Ren-Hui Yang

Atrial natriuretic factor prevents NaCl-sensitive hypertension in spontaneously hypertensive rats.

Our previous studies demonstrated that acute infusion of atrial natriuretic factor (ANF) produces an enhanced depressor response in NaCI-sensitive spontaneously hypertensive rats (SHR-S) fed a high (8%) NaCl diet compared with control SHR-S fed a normal (1%) NaCl diet and that dietary NaCl loading increases circulating ANF levels in Wistar-Kyoto (WKY) rats but not in SHR-S. The current study tested the hypotheses that 1) long-term infusion of ANF at a dose that elevates plasma ANF to levels comparable with those seen in high NaCl-fed WKY rats prevents the NaCl-induced exacerbation of hypertension in SHR-S and 2) ANF lowers blood pressure in this model by a sympatholytic effect Male SHR-S received infusions of ANF (0.1 (ig/hr) or vehicle intravenously via osmotic minipump for 3 weeks beginning immediately before initiation of 1% or 8% NaCl diets at age 7 weeks. Chronic ANF infusion prevented the increase in arterial pressure in response to a high NaCl diet in SHR-S but had no effect in 1% NaCl-fed SHR-S. Thus, the NaCI-sensitive component of hypertension in SHR-S was more sensitive to ANF than the non-NaCl-sensitive component Plasma norepinephrine was significantly increased in ANF-treated, 8% NaCl-fed SHR-S compared with vehicle controls, suggesting that ANF did not prevent NaCI-sensitive hypertension by a sympatholytic effect During ANF infusion, plasma ANF was increased by only 36% and 40% in the 1% and 8% NaCl groups, respectively, so that long-term infusion of exogenous ANF in a dose that resulted in plasma ANF levels well within the physiological range abolished the NaCl-induced exacerbation of hypertension in SHR-S. The data suggest that a deficiency in circulating endogenous ANF may play a role in NaCI-sensitive hypertension in this model.

Pressor effect of blocking atrial natriuretic peptide in nucleus tractus solitarii.

Previous studies have shown that microinjection of atrial natriuretic peptide into the caudal nucleus tractus solitarii produces significant increases in local neuronal firing rate associated with reductions in arterial pressure in anesthetized Wistar rats. Single units excited by microinjection of atrial natriuretic peptide into the caudal nucleus tractus solitarii were also excited by activation of arterial baroreceptors and inhibited by baroreceptor unloading. To test the hypothesis that endogenous atrial natriuretic peptide in caudal nucleus tractus solitarii is involved in the tonic control of blood pressure in the rat, we administered a blocking monoclonal antibody to atrial natriuretic peptide in a volume of 50 nl artificial cerebrospinal fluid via microinjection into the caudal nucleus tractus solitarii of spontaneously hypertensive and Wistar-Kyoto rats and observed the effects on mean arterial pressure and heart rate. Control injections of monoclonal antibody were administered into the rostral nucleus tractus solitarii, hypoglossal nucleus, spinal trigeminal nucleus, and cuneate nucleus of spontaneously hypertensive rats. Microinjection of monoclonal antibody into the caudal nucleus tractus solitarii caused significant increases in mean arterial pressure in spontaneously hypertensive rats but not in Wistar-Kyoto rats. There was no concomitant change in heart rate. Control injections of purified mouse immunoglobulin into the caudal nucleus tractus solitarii and of monoclonal antibody into the control neuronal groups listed above had no effect on mean arterial pressure. These results suggest that endogenous atrial natriuretic peptide in the caudal nucleus tractus solitarii mediates tonic control of blood pressure in spontaneously hypertensive rats but not in normotensive Wistar-Kyoto rats.

