Role of brain acetylcholine in vasopressin release during osmotic stimulation and hemorrhage

Summary There is considerable evidence to suggest that there is a cholinergic link in the neural control of vasopressin release, but the precise role for this link has not been adequately demonstrated in the intact animal. We have, therefore, examined in conscious unrestrained rats the effects of central cholinergic blockade on the stimulation of vasopressin release by increased plasma osmotality (iv infusion of 2.5 M NaCl at 0.1 mg/kg body weight · min for 30 min) and by decreased blood volume (2 successive hemorrhages of 10% of blood volume each). The vasopressin responses to these stimuli were unaffected by either intracerebroventricular (icv) atropine (10 g; muscarinic blockade) or icv hexamethonium (10 g; nicotinic blockade) in doses which block the vasopressin responses to icv cholinergic agonists. The implications of these findings are discussed.On leave from the Second Department of Internal Medicine, Tohoku University School of Medicine, Sendai, JapanOn leave from the Third Department of Internal Medicine, University of Tokyo School of Medicine, Tokyo, Japan     

Preservation of electrocortical brain activity during hypoxemia in preterm lambs

Adequate cerebral perfusion is necessary to preserve cerebral O₂ supply in order to maintain brain cell function. Our aim was to assess the influence of gestational age on the response of cerebral hemodynamics to hypoxemia and to determine thresholds of cerebral O₂ supply for preservation of brain cell function in preterm born lambs. Lambs were delivered by hysterotomy at 141 (n=5), 134 (n=5) or 127 (n=7) days of gestation. Decreases in arterial oxygen content (CaO₂) were induced by stepwise reduction of the fraction of O₂ in inspired air (FiO₂). Mean arterial blood pressure (MABP), carotid artery blood flow (Qcar), and electrocortical brain activity as a measure of brain cell function, were continuously recorded. Cerebral arterial blood gases were analyzed at the end of each hypoxemic level to calculate CaO₂ and cerebral O₂ supply. In contrast to 141-day lambs, MABP could not be maintained in 134-day and 127-day lambs at levels of severe hypoxemia. Increases in Qcar were observed at levels of moderate hypoxemia in all gestational age-groups. Albeit Qcar increased further at levels of severe hypoxemia in the 141-day lambs, Qcar declined under these conditions in the 134-day and 127-day lambs. The threshold of cerebral O₂ supply for the preservation of brain cell function was however similar in all gestational age-groups (1.7 ml/min). It is concluded that the ability to maintain cerebral function during hypoxemia depends upon the ability to preserve cerebral O₂ supply by means of cerebral hemodynamic compensatory mechanisms, which are not fully matured until 96% of gestation.     

Arginine Vasopressin Fragment AVP4-9 Facilitates Induction of Long-Term Potentiation in the Hippocampus

Long-term potentiation of CA1 field potentials was induced by weak tetanic orthodromic stimulation of the Schaffer collateral/commissural fibers in isolated hippocampal slices perfused with a medium containing arginine vasopressin fragment AVP_4-9 in micromolar concentrations. It is hypothesized that AVP_4-9 affects induction of long-term potentiation at the intracellular level.     

Characterization of the cardiovascular actions of endothelin in vivo: comparisons with neuropeptide Y and angiotensin II

The cardiovascular actions of the endothelium-derived peptide endothelin were investigated and characterized in vivo. Intravenous bolus administration of endothelin (4-200 pmol kg-1) in the anaesthetized and chlorisondamine-pre-treated pig caused a dose-dependent increase in mean arterial blood pressure (MABP) with a threshold effect at 20 pmol kg-1 without affecting heart rate. Endothelin induced dose-dependent and long-lasting renal vasoconstriction. A slight effect was observed at 4 pmol kg-1 and the maximal response at 200 pmol kg-1 was a 648 +/- 210% increase in renal vascular resistance. The potency of endothelin in increasing MABP and renal vascular resistance was, on a molar basis, similar to that of angiotensin II and six times higher than that of neuropeptide Y. Administration of the calcium antagonist nifedipine (100 micrograms kg-1 i.v.) markedly inhibited the endothelin-induced increases in MABP and renal vascular resistance. The renal vasoconstrictor responses to angiotensin II and neuropeptide Y were similarily reduced by nifedipine (100 micrograms kg-1). A lower dose of nifedipine (10 micrograms kg-1) slightly attenuated the response to angiotensin II but not that to endothelin or neuropeptide Y. It is concluded that i.v. endothelin induces potent increases in systemic blood pressure and renal vasoconstriction in the pig. Nifedipine reduces the vasoconstrictor response to endothelin but not more than the responses to angiotensin II and neuropeptide Y.     

