Aldosterone receptor antagonism alleviates proteinuria, but not malignant hypertension, in Cyp1a1-Ren2 transgenic rats.
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.
Ortiz
Rudy M
RM
Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana, USA. rortiz@ucmerced.edu
Graciano
Miguel L
ML
Mullins
John J
JJ
Mitchell
Kenneth D
KD
D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D000450:Aldosterone / Q000378:metabolism / Q000652:urine; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D006400:Hematocrit; D006974:Hypertension, Malignant / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D011507:Proteinuria / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000652:urine; D013148:Spironolactone / Q000494:pharmacology
D000451:Mineralocorticoid Receptor Antagonists; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D012964:Sodium; D019363:Cytochrome P-450 CYP1A1; D012083:Renin