MARINOBUFAGENIN-INDUCED SODIUM PUMP INHIBITION ASSOCIATES WITH PRESSOR RESPONSE TO MILD SALT LOADING IN PATIENTS WITH RESISTANT HYPERTENSION: 4B.07

Abstract

Objective: Marinobufagenin (MBG), an endogenous natriuretic and vasoconstrictor cardiotonic steroid, is implicated in natriuretic and pressor responses to salt-loading (SL) in normotensive human subjects. We hypothesized that MBG-induced Na/K-ATPase (NKA) inhibition is associated with salt-sensitivity of blood pressure (BP) in hypertension (HTN). Design and Methods: We studied 22 patients (11 males, 11 females; 56Â ± 6 yrs) with resistant HTN on a combined therapy (lisnopril/amlodipine/hydrochlorothiazide) and 16 healthy normotensive subjects (7 males, 9 females; 44Â ± 2 yrs). SL was performed via i.v. infusion of 1000 mL saline for 1 hour. Beat-to-beat BP was registered using Finometer Pro device. Activity of NKA in erythrocytes measured in the absence and in the presence of a monoclonal anti-MBG antibody (mAb) at baseline and following SL was correlated with SL-induced BP changes and with central BP assessed by applanation tonometry. Results: Within 1 hour of SL patients with HTN exhibited elevation of systolic and diastolic BP (188Â ± 6 vs. 161Â ± 4 and 104Â ± 2 vs. 89Â ± 2 mm Hg, both P < 0.01 vs. baseline). In one hour following SL, BP returned to baseline (158Â ± 4 and 86Â ± 2 mm Hg, respectively). At baseline, activity of the NKA in HTN was suppressed vs. that in controls (1.97Â ± 0.08 vs. 2.84Â ± 0.10 umol Pi/ml/hr; P < 0.01) and was negatively associated with the magnitude of NaCl-induced response of systolic (r = −0.48; P = 0.02) and diastolic (r = −0.44; P = 0.04) BP. Within 60 min of SL, NKA activity was inhibited (1.26Â ± 0.08 umol Pi/ml/hr; P < 0.01), and magnitude of NKA inhibition was positively related to NaCl-induced increase in systolic BP (r = 0.54;P = 0.02) and to central diastolic BP (r = 0.54; P = 0.02). Ex vivo, anti-MBG mAb restored NKA activity (2.66Â ± 0.12 umol Pi/ml/hr; P < 0.01), and magnitude of mAb effect was positively associated with systolic BP following SL (r = 0.47; P = 0.02) and with central diastolic BP (r = 0.67; P = 0.003). Conclusion: In patients with resistant HTN, NKA activity is suppressed and is negatively associated with the magnitude of pressor response to SL. MBG-dependent NKA inhibition associates with NaCl-induced BP elevation.