Digoxin Prevents Ouabain and High Salt Intake–Induced Hypertension in Rats With Sinoaortic Denervation

Abstract

Abstract-Digoxin prevents ouabain-induced hypertension in rats. In the present study, we tested whether this effect of digoxin depends on its sensitizing effect on baroreflex function or is due to an antagonistic action on exogenous ouabain or endogenous ouabainlike activity ("ouabain") in the brain. In Wistar rats, resting mean arterial pressure (MAP) was significantly increased by long-term subcutaneous (SC) ouabain (75 g/d) plus high salt (8%) intake for 12 days (but not after only 5 days). In rats with chronic sinoaortic denervation (SAD), MAP was increased within 5 days of ouabain treatment to the same extent as MAP after 12 days of treatment in intact rats. The effect of ouabain and high salt was prevented when digoxin was given SC concomitantly via osmotic minipump (200 g ⅐ kg Ϫ1 ⅐ d Ϫ1 ). Resting MAP was not changed in rats treated with digoxin alone. In a second set of rats with chronic SAD or sham surgery, high salt intake was given for 14 days, with or without SC digoxin (200 g ⅐ kg Ϫ1 ⅐ d Ϫ1 ) or intracerebroventricular (ICV) antibody Fab fragments (200 g/d), which bind "ouabain" with high affinity. On day 14, MAP, central venous pressure, heart rate, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air-jet stress, IV phenylephrine and nitroprusside, and acute volume expansion with 5% dextrose IV. In rats with SAD versus sham surgery, high salt significantly increased resting MAP as well as excitatory responses of MAP, heart rate, and renal sympathetic nerve activity to air stress. These effects of high salt in rats with SAD were prevented by digoxin or Fab fragments. Arterial baroreflex function was blunted but cardiopulmonary baroreflex function was not affected in rats with SAD. Digoxin and Fab fragments had no effects on either function. In an in vitro assay for the inhibitory effects on Na ϩ ,K ϩ -ATPase activity, 20 ng of ouabain caused 29% inhibition, but 20 ng of ouabain plus 13 or 53 ng of digoxin caused only 16% or 4% inhibition, respectively. These data indicate that the arterial baroreflex opposes sympathoexcitatory responses to ouabain and "ouabain" in the brain, thereby delaying ouabain-and preventing high salt-induced hypertension in Wistar rats. In addition to possible effects on the arterial baroreflex, digoxin appears to act centrally to prevent the sympathoexcitatory and pressor effects of increased brain "ouabain" or ouabain. Key Words: digoxin Ⅲ nerve activity, sympathetic, renal Ⅲ sodium intake Ⅲ baroreflex Ⅲ ouabain Ⅲ denervation, sinoaortic Ⅲ stress, air Ⅲ Fab H igh salt intake increases endogenous compounds with ouabainlike activity ("ouabain") in the brain of rats with salt-sensitive blood pressure (BP) and to a lesser extent in the brain of normotensive rats with salt-insensitive BP. 1,2 In saltsensitive rats, such as spontaneously hypertensive and Dahl salt-sensitive rats, the increase in brain "ouabain" appears to mediate salt-induced sympathetic hyperactivity, impairment of baroreflex function, and hypertension. [3][4][5][6]...

Activation of c-SRC underlies the differential effects of ouabain and digoxin on Ca2+ signaling in arterial smooth muscle cells

“…Similarly, the absence of long-term pressor activity with digoxin is also an enigma (24,29,39). The present results are thus of relevance as they show that ouabain and digoxin have very different effects on ASMC Ca 2ϩ signaling that are mediated by specific Na ϩ and Ca 2ϩ transport proteins (Figs.…”

“…These findings also provide the first molecular explanation for the paradoxical antihypertensive effects of digoxin in salt-sensitive and ouabain hypertensive rats (24,39), and the antihypertensive effect of digitalis preparations in some hypertensive patients (1).…”

“…Moreover, digoxin is an effective antihypertensive in the OH rat (24,29,39), and Digitalis preparations have antihypertensive actions in some patients with essential hypertension (1). As the opposing effects of these CTS on long-term BP are not explained by differences in their ability to inhibit ␣2 Na ϩ pumps, the hypertensinogenic action of ouabain involves binding to ␣2 Na ϩ pumps (14,15,37) followed by the specific triggering of a co-related signaling event.…”

Ouabain-Like Compound Changes Rapidly on Physical Exercise in Humans and Dogs

“…Prolonged elevated plasma ouabain concentrations lead to arterial hypertension. 31 Because Ϸ50% of whites with uncomplicated arterial hypertension show elevated concentrations of OLC in blood plasma, 32 the present observation may stimulate more detailed investigations of whether enduring stress, a defective elimination system, or both may lead to increased OLC concentrations in blood and hence to hypertension. …”

Structure-Activity Relationships for the Hypertensinogenic Activity of Ouabain

“…28 Recent work shows not only that low nanomolar circulating concentrations of digoxin do not induce hypertension under conditions in which OUA is effective, but strikingly that digoxin and digitoxin antagonize the hypertensive effect of OUA. 13,14,29 Thus, the activity of OUA on long-term blood pressure is not a class effect of the cardiac glycosides.…”