Inhibitory effect of brain natriuretic peptide on central angiotensin II-stimulated pressor response in conscious rats

The effect of intracerebroventricular injection of brain natriuretic peptide (BNP) on blood pressure and heart rate was studied in conscious, unrestrained rats. The intracerebroventricular (i.c.v.) injection of BNP did not affect basal blood pressure and heart rate, but it attenuated i.c.v. angiotensin II (AII)-induced pressor response in a dose-dependent manner. These results suggest that BNP plays a role in the regulation of blood pressure in the central nervous system.     

Evidence for the involvement of a GABA-mediated inhibition in the hypovolaemia-induced vasopressin release

The influence of GABA and of drugs, known to alter GABA-metabolism, on the hypovolaemia-provoked vasopressin release was investigated in rats. Blood volume was decreased without altering plasma osmolality or arterial blood pressure by i.p. injection of polyethylene glycol and the resulting plasma vasopressin concentration was measured using a radioimmunoassay. I.c.v. injections of GABA (0.4–2 mg) markedly suppressed the hypovolaemia-induced vasopressin release. The central inhibitory effect of GABA could not be related to appropriate changes in peripheral parameters believed to regulate vasopressin release (arterial blood pressure, renin-angiotensin system). Aminooxyacetic acid (9–81 mg kg^–1, i.m.) and gamma-vinyl-GABA (1.5 g kg^–1, i.p.), two potent inhibitors of GABA aminotransferase and known to increase brain GABA content, reduced vasopressin release to a comparable as did GABA (i.c.v.). On the other hand, 3-mercaptopropionic acid (10–90 mg kg^–1, i.p.), an inhibitor of the GABA synthetizing enzyme glutamic acid decarboxylase, promoted the release of vasopressin when the rats were killed prior to the onset of convulsions. These results, on the whole, intimate the existence of a GABA-mediated inhibition in the central control of vasopressin release.     

Endogenous brain Na pumps, brain ouabain-like substance and the α2 isoform in salt-dependent hypertension

An endogenous ouabain-like substance (OLS) plays a critical role in the etiology of experimental models of human hypertension induced by a high salt diet. Early on, evidence for a role of this Na, K-ATPase inhibitor in blood pressure regulation was provided mainly by correlations of blood pressure with the levels of circulating Na, K-ATPase inhibitor. However, over the past decade, numerous studies have shown that endogenous Na pump inhibitors in the brain mediate salt-dependent hypertension in a variety of experimental models, including Dahl salt-sensitive (Dahl-S) and spontaneously hypertensive (SHR) rats on a high-salt diet. Other forms of hypertension that are known to be mediated by endogenous ouabain-like substances include steroid/salt- (e.g., DOCA-salt) and ACTH-induced hypertension. Even when exogenous ouabain is peripherally administered and/or the plasma ouabain/OLS level is increased in rats, the resulting hypertension is of CNS origin. After peripheral ouabain administration, ouabain levels increase in the plasma and the inhibitor subsequently accumulates in the brain. The ensuing hypertension is abolished by the intracerebroventricular (icv) administration of an anti-ouabain antibody (but not by the same antibody dose given iv), by discrete excitotoxic lesions in the brain or by ganglionic blockade, demonstrating that the response is neurally mediated. The pressor response to stimuli that increase the brain OLS (high salt diet, icv sodium) or to icv ouabain is abolished by icv losartan, demonstrating that the brain OLS activates the brain renin-angiotensin system (RAS) downstream. There are three isoforms of the catalytic α subunit of the Na, K-ATPase in the brain and cardiovascular system (α1, α2 and α3), but it is not known which brain isoform(s) mediate the hypertensive effects of circulating/CNS ouabain. Preliminary studies in gene-targeted mice suggest that the α2 isoform plays a critical role.     

Endogenous brain Na pumps, brain ouabain-like substance and the alpha2 isoform in salt-dependent hypertension.