The Neural Basis of Salt Sensitivity in the Rat: Altered Hypothalamic Function

Dietary NaCl supplementation in NaCl-sensitive spontaneously hypertensive rats (SHR-S) elevates blood pressure, increases peripheral sympathetic nervous system activity and depresses endogenous noradrenaline stores and noradrenaline release in the anterior hypothalamus. NaCl-resistant spontaneously hypertensive rats (SHR-R) and normotensive Wistar Kyoto (WKY) rats are resistant to the NaCl-induced alterations in blood pressure and central and peripheral noradrenergic activity, suggesting that the alterations observed in the SHR-S during NaCl loading are genetically mediated. The anterior hypothalamus is a major cardiovascular regulatory region, and depressor responses elicited by pharmacologic (alpha 2 adrenoceptor) stimulation of this area are exaggerated in SHR-S fed a high NaCl diet compared with SHR-S fed a basal diet and compared with SHR-R and WKY fed a high or basal NaCl diet. Membrane-binding techniques confirm that alpha 2 adrenoceptors in the anterior hypothalamic area are increased in number in SHR-S fed a high NaCl diet, presumably reflecting upregulation in response to reduced local noradrenaline release. These findings are consistent with the hypothesis that decreased noradrenergic activity of sympathoinhibitory neurons in the anterior hypothalamic area may mediate the exacerbation in hypertension that occurs in SHR-S during dietary NaCl supplementation.

Impaired release of atrial natriuretic factor in NaCl-loaded spontaneously hypertensive rats.

Our previous studies demonstrated that NaCl-sensitive spontaneously hypertensive rats (SHR) of the Okamoto strain exhibit increased blood pressure and reduced noradrenergic input to the anterior hypothalamus area when fed high NaCl diets. The current study tested the hypotheses that 1) release of atrial natriuretic factor (ANF) into the plasma is Impaired in NaCI-loaded SHR, a defect that would tend to elevate blood pressure, and 2) ANF levels in regions of brain involved in blood pressure regulation, such as the anterior hypothalamk area, are altered in SHR. SHR and control Wistar-Kyoto rats (WKY) were placed on 1% or 8% NaCl diets at age 7 weeks; 2 weeks later, ANF levels were measured in plasma, left and right atria, anterior hypothalamic area, ventral hypothalamic area, posterior hypothalamic area, pons, and medulla by radioimmunoassay. Blood for ANF assay was obtained from intra-arterial cannulas in conscious, unrestrained rats studied in the resting state. The 8% NaCl diet produced an increase in blood pressure in the SHR, but not in the WKY. Plasma ANF levels were significantly greater in WKY fed 8% NaCl than in WKY fed 1% NaCl, but dietary NaCl loading did not produce similar increases in plasma ANF in the SHR. Plasma ANF levels were not significantly different between SHR and WKY fed the 1% NaCl diet. The observation that dietary NaCl loading stimulated ANF release into the plasma in WKY but not in SHR suggests that the exacerbation in hypertension seen in NaCI-loaded SHR may be related to an impairment in ANF release. In addition, ANF stores were elevated in the anterior hypothalamic area of SHR fed either diet as compared with WKY. The role of this alteration in central nervous system ANF in the pathogenesis of NaCl-sensitive hypertension remains to be determined.

Vasopressin Lowers Pulmonary Artery Pressure in Hypoxic Rats by Releasing Atrial Natriuretic Peptide

The authors previously demonstrated that arginine vasopressin (AVP) lowers pulmonary artery pressure in rats with hypoxic pulmonary hypertension by activation of the V1 receptor. The pulmonary depressor effect of AVP in hypoxia-adapted rats is not due to its effect on cardiac output. The current study tested two alternative hypotheses: that AVP lowers pulmonary artery pressure in the hypoxia-adapted lung by (1) dilating pulmonary vasculature directly, or (2) releasing atrial natriuretic peptide (ANP) from the heart. The first hypothesis was tested by injecting AVP into the pulmonary arteries of isolated, buffer perfused lungs and monitoring pulmonary artery pressure, and by exposing preconstricted pulmonary artery rings to graded doses of AVP and monitoring the tension generated. AVP caused minimal vasodilation in perfused lungs and only a small vasodilator effect in pulmonary artery rings. The second hypothesis was tested by injecting AVP (160 ng/kg) or vehicle intravenously in conscious hypoxia-adapted (4 weeks) or air control rats and measuring ANP in arterial blood and atria, and by testing pretreatment with the V1 receptor antagonist d(CH2)5 Tyr(Me)AVP (130 micrograms/kg) on the AVP-induced increase in plasma ANP. AVP produced a 7-fold increase in plasma ANP (209 +/- 33 to 1346 +/- 233 pg/ml; p less than 0.05) in hypoxia-adapted rats and a 5-fold increase in ANP (122 +/- 22 to 573 +/- 174 pg/ml; p less than 0.05) in air controls. ANP release was abolished by pretreatment of both groups with d(CH2)5 Tyr(Me)AVP. The AVP-induced ANP release came mainly from left atrium. These data strongly suggest that the pulmonary depressor effects of AVP in hypoxia-adapted rats is due to augmented V1 receptor-induced release of ANP from left atrium.

