Central and peripheral renin-angiotensin systems in ouabain-induced hypertension

Abstract

Chronic subcutaneous infusion of ouabain causes hypertension via central pathways involving angiotensin type 1 (AT(1)) receptor stimulation. The present study assessed plasma and tissue ANG I and II levels as well as AT1 receptor and angiotensin-converting enzyme (ACE) mRNA levels and binding densities by real-time PCR and in vitro autoradiography in relevant brain nuclei and peripheral tissues (heart and kidney) in rats at 1 and/or 2 wk after start of ouabain infusion at 50 microg/day. After 2 wk (but not after 1 wk), blood pressures significantly increased (+15 mmHg). At 2 wk, plasma ANG I and II levels were markedly suppressed by ouabain. In contrast, in the heart and kidneys, ANG I levels were not affected, and ANG II levels tended to decrease, whereas in the hypothalamus ANG II content clearly increased. At 1 wk, no changes in ACE and AT1 receptor densities were seen. After 2 wk, there were significant decreases in AT(1) receptor mRNA and densities in the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and paraventricular nucleus (PVN). ACE densities decreased only in the OVLT and SFO, but ACE mRNA showed more variable responses (decrease in OVLT vs. increase in PVN). In the kidneys, at 2 wk both AT1 receptor and ACE densities were decreased, but mRNA abundance did not change. The heart showed no significant changes. The increase in hypothalamic ANG II content and associated decreases in central AT1 receptor and ACE densities support the involvement of the brain renin-angiotensin system in the central hypertensive mechanism of action of ouabain.

Novel Digitalis-Like Factor, Marinobufotoxin, Isolated From Cultured Y-1 Cells, and Its Hypertensive Effect in Rats

“…Similar magnitude of hypertensive effects by cardiac glycosides was observed with ouabain infused for 2 weeks (118Ϯ2 versus 103Ϯ2 mm Hg; PϽ0.05). 32 We further confirmed that the given MBT was excreted into urine. This means that MBT acts as a vasopressor substance in rats without any toxic effects on kidney function, because serum creatinine and urea nitrogen levels were not influenced by MBT.…”

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

“…The release of angiotensin II may act on vascular smooth muscle, promoting vasoconstriction and increasing peripheral resistance and, consequently, the diastolic pressure (32). Considering that ouabain stimulates angiotensin II release (15,17) and increases sympathoexcitatory activity (14), the sharp reduction of the pressor reactivity to phenylephrine after blockade of the renin-angiotensin system could be explained by a reduced stimulation of the sympathetic nervous system.…”

“…However, the mechanism(s) by which acute administration of nanomolar concentrations of ouabain, similar to the normal plasma concentrations (2), exerts its effects in vivo on blood pressure and on pressor responses to vasoconstrictor agents is still under debate. It is not clear yet which is the contribution of central (15,16) or peripheral mechanisms (9,12,17), or of both simultaneously to this increased pressor response.…”

“…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). Thus, in addition to peripheral mechanisms, central mechanisms may contribute to the ouabain-induced elevation of arterial blood pressure.…”

Enhanced pressor response to increased CSF sodium concentration and to central ANG I in heterozygous α2Na+-K+-ATPase knockout mice

“…Forms of hypertension that are mediated by increases in brain concentration of OLS or ouabain are abolished by ICV losartan [e.g., a high-salt diet in Dahl-S rats (62); Wistar rats and mice given ICV sodium-rich aCSF (20,51); rats and mice given ICV ouabain (7,51)]. Thus, chronic inhibition/downregulation of the brain Na ϩ -K ϩ -ATPase by the brain OLS or by ICV ouabain increases blood pressure by activating the brain RAS.…”