An endogenous ouabain-like substance (OLS) plays a critical role in the etiology of experimental models of human hypertension induced by a high salt diet. Early on, evidence for a role of this Na, K-ATPase inhibitor in blood pressure regulation was provided mainly by correlations of blood pressure with the levels of circulating Na, K-ATPase inhibitor. However, over the past decade, numerous studies have shown that endogenous Na pump inhibitors in the brain mediate salt-dependent hypertension in a variety of experimental models, including Dahl salt-sensitive (Dahl-S) and spontaneously hypertensive (SHR) rats on a high-salt diet. Other forms of hypertension that are known to be mediated by endogenous ouabain-like substances include steroid/salt- (e.g., DOCA-salt) and ACTH-induced hypertension. Even when exogenous ouabain is peripherally administered and/or the plasma ouabain/OLS level is increased in rats, the resulting hypertension is of CNS origin. After peripheral ouabain administration, ouabain levels increase in the plasma and the inhibitor subsequently accumulates in the brain. The ensuing hypertension is abolished by the intracerebroventricular (icv) administration of an anti-ouabain antibody (but not by the same antibody dose given iv), by discrete excitotoxic lesions in the brain or by ganglionic blockade, demonstrating that the response is neurally mediated. The pressor response to stimuli that increase the brain OLS (high salt diet, icv sodium) or to icv ouabain is abolished by icv losartan, demonstrating that the brain OLS activates the brain renin-angiotensin system (RAS) downstream. There are three isoforms of the catalytic alpha subunit of the Na, K-ATPase in the brain and cardiovascular system (alpha1, alpha2 and alpha3), but it is not known which brain isoform(s) mediate the hypertensive effects of circulating/CNS ouabain. Preliminary studies in gene-targeted mice suggest that the alpha2 isoform plays a critical role.     

Vasopressin secretion in response to haemorrhage: Mathematical modelling of the factors involved

The secretion of vasopressin (estimated in terms of its plasma concentration — AVP) in response to haemorrhage was analysed as a function of blood volume (expressed in terms of % removed plasma — PV) and of mean arterial blood pressure (MABP). Blood was removed from lightly anaesthetized dogs in a carefully controlled, graded manner, so as to ensure a very precise control of each of the three variables under study: PV, MABP and AVP. The data thus obtained (126 triads of PV, MABP and AVP) were analysed and showed:

1. That AVP correlates in a highly significant manner with PV and with MABP.
2. That AVP can be plotted either as a function of PV, within fixed classes of MABP or as a function of MABP, within fixed classes of PV. In the first case, it was found that AVP behaves as an exponential function of PV, for MABP>80 mm Hg. For MABP<80 mm Hg, no functional relation between AVP and PV can be obtained. In the second case, AVP was found to be an exponential function of MABP for PV<40% removed plasma. For PV>40% removed plasma, AVP was found to be a linear function of MABP. The possible physiological significance of these data, as they relate to the control of vasopressin secretion in response to stimuli of cardiovascular origin is discussed.

     

Interleukin-1 receptor antagonist reduces the magnitude of the pressor response to acute stress

The purpose of the present study was to establish the effect of chronic central interleukin-1 receptors blockade and central chronic infusion of interleukin-1 beta (IL-1β) on cardiovascular response to an acute stressor. The experiments were performed on 12–14-week-old, male WKY rats, divided into three experimental groups. Each group was subjected to chronic intracerebroventricular (ICV) infusion of one of the following compounds: saline (control, group C), recombinant rat IL-1 receptor antagonist (IL-ANT group) or interleukin-1 beta (IL-1B group). After 5 days of the ICV infusions mean arterial blood pressure (MABP) and heart rate (HR) were recorded continuously under baseline conditions and after the application of an air jet stressor. The stressor was applied three times with 10-min intervals. There were no significant differences in MABP and HR between groups under baseline conditions and immediately before the application of the three consecutive air jets. After the first stressor the IL-ANT group responded with a significantly lower increase in blood pressure than the control and IL-1B group. After the application of the two following air jets only the trend for an intergroup difference was present. The results of the present study provide further evidence that cytokines play an important role in the regulation of the circulatory system. The most important new finding is that the magnitude of the pressor response to the alarming stress is strongly influenced by IL-1 receptors in the brain.     

