Acute Pressor Actions of Ouabain Do Not Enhance the Actions of Phenylephrine or Norepinephrine in Anesthetized Rats

Abstract

The inhibition of high-affinity isoforms of the Na+,K+-ATPase by nanomolar levels of ouabain has been proposed to enhance the actions of vasoconstrictor agents that act via a Ca+2-dependent mechanism. The present study tested this hypothesis by evaluating the effects of ouabain (6 and 18 microg/kg, i.v.) on the vasopressor actions of phenylephrine and norepinephrine in anesthetized, reflex-blocked rats. In separate groups of animals, dose-response curves for increases in diastolic pressure produced by phenylephrine were generated after the administration of saline (control), ouabain (18 microg/kg), L-omega-N-nitro arginine methyl ester (L-NAME, 3 micromol/kg) and angiotensin II (15 ng/kg per min). Treatment with ouabain (18 microg/kg) produced an increase in diastolic pressure of 19+/-3 mm Hg but did not significantly alter the potency or maximal response produced by phenylephrine. In contrast, treatment with angiotensin II and L-NAME, agents known to enhance the actions of alpha-adrenoceptor agonists, increased the potency of phenylephrine. In animals in which the pressor actions of norepinephrine were evaluated before and after the administration of ouabain (6 microg/kg), ouabain did not alter the pressor response to norepinephrine. Blockade of alpha-adrenoceptors with phentolamine was found to attenuate as well as partially reverse the increase in diastolic pressure produced by ouabain. These observations suggest that ouabain produces a pressor response by actions on sympathetic nerve endings as well as on vascular smooth muscle and that these actions do not alter the sensitivity to phenylephrine or norepinephrine.

Ouabain-induced hypertension is accompanied by increases in endothelial vasodilator factors

“…Higher micromolar concentrations of ouabain induce contractions by a direct action on the vascular smooth muscle and/or by releasing norepinephrine from the perivascular adrenergic nerve endings (35,42). In the anesthetized normotensive rat, acutely administered ouabain at doses of 10 and 30 nmol/kg iv can increase arterial pressure, in part, by causing the release of norepinephrine from peripheral nerve endings (2,44). However, the reactivity of phenylephrine is reduced in some vascular beds following long-term ouabain treatment.…”

Hypertensive effects of the iv administration of picomoles of ouabain

“…Indeed, low doses of ouabain (6 and 18 µg/kg, which correspond to approximately 10 and 30 nmol/kg) increase the vasoconstrictor response to phenylephrine (24).…”

“…In normal human volunteers (23) and rats (14,24), shortterm iv administration of ouabain in the range of 10-30 nmol/ kg produces a pressor response that is peripheral in origin.…”

“…Acutely, ouabain in picomole quantities increases blood pressure (24,(28)(29)(30)(31), pressor and vascular reactivity to vasoconstrictor agents (14,24,(28)(29)(30)(31)40,41), and sympathoexcitatory activity (9,53). These effects of ouabain are due at least in part to activation of the central and peripheral renin-angiotensin system (31,28,(50)(51)(52).…”

A low concentration of ouabain (0.18 µg/kg) enhances hypertension in spontaneously hypertensive rats by inhibiting the Na+ pump and activating the renin-angiotensin system

“…Consequently, the intracellular Ca 2+ concentration increases and is taken up by the sarcoplasmic reticulum, which, upon activation, releases more calcium and increases the vascular smooth muscle tone (11). According to Vassallo et al (12) and Rossoni et al (9), acute treatment with ouabain enhances the vascular reactivity to vasopressor agents, and Barker et al (13) reported that it also enhances the release of norepinephrine from the perivascular adrenergic nerve endings. Additionally, the hypertension induced by oua-bain has been associated with central mechanisms that increase sympathetic tone, subsequent to the activation of the cerebral renin-angiotensin (14,15) and endothelin systems (16).…”