Body fluid distribution in the maintenance of DOCA-salt hypertension in rats

Abstract-To test the hypothesis that increased osmolality contributes to hypertension in deoxycorticosterone acetate (DOCA)-salt-hypertensive rats by acting in the brain, DOCA-salt and Sham-salt rats were instrumented with bilateral, nonoccluding intracarotid and femoral catheters. Two weeks prior, rats were uninephrectomized and received subcutaneous implants with or without DOCA (65 mg) and began drinking salt water (1% NaCl and 0.2% KCl). DOCA-salt rats (nϭ28) exhibited elevated blood pressure (159Ϯ4 mm Hg; PϽ0.05) and heart rate (392Ϯ10 bpm; PϽ0.05) compared with Sham-salt animals (nϭ5; blood pressure: 107Ϯ5 mm Hg; heart rate: 355Ϯ10 bpm). Bilateral intracarotid infusion of hypotonic fluid (osmolality: Ϸ40 mOsm/L), which lowers osmolality of blood to the brain by Ϸ2%, rapidly decreased blood pressure in DOCA-salt rats (Ϫ22Ϯ4 mm Hg after 15 minutes; PϽ0.05; nϭ7) but not Sham-salt rats (2Ϯ2 mm Hg; nϭ5). Hypotonic fluid infused intravenously did not lower blood pressure (0Ϯ2 mm Hg) in DOCA-salt rats (nϭ7). In DOCA-salt rats pretreated with a V 1 vasopressin antagonist (Manning compound, 5 g, IV), intracarotid hypotonic infusion still decreased blood pressure (Ϫ10Ϯ3 mm Hg; PϽ0.05; nϭ9), but the response was smaller (PϽ0.05). Finally, in DOCA-salt rats (nϭ4) pretreated with the V 1 antagonist and the ganglionic blocker hexamethonium, decreasing osmolality of blood to the brain did not reduce blood pressure. These data indicate that, in DOCA-salt rats, hypertonicity acts in the brain to support blood pressure, in part by stimulating vasopressin secretion and in part by stimulating another rapidly reversible mechanism, likely the sympathetic nervous system. Key Words: hypertension, sodium-dependent Ⅲ central nervous system Ⅲ hypertension, mineralocorticoid Ⅲ sodium Ⅲ sympathetic nervous system Ⅲ vasopressin I ncreasing evidence supports a role for body fluid osmolality (OSM) in the regulation of blood pressure (BP) and sympathetic nerve activity (for reviews see References 1,2 ). Acute increases in OSM rapidly elevate BP and sympathetic nerve activity to specific beds, 3-5 and more chronic increases in plasma OSM, such as during water deprivation, seem to sustain this rapid sympathoexcitation. 6 Moreover, recent studies suggest that increased OSM contributes to sympathoexcitation in at least one model of salt-sensitive hypertension, the deoxycorticosterone-treated rat consuming excess salt (DOCA-salt) rat. More specifically, DOCA-salt rats exhibit hypertension and elevated OSM and/or NaCl levels, 7-10 and normalization of OSM results in profound decreases in BP and lumbar sympathetic nerve activity. 8 However, the site at which OSM is sensed to trigger sustained sympathoexcitation in DOCA-salt rats has not been identified.Osmoreceptors are present in numerous organs, including the liver, kidney, and brain, but significant indirect evidence implicates the brain in this action. First, forebrain circumventricular organs contain osmoreceptors that are exquisitely sensitive to minute changes in OSM. 11 Second, forebrain...

Section: Discussioncontrasting

confidence: 95%

mentioning

confidence: 99%

Central Action of Increased Osmolality to Support Blood Pressure in Deoxycorticosterone Acetate–Salt Rats

O'Donaughy

Brooks

2006

“…The excitatory amino acid GLU was used to stimulate RVLM neurons because GLU activates virtually all neurons in the CNS and selectively depolarizes cell somata without affecting axons of passage. 33 Augmented RVLM pressor responses produced by increased dietary NaCI were observed in rats obtained from two different suppliers. This result indicates that potentiation of pressor responses by NaCI is reproducible across substrains of Sprague-Dawley rats and was not due to unique genetic factors peculiar to a particular colony of animals.…”

Section: Discussionmentioning

confidence: 99%

Increased dietary salt sensitizes vasomotor neurons of the rostral ventrolateral medulla.

