P1.03 ALDOSTERONE ANTAGONISTS REVERSE EFFECTS OF CARDIOTONIC STEROIDS ON VASCULAR ELASTICITY AND COLLAGEN SYNTHESIS
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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.
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TY - JOUR AU - A.O. Konradi AU - Y.N. Grigorova AU - K.A. Bagrov AU - A.V. Fadeev AU - I.V. Emelianov AU - O.V. Fedorova AU - A.Y. Bagrov PY - 2012 DA - 2012/11/17 TI - P1.03 ALDOSTERONE ANTAGONISTS REVERSE EFFECTS OF CARDIOTONIC STEROIDS ON VASCULAR ELASTICITY AND COLLAGEN SYNTHESIS JO - Artery Research SP - 151 EP - 152 VL - 6 IS - 4 SN - 1876-4401 UR - https://doi.org/10.1016/j.artres.2012.09.040 DO - 10.1016/j.artres.2012.09.040 ID - Konradi2012 ER -