Specificity of the vascular smooth muscle contractile response to a labile digitalis-like factor in peritoneal dialysate: the influence of potassium.

Although multiple lines of evidence have suggested that a circulating endogenous digitalis-like factor (DLF) might contribute to the pathogenesis of sodium-sensitive hypertension, the subject remains controversial. This study was designed to compare the influence of potassium on vascular responses to an endogenous DLF isolated from peritoneal dialysate (PD) in volume-expanded patients with other sodium pump inhibitors, such as ouabain and bufalin, and the influence of serotonin as an index of specificity. An increase in bath potassium (K+) concentration from 2.7 to 10 mmol/L relaxed bovine facial artery precontracted with serotonin, but induced a secondary paradoxical contractile response in vascular-smooth muscle (VSM) precontracted with ouabain, bufalin, or the endogenous DLF from PD. There was a strong correlation between the primary contraction induced by each sodium pump inhibitor, and the magnitude of the paradoxical secondary contractile response. The increase in potassium concentration did not influence ouabain binding in the 20 min required for the experimental protocol, although binding was decreased after 120 min. The findings indicate that the VSM contractile response induced by the agent isolated from PD reflects VSM sodium pump inhibition, supporting its candidacy as a circulating regulator of the sodium pump.

Reversal of sodium pump inhibitor induced vascular smooth muscle contraction with digibind. Stoichiometry and its implications.

The possibility that a circulating sodium pump inhibitor contributes to the pathogenesis of volume-dependent hypertension via an action on vascular smooth muscle (VSM) is supported by multiple lines of investigation, but remains controversial. We had two goals in this study. The first was to compare the pattern of contractile response of rabbit aorta induced by two candidates, ouabain and a labile sodium pump inhibitor that we have identified in the peritoneal dialysate of volume-expanded hypertensive patients with chronic renal failure. Our second goal was to examine the ability of Digibind, a Fab fragment of antisera directed against digoxin, to reverse VSM contraction induced by both agents. Ouabain induced a concentration-dependent contraction, which was delayed in onset, was gradual, and reached a stable plateau after many hours. The labile sodium pump inhibitor induced a qualitatively similar series of responses. Digibind rapidly reversed the contractile responses to both sodium pump inhibitors, with a rate of relaxation that matched that induced by physical removal of the pump inhibitor from the bath. For ouabain, the Digibind:ouabain stoichiometry was highly predictable. When Digibind was present in a molar concentration equivalent to that of ouabain, or less, it had no effect. When the Digibind concentration was twice that of ouabain, complete relaxation occurred. Although the concentration:VSM response relationship for ouabain was steep, the concentration:effect interaction with Digibind was even more steep. The molar concentration of Digibind required to reverse the effects of the labile endogenous inhibitor from peritoneal dialysate was consistently lower than that for ouabain, which is compatible with either greater potency of the labile factor in VSM or greater affinity for Digibind. These findings are compatible with a role for one or more endogenous sodium pump inhibitors as the determinant of vascular smooth muscle tone in the volume-sensitive hypertension of renal disease.