Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists.

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.