotensin II (metabolism)
• Animals
• Animals, Genetically Modified
• Blood Pressure
• Cytochrome P-450 CYP1A1 (genetics, metabolism)
• Hematocrit
• Hypertension, Malignant (metabolism, pathology, physiopathology, prevention & control)
• Kidney (metabolism, pathology)
• Male
• Mineralocorticoid Receptor Antagonists (pharmacology)
• Myocardium (pathology)
• Organ Size
• Proteinuria (metabolism, physiopathology)
• Rats
• Renin (genetics, metabolism)
• Sodium (urine)
• Spironolactone (pharmacology)