Dopamine D2 receptors in the posterior region of the nucleus tractus solitarius mediate the central pressor action of quinpirole (LY171555)

Our previous studies demonstrated that intravenous (IV) administration of the selective dopamine (DA) D2 receptor agonist quinpirole (LY171555) induces a pressor response in conscious Sprague-Dawley (S-D) rats through a central mechanism. The present study was designed to identify the neurons which medicate this pressor response. Injection of quinpirole (1-150 micrograms/kg) into the 4th ventricle produced a greater pressor response of a more rapid onset than similar injections into the lateral ventricle in conscious, freely moving S-D rats, suggesting a site of action in brainstem. Further, microinjections (5-10 micrograms/kg in 200 nl) of quinpirole into major hypothalamic nuclei of conscious, freely moving rats elicited no pressor response. Uni- or bilateral microinjections of quinpirole (5 micrograms/200 nl) into the posterior region of nucleus tractus solitarius (P-NTS) caused a consistent increase in mean arterial pressure (MAP) (Max = 12.4 +/- 1.1 mmHg, n = 12) with a rapid onset (less than 30 sec) in unanesthetized decerebrate S-D rats, while microinjections into the anterior region of NTS, area postrema, C1/A1 regions, raphe obscurus nucleus, locus coeruleus or regions 0.5 mm lateral, superior or inferior to P-NTS produced little or no response. The pressor response induced by bilateral microinjections of quinpirole into P-NTS was not different from that of unilateral microinjection. The pressor response to microinjection of quinpirole into P-NTS was abolished by pretreatment with metoclopramide (5 mg/kg, IV or 25 micrograms/200 nl, P-NTS injection; 5 min before), a selective DA D2 antagonist that crosses the blood-brain barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Pressor and Bradycardic Effects of Centrally Administered Relaxin in Conscious Rats

The current study tested the hypothesis that centrally administered relaxin elevates arterial pressure in conscious rats and that this hypertensive effect is mediated, at least in part, by central or peripheral vasopressin. Injection of human relaxin (0.068 or 0.34 microgram in 200 nL artificial cerebrospinal fluid) into the right lateral ventricle of conscious, unrestrained Sprague-Dawley rats caused significant dose-related increases in arterial pressure and decreases in heart rat. The pressor and bradycardic responses to intracerebroventricular injections of relaxin were significantly blunted by pretreatment with either intracerebroventricular or intravenous injection of a vasopressin receptor (V1) antagonist, suggesting that the cardiovascular effects of central relaxin are mediated, at least in part, by V1 receptors in the brain and perhaps also by vasopressin released into the peripheral circulation. Neither intracerebroventricular injection of the vehicle alone nor intravenous injection of relaxin (0.34 microgram) altered arterial pressure or heart rate. In contrast to the above, intravenous injections of relaxin (40 micrograms/kg) elicited pressor and tachycardic responses that were not blunted by pretreatment with either intracerebroventricular or intravenous injection of the V1 receptor antagonist. Together, these data suggest that in the central nervous system relaxin contributes to the regulation of cardiovascular function and that the mechanisms for the cardiovascular effects of central and peripheral relaxin are distinct.

