Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists. Issue 8 (August 2015)

• Record Type: Journal Article
• Authors: Fedorova, Olga V.; Emelianov, Igor V.; Bagrov, Konstantin A.; Grigorova, Yulia N.; Wei, Wen; Juhasz, Ondrej; Frolova, Elena V.; Marshall, Courtney A.; Lakatta, Edward G.; Konradi, Alexandra O.; Bagrov, Alexei Y.
• Is Part Of: Journal of hypertension. Volume 33:Issue 8(2015:Aug.)
• Publication Date: 2015-08
• Subjects: Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/HJH.0000000000000591
• Languages: English
• ISSNs: 1473-5598

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Objective:</title> <p>Endogenous cardiotonic steroids, including marinobufagenin (MBG), stimulate vascular synthesis of collagen. Because mineralocorticoid antagonists competitively antagonize effect of cardiotonic steroids on the Na/K-ATPase, we hypothesized that spironolactone would reverse the profibrotic effects of MBG.</p> </sec> <sec> <title>Methods:</title> <p>Experiment 1: Explants of thoracic aortae and aortic vascular smooth muscle cells from Wistar rats were cultured for 24 h in the presence of vehicle or MBG (100 nmol/l) with or without canrenone (10 μmol/l), an active metabolite of spironolactone. Experiment 2: In 16 patients (56 ± 2 years) with resistant hypertension on a combined (lisinopril/amlodipine/hydrochlorothiazide) therapy, we determined arterial pressure, pulse wave velocity, plasma MBG, and erythrocyte Na/K-ATPase before and 6 months after addition of placebo (<italic>n</italic> = 8) or spironolactone (50 mg/day; <italic>n</italic> = 8) to the therapy.</p> </sec> <sec> <title>Results:</title> <p>In rat aortic explants and in vascular smooth muscle cells, pretreatment with MBG resulted in a two-fold rise in collagen-1, and a marked reduction in the sensitivity of the aortic rings to the vasorelaxant effect of sodium nitroprusside following endothelin-1-induced constriction (EC<sub>50</sub> = 480 ± 67 vs. 23 ± 3 nmol/l in vehicle-treated rings; <italic>P</italic> < 0.01). Canrenone blocked effects of MBG on collagen synthesis and restored sensitivity of vascular rings to sodium nitroprusside (EC<sub>50</sub> = 17 ± 1 nmol/l). Resistant hypertension patients exhibited elevated plasma MBG (0.42 ± 0.07 vs. 0.24 ± 0.03 nmol/l; <italic>P</italic> = 0.01) and reduced Na/K-ATPase activity (1.9 ± 0.15 vs. 2.8 ± 0.2 μmol Pi/ml per h, <italic>P</italic> < 0.01) vs. seven healthy individuals. Six-month administration of spironolactone, unlike placebo treatment, was associated with a decrease in pulse wave velocity and arterial pressure, and with restoration of Na/K-ATPase activity in the presence of unchanged MBG levels.</p> </sec> <sec> <title>Conclusion:</title> <p>MBG-induced vascular fibrosis is a likely target for spironolactone.</p> </sec> </abstract>