Journal of hypertension · 2015
Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists.
СтатьяResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
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
Аннотация
OBJECTIVE: 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.
METHODS: 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 (n = 8) or spironolactone (50 mg/day; n = 8) to the therapy.
RESULTS: 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 (EC50 = 480 ± 67 vs. 23 ± 3 nmol/l in vehicle-treated rings; P < 0.01). Canrenone blocked effects of MBG on collagen synthesis and restored sensitivity of vascular rings to sodium nitroprusside (EC50 = 17 ± 1 nmol/l). Resistant hypertension patients exhibited elevated plasma MBG (0.42 ± 0.07 vs. 0.24 ± 0.03 nmol/l; P = 0.01) and reduced Na/K-ATPase activity (1.9 ± 0.15 vs. 2.8 ± 0.2 μmol Pi/ml per h, P < 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.
CONCLUSION: MBG-induced vascular fibrosis is a likely target for spironolactone.
METHODS: 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 (n = 8) or spironolactone (50 mg/day; n = 8) to the therapy.
RESULTS: 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 (EC50 = 480 ± 67 vs. 23 ± 3 nmol/l in vehicle-treated rings; P < 0.01). Canrenone blocked effects of MBG on collagen synthesis and restored sensitivity of vascular rings to sodium nitroprusside (EC50 = 17 ± 1 nmol/l). Resistant hypertension patients exhibited elevated plasma MBG (0.42 ± 0.07 vs. 0.24 ± 0.03 nmol/l; P = 0.01) and reduced Na/K-ATPase activity (1.9 ± 0.15 vs. 2.8 ± 0.2 μmol Pi/ml per h, P < 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.
CONCLUSION: MBG-induced vascular fibrosis is a likely target for spironolactone.
Предметные рубрики MeSH
AnimalsAortaArterial PressureBufanolidesCanrenoneCells, CulturedCollagen Type IEndothelin-1ErythrocytesFemaleFibrosisHumansHypertensionMaleMiddle AgedMineralocorticoid Receptor AntagonistsMuscle, Smooth, VascularMyocytes, Smooth MuscleNitroprussidePulse Wave AnalysisRatsRats, WistarSodium-Potassium-Exchanging ATPaseSpironolactoneVasodilator Agents