Endogenous cardiotonic steroids (CS), including marinobufagenin (MBG) stimulate vascular synthesis of collagen. Because aldosterone antagonists competitively antagonize effect of CS on the Na/K-ATPase (NKA) (Hypertension 2010;56:914–9), we hypothesized that aldosterone antagonists would reverse the pro-fibrotic effects of MBG.

Explants of thoracic aortae from Wistar rats were cultured for 24 hours in the presence of vehicle or MBG (100 nmol/L) with or without 1 umol/L canrenone, an active metabolite of spironolactone. In 8 male patients (56±1 yrs) with resistant hypertension (RH) on a combined (lisinopril/amlodipine/hydrochlorothiazide) therapy we measured arterial stiffness using Sphygmocor Px device, calculated pulse wave velocity (PWV) and determined erythrocyte NKA activity before and after addition of spironolactone (50 mg/day) to the therapy.

In rat aortic explants, treatment with MBG resulted in a two-fold rise in the levels of collagen-1 and a marked reduction in the sensitivity to the vasorelaxant effect of sodium nitroprusside following endothelin-1-induced constriction (EC₅₀ = 0.05 umol/L vs. 1.98 umol/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=1.7 umol/L)

Patients with RH exhibited elevated plasma MBG concentration (0.18±0.02 vs. 0.37±0.05 nmol/L; P=0.01) and reduced NKA activity (1.9±0.15 vs 2.8±0.1 umol Pi/ml/hr, P<0.01) vs. 16 healthy controls. Six-month administration of spironolactone was associated with a decrease in PWV (P<0.01) and systolic/diastolic BP (12±3/7±2 mmHg; P<0.01), and restoration of NKA activity (1.9±0.15 to 2.3±0.11 umol Pi/ml/hr, P<0.01). These results demonstrate that CS-induced vascular fibrosis is a likely target for aldosterone antagonists.