Pawloski-Dahm

Gordon

1993

Excess dietary sodium is a major contributing factor to the incidence and severity of hypertension. However, the precise mechanism or mechanisms by which salt contributes to the severity of hypertension are unknown. The region of the rostral ventrolateral medulla (RVLM) is a principal brain stem locus critical for the regulation of arterial blood pressure by the sympathetic nervous system. The purpose of this study was to determine if excess dietary sodium chloride might alter the function or responsiveness of neurons In the RVLM. Male Sprague-Dawiey rats were given either tap water or 0.9% sodium chloride solution to drink for 10 to 14 days. Excess sodium chloride did not affect baseline blood pressure. However, when neurons of the RVLM were stimulated by microinjections of L-glutamate, evoked increases in arterial pressure were potentiated in rats given sodium chloride. Augmented pressor responses could not be accounted for by increased vascular reactivity because both groups responded similarly to intravenously administered phenylephrine and norepinephrine. Additionally, electrical stimulation of descending spinal sympathoexcitatory axons produced identical pressor responses in both groups, indicating that altered synaptic transmission at central or peripheral neuroeffector junctions distal to the RVLM could not explain enhanced pressor responses produced by direct stimulation of RVLM cell somata. Finally, impaired arterial baroreceptor reflexes could not account for augmented RVLM pressor responses, as depressor and bradycardic responses produced by electrical stimulation of aortic baroreceptor afferents were not reduced in rats given excess dietary sodium chloride. These results indicate that increased dietary salt intake sensitizes RVLM sympathoexcitatory neurons and may predispose toward the exaggerated expression of hypertension, suggesting a potential link between salt, hypertension, and the brain. (NaCl) to the pathogenesis of hypertension has been debated for almost half a century. 12 Although an increase in NaCl intake is not invariably associated with elevated arterial blood pressure, a large subset of individuals exhibits fluctuations in arterial pressure when daily salt intake is varied. 35 However, a diet high in salt alone is not sufficient to produce hypertension in otherwise normotensive individuals but instead plays a permissive role in enabling the exaggerated expression of hypertension.3 Salt sensitivity of blood pressure has been studied intensively, but the mechanism or mechanisms by which increased dietary salt imparts enhanced sensitivity to hypertensive stimuli are not known.In several experimental models of hypertension, excess NaCl intake is essential for either the development or full expression of hypertension.611 Additionally, the central nervous system (CNS) and peripheral sympathetic nervous system contribute significantly to the maintenance of elevated arterial pressure in many of

“…In the latter, the development of hypertension is paralleled by salt and water retention with expansion of intravascular volume and is reversed on a low salt diet. 8 ' 24 However, both share a common hemodynamic basis for the elevation of arterial pressure (i.e., by increases in total peripheral resistance). Whether hypertension induced by i.c.v.…”

Section: Discussionmentioning

confidence: 99%

Hypertensive mechanisms associated with centrally administered aldosterone in dogs.

Kageyama

Bravo

1988

SUMMARY The mechanism by which intracerebroventricularty administered aldosterone increases arterial pressure was investigated in trained, conscious dogs with cannulas chronically implanted in a lateral cerebral ventricle. In salt-replete and salt-depleted dogs, artificial cerebrospinal fluid with or without aldosterone (0.05 /ig/kg/hr) was infused intracerebroventricularly for 12 days by an osmotic minipump. A similar dose of aldosterone was infused subcutaneously for 12 days. Aldosterone infused intracerebroventricularly increased blood pressure significantly in both salt-replete and salt-depleted dogs. In salt-replete animals the hypertension was associated with increased total peripheral resistance without concomitant changes in blood volume, cardiac output, or in any of the neurohumoral parameters measured. We conclude that this type of hypertension is resistance-mediated from its outset and appears to be relatively independent of salt and water retention. The mechanism by which intracerebroventricularly administered aldosterone increases vascular resistance remains to be determined. (Hypertension 11: 750-753, 1988) KEY WORDS hemodynamics mineralocorticoid hypertension « centrally administered aldosterone H IGH affinity specific binding sites for mineralocorticoids have been described in various areas of the brain. 1 " 4 Quantitative autoradiography with intravenously injected [ 3 H]aldosterone has shown a wide distribution of specific binding sites in the brain, including the anterior hypothalamus, hippocampus, anterior pituitary, nucleus ventromedialis hypothalami, nucleus ambiguus, nucleus tractus solitarii, locus ceruleus, and area postrema.3 The functional importance of these binding sites was recently examined by Gomez-Sanchez in the rat.3 She found that a dose of aldosterone that was too small to produce changes in blood pressure when infused systemically produced elevations of blood pressure when infused into the lateral cerebral ventricle. The fact that the pressor effect could be blocked by the concomitant infusion of a specific aldosterone antagonist, prorenone, lent support to the concept that these mineralocorticoid binding sites in the brain are functional and that they could subserve a role in cardiovascular regulation.We have extended these observations by confirming