ABSTRACT
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 24âh in the presence of vehicle or MBG (100ânmol/l) with or without canrenone (10âµmol/l), an active metabolite of spironolactone. Experiment 2: In 16 patients (56â±â2 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 (nâ=â8) or spironolactone (50âmg/day; nâ=â8) 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 (EC50â=â480â±â67 vs. 23â±â3ânmol/l in vehicle-treated rings; Pâ<â0.01). Canrenone blocked effects of MBG on collagen synthesis and restored sensitivity of vascular rings to sodium nitroprusside (EC50â=â17â±â1ânmol/l). Resistant hypertension patients exhibited elevated plasma MBG (0.42â±â0.07 vs. 0.24â±â0.03ânmol/l; Pâ=â0.01) and reduced Na/K-ATPase activity (1.9â±â0.15 vs. 2.8â±â0.2âµmol Pi/ml per h, Pâ<â0.01) 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.
