Aldosterone antagonist facilitates the cardioprotective effects of angiotensin receptor blockers in hypertensive rats

• Published in: Journal of hypertension Vol. 22; no. 5; pp. 1017 - 1023
• Main Authors: Tanabe, Akiyo, Naruse, Mitsuhide, Hara, Yoshiko, Sato, Atsuhisa, Tsuchiya, Ken, Nishikawa, Toshio, Imaki, Toshihiro, Takano, Kazue
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins, Inc 01-05-2004; Lippincott Williams & Wilkins
• Subjects: Aldosterone - blood; Angiotensin II - blood; Animals; Antihypertensive Agents - pharmacology; Arterial hypertension. Arterial hypotension; Benzimidazoles - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Body Weight; Cardiology. Vascular system; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cardiotonic Agents - pharmacology; Collagen Type I - genetics; Collagen Type III - genetics; Drug Synergism; Fibrosis; Hypertension - complications; Hypertension - drug therapy; Hypertension - physiopathology; Male; Medical sciences; Mineralocorticoid Receptor Antagonists - pharmacology; Myocardium - pathology; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1 - metabolism; RNA, Messenger - analysis; Spironolactone - pharmacology; Tetrazoles - pharmacology; Hypertension; Peptides; Rat; Steroid hormone; Mineralocorticoid; Rodentia; angiotensin type 1 receptor blocker; Cardiovascular disease; Aldosterone; Renin angiotensin system; Vertebrata; Aldosterone antagonist; Mammalia; cardiac fibrosis; Animal; Fibrosis; Adrenal hormone; cardioprotection; Angiotensin II; aldosterone breakthrough; angiotensin type 2 receptor
• ISSN: 0263-6352; 1473-5598
• DOI: 10.1097/00004872-200405000-00025

Background There is increasing evidence to support the importance of blocking aldosterone to prevent target-organ damage in hypertension. We recently demonstrated an aldosterone breakthrough phenomenon during administration of an angiotensin type 1 receptor blocker (ARB).Objective To elucidate the pathophysiological significance of residual aldosterone by investigating the influence of the aldosterone antagonist on the cardioprotective effects of the ARB in hypertensive rats.Methods Injection vehicle alone, ARB (1.0 mg/kg per day candesartan by mouth), aldosterone antagonist (10 mg/kg per day spironolactone, subcutaneously), or combined treatment were administered to male stroke-prone spontaneously hypertensive rats for 24 weeks from the age of 4 weeks. Blood pressure, plasma angiotensin II and aldosterone concentrations, left ventricular weight, expression of type I and type III collagen mRNA, and histological findings were determined.Results In the ARB-treated group, aldosterone concentrations remained unchanged (1.10 ± 0.20 nmol/l, compared with 1.17 ± 0.46 nmol/l in the control group), whereas systolic blood pressure (178 ± 9 mmHg), left ventricular weight (0.372 ± 0.035 g/100 g body weight), expression of collagen mRNA, and cardiac interstitial and perivascular fibrosis all decreased significantly compared with the control group (systolic blood pressure222 ± 10 mmHg, P < 0.05; left ventricular weight0.483 ± 0.021 g/100 g body weight, P < 0.05). Although blood pressure (217 ± 9 mmHg) and left ventricular weight (0.467 ± 0.027 g/100 g body weight) remained unchanged in the group receiving spironolactone, the expression of both types of collagen mRNA and cardiac interstitial and perivascular fibrosis showed a significant decrease compared with the vehicle-treated group. In the rats receiving combined treatment with the ARB and spironolactone, left ventricular weight (0.352 ± 0.005 g/100 g body weight, P < 0.05), expression of collagen mRNA, and cardiac interstitial and perivascular fibrosis all showed a further improvement compared with both the ARB and spironolactone groups.Conclusions These results demonstrate that residual aldosterone has a significant impact on target-organ damage in hypertension, even during chronic administration of an ARB. The addition of an aldosterone antagonist has an advantage in facilitating the cardioprotective effects of ARBs.