Genetic Basis of NaCI-Sensitive Hypertension

Summary: Sensitivity to the pressor effect, of dietary NaCI and the depressor effect, of dietary Ca is inherited. High NaCl diets accelerate the development and or exacerbate the severity of hypertension in NaCl-sensitive substrains of spontaneously hypertensive rat (SHR-S) but not in NaCl-resistant substrains of SHR (SHR-R) or in normotensive Wistar-Kyoto (WKY) control rats. High NaCl intake leads to increased circulating noradenaline levels and increased depressor responses to ganglionie blockade in SHR-S but not in SHR-R or WKY rats, indicating that peripheral sympathetic nervous system activity and neurogenic peripheral vascular tone are increased by NaCl supplementation in SHR-S. but not in SHR-R or WKY rats. Further. dietary NaCl loading in SHR-S decreases endogenous noradrenaline stores and noradrenaline release in the anterior hypothalamus, a brain region that contains neurons that give rise to depressor responses when stimulated chemically or electrically. These findings are consistent with the hypothesis that decreased activity of noradrenergic depressor neurons in the anterior hypothalamus mediate and increase in blood pressure that occurs in NaCI-sensitine animals during dietary NaCl supplementation by releasing tonic inhibition of sympathetic outflow. The exacerbation of hypertension and changes in central noradrenergic activity are observed only in NaCl-loaded SHR-S. not in SHR-R or WKY rats. indicating that these NaCl-induced alterations in central noradrenergic activity are genetically mediated. Dietary Ca supplementation prevents for reversest the NaCl-induced changes in blood pressure. peripheral sympathetic nervous system activity, and anterior hypothalamic noradrenaline release in SHR-S. suggesting that dietary NaCI and Ca may have opposing effects on the same regulators pathway. The genetic defect in NaCl Ca2+ sensitivity of blood pressure is not yet identified. but probably involve cation transport at the cellular level.

Dietary Ca2+ prevents NaCl-sensitive hypertension in spontaneously hypertensive rats via sympatholytic and renal effects.

NaCl-sensitive spontaneously hypertensive rats (SHR-S) were used to test the hypotheses that dietary Ca2+ supplementation 1) prevents NaCl-sensitive hypertension via a sympatholytic mechanism, and 2) increases diuretic and natriuretic responses to acute volume loading. SHR-S and control WKY rats were begun on one of four diets at age 8 wk: control, high NaCl, high Ca2+, or high NaCl and high Ca2+. In SHR-S, dietary Ca2+ supplementation prevented the NaCl-induced increases in blood pressure and plasma norepinephrine concentrations, the reductions in anterior hypothalamic norepinephrine stores and turnover, and the secondary increases in alpha 2 adrenoceptor number. Thus, Ca2+ prevented NaCl-sensitive hypertension in SHR-S by increasing noradrenergic input to the anterior hypothalamus. High-NaCl-fed SHR-S had impaired diuretic and natriuretic responses to an isotonic volume load; Ca2+ enhanced the ability of these animals to adjust fluid volume rapidly via diuresis and natriuresis. This alteration in renal function may contribute to the hypotensive effect of a high Ca2+ diet in NaCl-sensitive hypertension.

Intrahypothalamic clonidine infusion prevents NaCl-sensitive hypertension.

We have previously shown that dietary NaCl supplementation increases blood pressure and sympathetic nervous system activity in association with decreased norepinephrine release and increased a2-adrenergic receptor number in the anterior hypothalamic area of salt-sensitive spontaneously hypertensive rats (SHR-S) but not in salt-resistant spontaneously hypertensive rats (SHR-R) or Wistar-Kyoto (WKY) rats. Further, acute microinjection of clonidine into the anterior hypothalamic area produced depressor responses that were augmented by high salt feeding in SHR-S but not in SHR-R or WKY rats. The current study tested the hypothesis that chronic infusion of clonidine into the anterior hypothalamic area prevents salt-sensitive hypertension in SHR-S. Beginning at age 7 weeks, immediately before initiation of 1% or 8% salt diets, clonidine (2 ng/min) or saline vehicle was infused into the anterior hypothalamic area or femoral vein of male SHR-S via osmotic minipump for 20 days. In SHR-S fed an 8% salt diet, chronic microinfusion of clonidine into the anterior hypothalamic area offset the hypertensive effect of the dietary salt supplementation and reduced the enhancing effects of dietary salt on left ventricular weight and plasma norepinephrine levels. In contrast, chronic microinfusion of clonidine into the anterior hypothalamic area did not significantly affect any of these measures in 1% salt-fed SHR-S. Intravenous infusion of clonidine at the rate used for the anterior hypothalamic area infusion did not alter any of these measures in 8% salt-fed SHR-S. These data support the hypothesis that salt-induced hypertension in SHR-S is associated with diminished sympathoinhibitory function of central o^-adrenergic receptors and that chronic microinfusion of clonidine into the anterior hypothalamic area prevents salt-sensitive hypertension in this model, at least in part, by enhancing o-adrenergic receptor-mediated sympathoinhibition.