Chronic central versus peripheral ouabain, blood pressure, and sympathetic activity in rats.

Abstract

To assess whether chronic ouabain administration causes hypertension by increasing sympathetic activity, we recorded arterial blood pressure and heart rate at rest and after ganglionic blockade in conscious Wistar rats following 10 to 14 days of central or peripheral administration of ouabain. Intracerebroventricular or intravenous infusion of ouabain (10 fig/d for both) as well as subcutaneous ouabain pellets (releasing 25 fig ouabain/d per pellet) increased mean arterial pressure by 20 to 30 mm Hg and heart rate by 40 to 60 beats per minute. Ouabain pellets increased blood pressure and heart rate in a dose-related manner. After 2 weeks of all ouabain treatments, ouabainlike activity in plasma was not changed but increased significantly in hypothalamus and adrenals. Ouabainlike activity in the adrenals was increased more T he relation between high sodium intake and hypertension in salt-sensitive hypertensive rats is complex and not yet understood. We have postulated that high sodium intake intermittently increases Na + concentrations in the cerebrospinal fluid, inducing increased central levels of ouabainlike activity (OLA) and thereby an increase in sympathetic outflow and blood pressure (BP).1 ' 2 Substances with OLA are present peripherally and centrally in both normotensive and hypertensive humans and animals 2 -4 and may be of central origin.2 -4 Brain OLA content is higher in spontaneously hypertensive rats (SHR) than Wistar-Kyoto (WKY) rats, and high sodium intake further increases brain OLA in SHR. 4 Augmented sympathetic activity has been documented in several forms of sodiumdependent hypertension, including Dahl salt-sensitive (DS) rats 5 and SHR. 6 Brain OLA may play a primary role in mediating the sympathoexcitatory and hypertensive effects of high sodium intake in SHR 7 and DS rats. In humans, circulating OLA is indistinguishable from the glycoside ouabain in terms of biochemical structure and several physiological effects.3 Furthermore, receptors for ouabain in, for instance, arterial smooth muscle cells 9 and the central nervous system 10 appear to be identical to those for OLA. If an increase in brain or peripheral OLA contributes to the development of hypertension in sodium-sensitive rats, chronic administration of exogenous ouabain should induce hypertension in normotensive rats as well. In normotensive rats, From the Hypertension Unit, University of Ottawa (Ontario, Canada) Heart Institute.Correspondence to Frans H.H. Leenen, MD, PhD, FRCPC, Hypertension Unit, Room H360, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario, Canada K1Y 4E9. by intravenous than subcutaneous or intracerebroventricular ouabain treatment, but the different treatment modes caused similar increases in the hypothalamus. Concomitant central infusion of antibody Fab fragments against ouabain prevented the ouabain pellet-induced increases in blood pressure and heart rate. Ganglionic blockade by intravenous hexamethonium normalized blood pressure and heart rate in ouabaintreated rats. These data s...

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

“…As previously demonstrated, long-term treatment with ouabain induces the development of a time-dependent hypertension (10,21,23,26,32,45,54) as well as regional changes in the ouabain-sensitive sodium pump activity and expression of the ␣-isoforms (45). This hypertension is also associated with a reduction of phenylephrine-induced contractile activity in the thoracic aorta, but not in caudal arteries, and with an increase in the negative endothelial modulation of the actions of phenylephrine in both arteries (45).…”

“…With the rats under diethyl ether anesthesia (Panreac; Barcelona, Spain), a small incision was made on the back of the neck, and one controlled time-release pellet (Innovative Research) containing either ouabain (0.5 mg/pellet) or vehicle (placebo) was implanted subcutaneously according to the method described by Huang et al (21). These pellets are designed to release a constant amount of either ouabain (ϳ25 g/day) or vehicle for a 60-day period.…”

Selective association of endogenous ouabain with subclinical organ damage in treated hypertensive patients

“…[7][8][9] Experimental use of low doses of ouabain increased arterial blood pressure in rats. 10 Beyond the classical effects of EO, the digitalis-like factors have genomic effects inducing hypertrophy in myocardial and vascular smooth muscle cells because of the activation of numerous known intracellular signaling pathways. [11][12][13] The digitalis-like factors also stimulate fibroblast causing collagen overproduction and fibrosis in rats, which is perhaps important in the development of cardiomyopathy.…”

Estudo dos mecanismos envolvidos no remodelamento de artérias de resistência de ratos hipertensos induzidos pelo tratamento com ouabaína.

“…Além disso, o tratamento crônico com OUA em animais é bem descrito na literatura como sendo capaz de induzir a HA (DI-FILIPPO et al, 2003;HUANG et al, 1994;LEENEN, 1999;MANUNTA et al, 1994; HAMILTON; HAMLYN, 2001; ROSSONI et al, 2002a e b;XAVIER et al, 2004a, b e c). Nesse modelo de HA, a administração subcutânea de OUA (30 µg/Kg/dia), em ratos, é capaz de induzir o aumento da pressão arterial e elevar as concentrações circulantes (5 nmol/L), renais, hipotalâmica e na pituitária anterior de OUA (MANUTA el at, 1994).…”

“…Além disso, apesar do efeito pressórico não requerer a glândula adrenal para sua ocorrência e não ser sensível a sal, observa-se o aumento das concentrações plasmáticas de aldosterona (MANUNTA et al, 1994). Também neste modelo de HA, a OUA ativa tanto mecanismos centrais quanto periféricos, que agem nos diferentes territórios cardiovasculares para produzir o aumento da pressão arterial CARGNELLI et al, 2000;DI FILIPPO et al, 2003;HUANG et al, 1994;HUANG, LEENEN, 1999; ROSSONI et al, 2002a e b;WENCESLAU et al, 2011;XAVIER et al, 2004a;ZHANG et al, 2009 (BRIONES et al, 2009;CARGNELLI et al, 2000; HERNANZ et al, 2008; KIMURA et al, 2000; ROSSONI et al, 2002a b;XAVIER et al, 2004a, b e c).Entre essas, verificou-se: a redução na resposta constritora à fenilefrina, observada em anéis de aorta torácica e artéria mesentérica superior; a não alteração nas respostas contráteis mediadas por agonistas α-adrenenérgicos nas artérias caudal, basilar encefálica, coronária e mesentérica de resistência (AMR); e, por outro lado, o aumento dessa resposta contrátil em anéis de artéria renal (BRIONES et al, 2009;CARGNELLI et al, 2000; HERNANZ et al, 2008; KIMURA et al, 2000; ROSSONI et al., 2002a b;XAVIER et al, 2004a GAYTON, 1990;HALL, 1986). Essas mudanças resultam no aumento da transferência de sódio e água do lúmen tubular para o capilar peritubular, contribuindo para o aumento na pressão arterial.…”