Chronic hypertension induced by ouabain but not digoxin in the rat: Antihypertensive effect of digoxin and digitoxin

Elevated circulating levels of an endogenous ouabain (EO) have been associa ted with essential hypertension. To investigate structure-activity relation ships relevant to blood pressure, we infused either ouabain, ouabagenin, di goxin or digitoxin at 30 mu g/kg/day in normal Sprague Dawley rats. After f ive weeks, the ouabain and ouabagenin infused rats were hypertensive, where as blood pressures declined below their vehicle controls in rats infused wi th digoxin or digitoxin. In a second study, mean blood pressures were 118.5 +/- 1.7 mmHg in rats infused with ouabain (15 mu g/kg/day) on day 35 vs. 9 8,3 +/- 1.8 and 100.3 +/- 1.1 mmHg in the digoxin (30 mu g/kg/day) and vehi cle infused groups (both p < 0.005 vs. ouabain), respectively. Plasma and k idney levels of ouabain immunoreactivity were increased 4-8 fold in ouabain infused rats while blood pressure and plasma levels of ouabain returned to normal one week following discontinuation of the steroid infusion. In rats with ouabain-dependent hypertension, secondary infusions of digoxin or dig itoxin (30 mu g/kg/day) normalized blood pressure even though circulating o uabain remained elevated. In digoxin infused rats, neither blood pressure n or kidney digoxin immunoreactivity was raised whereas plasma digoxin was in creased, Collectively, the results show that the hemodynamic effects of the se sodium pump inhibitors differ dramatically during prolonged administrati on and that tissue rather than circulating levels of these agents appear to better explain their effects on blood pressure. These studies suggest that sodium pump inhibition is not the exclusive mediator of the hemodynamic ef fects of these cardiac glycosides and demonstrate the presence of structure -specific mechanisms that regulate their tissue levels and effects on long- term blood pressure.