Effect of hemorrhagic hypotension on extracellular level of dopamine, cortical oxygen pressure and blood flow in brain of newborn piglets

The present study describes the relationships between extracellular striatal dopamine, cortical oxygen pressure and blood flow in brain of newborn piglets during hemorrhagic hypotension. Cerebral oxygen pressure was measured optically by the oxygen dependent quenching of phosphorescence; extracellular dopamine by in vivo microdialysis; striatal blood flow was monitored by a laser Doppler. Following a 2 h stabilization period after implanting the microdialysis and laser Doppler probes in the striatum, the mean arterial blood pressure (MABP) was decreased in stepwise manner from 87 ± 4 Torr (control) to 35 ± 5 Torr, during 63 min. The whole blood was then reinfused and measurements were continued for 45 min. Statistically significant decrease in blood flow, 10%, was observed when arterial blood pressure decreased to about 53 Torr. With further decrease blood pressure to 35 Torr, blood flow decreased to about 35% of control (P < 0.01). Cortical oxygen pressure decreased almost proportional to decrease in blood pressure. The progressive decrease in MABP from 87 ± 4 Torr to 65 ± 6, 52 ± 7, and 35 ± 5 Torr resulted in cortical oxygen pressure decreasing from 45 ± 4 Torr to 33 ± 3 Torr (P < 0.05), 24 ± 4 Torr (P < 0.01) and 13 ± 3 Torr (P < 0.01). The levels of extracellular dopamine in the striatum increased with decreasing cortical oxygen pressure. As cortical oxygen decreased, the extracellular dopamine increased to 230%, 420% and 3200% of control, respectively. Our results show that in mild hypotension total blood flow is well maintained but oxygen pressure in the microvasculature decreases, possibly due to heterogeneity in the regulatory mechanism. The decrease in cortical oxygen pressure in striatum is parallel to increase in striatal dopamine which then can be use as early indicator of brain hypoxia.     

Prostaglandin and histamine release from stimulated rat peritoneal mast cells

The production of five prostanoids (PGD₂, PGE₂, PGF₂, 6-oxo-PGF₁, and TxB₂) was examined after mast cell activation. Prostaglandin D₂ (PGD₂) was the major prostanoid produced after stimulation of rat peritoneal mast cells with the calcium ionophore A 23187, compound 48/80 or anti-rat IgE. The amount of PGD₂ generated was not dependent on the quantity of histamine released. The time course of PGD₂ production paralleled the release of histamine following activation with A 23187 or anti-rat IgE but with compound 48/80 release of histamine reached a maximum within 15 sec, whereas production of PGD₂ was apparent only after 5 min and was still increasing at 30 min.     

Renin release, saralasin and the vasodilator-beta-blocker drug interaction in man.

Saralasin, an angiotensin antagonist, was used to study the role of renin-angiotensin in the vasodilator-beta-blocker drug interaction in hypertensive subjects. Plasma renin activity was elevated by withdrawal of propranolol in seven patients using minoxidil and propranolol. After propranolol withdrawal, saralasin caused hypotension (100/60 mm Hg or less) in five. Propranolol lowered blood pressure and plasma renin activity and diminished the hypotensive response to saralasin. Saralasin induced renin release in all patients, an effect blocked by propranolol. We conclude that angiotensin can be the major determinant of blood pressure in vasodilator-drug treated patients, that propranolol lowering of blood pressure in this vasodilator-beta-blocker drug interaction is related to suppression of renin release, and that the angiotensin feed-back-suppression mechanism for inhibiting renin release in functionally located proximal to beta-adrenergic receptors mediating renin release.     

急性颅脑损伤患者血浆神经肽和电解质水平变化及其临床意义

目的: 探讨颅脑损伤急性期血浆精氨酸血管加压素(AVP)、血管紧张素Ⅱ(AngⅡ)和电解质水平的变化。方法: 根据GCS评分将78例急性颅脑损伤患者分为轻度组、中度组和重度组,测定各组患者损伤后第1、3、7 d 血浆 AVP和AngⅡ水平,入院当天同时测定血浆电解质。另外选择正常对照组41例相比较。结果: 与正常对照组相比,颅脑损伤患者AVP和AngⅡ明显增高(P<0.01),颅脑损伤越重,上述指标升高越明显,损伤后第3 d达高峰。颅脑损伤患者血钾、血钙浓度降低(P<0.01),其下降程度与颅脑损伤严重程度相关,轻型颅脑损伤组与对照组比较无显著差异。颅脑损伤后血钠水平无明显变化。结论: 血浆AVP和AngⅡ水平的改变可作为判断颅脑损伤严重程度的指标;血钾与血钙降低可以作为颅脑损伤患者病情判断的指标。     

