Volume sensitive hypertension and the digoxin-like factor reversal by a fab directed against digoxin in DOCA-salt hypertensive rats

Abstract

Although volume and vasoconstriction have been considered polar elements in a useful pathogenetic hypertension model, many observations suggest that vasoconstriction is involved in volume-dependent hypertension, reflecting the effect of a digitalis-like factor. To examine that possibility, we assessed the depressor responses to Digibind, an antibody Fab directed against digoxin, in a volume-dependent model--DOCA-salt-induced hypertension in rats. Digibind (10 mg/kg, intravenously) induced a gradual blood pressure fall over 2 h that was sustained for 4 h (P < .001). Blood pressure did not fall with Digibind when DOCA was administered without salt or a high-salt intake was provided without DOCA. The intracellular sodium content of the rat aorta, measured by atomic absorption spectroscopy after cold choline wash, was increased in the DOCA-high-salt rats (23.3 +/- 2.7 mEq/L) compared to control rats (12.1 +/- 0.8 mEq/L; P < .001). Aorta sodium content, in parallel with blood pressure, was not increased either by dietary salt supplementation without DOCA, or by DOCA with a low-salt diet. Sodium pump activity was measured as 86Rb uptake into vascular smooth muscle (VSM). Both ouabain-sensitive and ouabain-resistant 86Rb uptake were significantly higher in VSM from DOCA-high-salt animals (P < .01). Despite its effectiveness in reducing blood pressure in this model, Digibind influenced neither VSM sodium content nor 86Rb uptake. The results are consistent with a role for a circulating digitalis-like factor in this volume-dependent model, but events at the VSM level are complex.

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

“…2B). These results are consistent with previous studies by using Digibind in rat models of hypertension (46)(47)(48)(49)(50)(51)(52). As a negative control, i.v.…”

New Approaches in the Treatment of Hypertension

“…Endogenous digitalis-like factors (EDLFs) are a family of circulating Na/Κ-ATPase inhibitors, including marinobufagenin, that are elevated in preeclampsia and contribute to its pathogenesis by mediating by guest on http://circres.ahajournals.org/ Downloaded from vasoconstriction and vascular fibrosis and inhibiting proliferation and invasion of the cytotrophoblast. [127][128][129][130] An antidigoxin antibody fragment (Digibind, Ovine Digoxin Immune Antibody) has been shown to attenuate the inhibitory effects of EDLFs on Na/Κ-ATPase, to lower BP in animal models of volume-dependent hypertension and to reduce maternal BP and preserve renal function in women with preeclampsia 131,132 (Table).…”

Arterial α2-Na+pump expression influences blood pressure: lessons from novel, genetically engineered smooth muscle-specific α2mice

“…In contrast, mice with one null ␣ 1 -allele (␣ 1 ϩ/Ϫ ) express many fewer total Na ϩ pumps in ASMCs (ϳ60% of normal) but have normal basal BP (57). In addition, plasma EO is elevated in many humans with essential hypertension or mineralocorticoid hypertension (33,39,49), in several rodent hypertension models (14,15,24,27), and in pregnant rats (19). Indeed, prolonged ouabain administration induces hypertension in rodents (11,12,34).…”