Regional differentiation of sympathetic nerve activity during fever caused by intracerebroventricular injection of PGE2

In urethane-anesthetized rabbits prostaglandin E₂ (PGE₂) injected into a lateral cerebral ventricle (icv) produced hyperthermia. During the phase of rising rectal temperature, renal sympathetic activity monitored by multi-unit recording was reduced while the drop of ear skin temperature indicated cutaneous sympathetic activation. These reciprocal changes in activity corresponded to those typical for cold stress as well as for the phase of rising body temperature in fever induced by endotoxic lipopolysaccharides (LPS). However, a slight early stimulation of the heart rate after icv PGE₂, contrasted to the initial reductions seen with LPS fever and in the cold. After sino-aortic denervation renal sympathetic inhibition in response to icv PGE₂ was reduced but not abolished. After cervical vagotomy the antagonism between cutaneous and visceral sympathetic activity and the increase in heart rate became more prominent. During the phase of subsiding hyperthermia after icv PGE₂, renal sympathetic activity returned to its control level, but, unlike LPS fever, did not exceed it. The results of this study indicate that the reciprocal changes in cutaneous and renal sympathetic activity, but not of sympathetic outflow to the heart, are identical during the phase of rising temperature in PGE₂ and LPS fever. During the phase of subsiding hyperthermia, renal sympathetic activities change to different extents in PGE₂ and LPS fever.     

Renal response to AVP and DDAVP after angiotensin II blockade in the rat

Inhibition of the renin-angiotensin system with saralasin or with SQ 20,881 was used to examine a possible interaction between endogenous angiotensin II and antidiuretic hormone in renal water excretion. In sodium-depleted anesthetized rats undergoing water diuresis, neither saralasin nor SQ 20,881 had any significant effect on water excretion. Both drugs, however, markedly potentiated the antidiuretic response to arginine vasopressin. A similarly enhanced antidiuresis was also observed when the renal response to 1-desamino-8-D-arginine vasopressin was investigated in the presence or absence of saralasin. There were no significant changes in sodium or potassium excretion or in glomerular filtration rate in any of the groups studied. Neither was there any interaction of the drugs with relation to blood pressure. These results seem to indicate that endogenous angiotensin II is capable of antagonizing the hydroosmotic effect of antidiuretic hormone.     

The release of vasopressin in response to haemorrhage and its role in the mechanism of blood pressure regulation

1. The release of vasopressin in response to haemorrhage and the effects of vasopressin infusions on blood pressure and heart rate have been investigated in anaesthetized dogs. Haemorrhage was produced by the method of Lamson & de Türk (1945), which allows for a precise control of the changes in arterial blood pressure.2. Blood samples were collected from an external jugular vein, from a femoral vein or from a femoral artery and extracted with alcohol; blood extracts were assayed for antidiuretic activity.3. Haemorrhage experiments showed that vasopressin secretion is increased when the fall in diastolic blood pressure (diastolic DeltaP) is 25 mm Hg or more. Mild hypotensions (diastolic DeltaP ranging from 21 to 30 mm Hg) produce an average fourfold increase in the concentration of vasopressin in blood. Such increase is maintained throughout the oligaemic period. Severe hypotensions produce, in most cases, a biphasic secretory response, with an initial high peak followed by a lower, constant, secretory plateau. In all experiments, the retransfusion of blood restored vasopressin to control levels.4. Vasopressin infusion experiments showed that the amounts of hormone secreted in response to haemorrhage are sufficient to cause vasopressor response, provided that the buffering action of blood pressure regulation mechanisms is suppressed. It was also found that the amounts of vasopressin secreted in response to haemorrhage are apparently adequate, if the function of such secretion is to combat the hypotension which follows haemorrhage.5. The effect of hypophysectomy on the blood pressure of animals previously submitted to bilateral division of the vagi and sinus nerves (deafferented animals) was also investigated. It was found that hypophysectomy is followed by a fall in arterial blood pressure which is positively correlated to the previous existing amounts of vasopressin. The time course of this hypotension is similar to that following the stopping of an infusion in a deafferented hypophysectomized animal. In some experiments it was shown that, following hypophysectomy, blood pressure can be restored to its pre-hypophysectomy level by an adequate infusion of vasopressin.6. It is proposed that the release of vasopressin in response to stimuli arising from cardiovascular sensory receptors plays a part in the mechanism of blood pressure regulation.     

The effect of angiotensin AT1 receptor blockade in the brain on the maintenance of blood pressure during haemorrhage in sheep

The effect of systemic or intracerebroventricular (ICV) infusion of the angiotensin AT₁ receptor antagonist losartan on blood pressure during hypotensive haemorrhage was investigated in five conscious sheep. Mean arterial pressure (MAP) was measured during haemorrhage (15 mL kg^?1 body wt). Losartan (1 or 0.33 mg h^?1) was given to sheep by ICV, intravenous or intracarotid administration, beginning 60 min before and continuing during the haemorrhage. During control infusion of ICV artificial cerebrospinal fluid, MAP was maintained until 13.16 ± 0.84 mL kg^?1 blood loss, when a rapid reduction of at least 15 mmHg in arterial pressure occurred (the decompensation phase). ICV infusion of losartan at 1 mg h^?1 caused an early onset of the decompensation phase after only 9.8 ± 0.8 mL kg^{? 1} of blood loss compared with control. Intravenous infusion of losartan (1 mg h^?1) also caused an early onset (P < 0.05) of the decompensation phase at 10.2 ± 1.0 mL kg^?1 blood loss. This dose of losartan inhibited the pressor response to ICV angiotensin II, but not to intravenously administered angiotensin II, indicating that only central AT₁ receptors were blocked. Bilateral carotid arterial administration of losartan at 0.33 mg h^?1 caused an early onset of the decompensation phase during haemorrhage at 11.06 ± 0.91 mL kg^?1 blood loss (P < 0.05), which did not occur when infused by intravenous or ICV routes. The results indicate that an angiotensin AT₁-receptor-mediated mechanism is involved in the maintenance of MAP during haemorrhage in sheep. The locus of this mechanism appears to be the brain.     

Genetic deletion and overexpression of angiotensin II receptors

Angiotensin II receptors are essential components of the renin-angiotensin system transducing angiotensin II mediated signals across the plasma membrane of many cell types in the cardiovascular system. To date, three subtypes of angiotensin II receptors have been identified by molecular cloning, termed angiotensin II type 1 (AT_1A, AT_1B) and type 2 (AT₂) receptors. This review focuses on recent transgenic animal models which have been generated to study the in vivo significance of angiotensin receptor diversity. AT_1A receptors are the major blood pressure regulators and have a potent growth-stimulatory effect on cardiac myocytes in vivo. The AT_1B receptor subtype may participate in the control of vascular tone if AT_1A receptors are absent. AT₂ receptors are abundantly expressed during embryonic development and may also play a role in blood pressure regulation by influencing vascular development and differentiation. Received: 16 February 1998 / Accepted: 10 August 1998     

Upregulation of the brain renin-angiotensin system in rats with chronic renal failure

Aim: We investigated how the brain renin–angiotensin system is involved in regulation of the sympathetic activity and arterial pressure in rats with chronic renal failure. Methods: Systolic arterial pressure, heart rate and diurnal urinary noradrenaline excretion were measured for 12 weeks in spontaneously hypertensive rats (SHR) with or without subtotal nephrectomy. Expression of mRNAs related to the brain renin–angiotensin system was measured using polymerase chain reaction. Effects of a 6‐day intracerebroventricular infusion of a type 1 angiotensin II receptor antagonist (candesartan) or bilateral dorsal rhizotomy on these variables were also investigated. Results: Systolic arterial pressure and urinary excretion of noradrenaline were consistently higher in subtotally nephrectomized SHR than in sham‐operated SHR (262 ± 5 vs. 220 ± 3 mmHg, P < 0.001; 2.71 ± 0.22 vs. 1.69 ±0.19 ng g^?1 body weight day^?1, P < 0.001). Expression of renin, angiotensin‐converting enzyme and type 1 angiotensin II receptor mRNAs in the hypothalamus and lower brainstem was greater in subtotally nephrectomized SHR than in sham‐operated SHR. Continuous intracerebroventricular infusion of candesartan attenuated hypertension and the increase in urinary noradrenaline excretion in subtotally nephrectomized SHR. Dorsal rhizotomy decreased arterial pressure, urinary excretion of noradrenaline and expression of renin–angiotensin system‐related mRNAs in brains of subtotally nephrectomized SHR. Conclusion: The brain renin–angiotensin system in subtotally nephrectomized SHR appears to be activated via afferent nerves from the remnant kidney, resulting in sympathetic overactivity and hypertension in this chronic renal failure model.