Yohimbine-induced alterations of monoamine metabolism in the spontaneously hypertensive rat of the Okamoto strain (SHR). II. The central nervous system (CNS)

Steady state levels of monoamine neurotransmitters were examined in SHR, a genetic model of hypertension and compared to its normotensive control (WKY). SHR and WKY were also challenged with alpha 2-adrenergic antagonists, (yohimbine, YOH, idazoxan) or an alpha 1-antagonist (prazosin) and alterations in CNS monoamine metabolism evaluated. SHR were found to have elevated levels of NE and 5-HT in a number of brain regions involved in cardiovascular control when compared to WKY. DA levels and metabolism were also altered in the SHR. Blockade of alpha 2-adrenoceptors and other direct and indirect actions of YOH exacerbated the abnormalities in central monoaminergic neurotransmission in SHR. Significant decreases in NE content were produced by YOH or idazoxan treatment in both SHR and WKY, presumably the result of the inhibition of alpha 2-adrenoceptor medicated presynaptic control of NE release. YOH treatment abolished the differences in steady state levels of NE between SHR and WKY, however, idazoxan did not. YOH administration resulted in significant increases in DA and 5-HT in a number of brain regions of both SHR and WKY. Idazoxan or prazosin produced few changes in DA and 5-HT metabolism except for increases in DA content in the spinal cord and brainstem of SHR given idazoxan. The YOH-induced increases in DA and 5-HT content of SHR were of a greater magnitude than the WKY in several brain regions. DOPAC levels were significantly elevated by YOH in both WKY and SHR, reflecting the antidopaminergic properties of YOH. 5-HIAA content was significantly reduced by YOH in a number of brain regions in both SHR and WKY, however, this effect was attenuated in several brain regions in SHR. The results of the present study demonstrate the multifarious nature of the alterations in CNS monoamine metabolism in SHR.     

Pial venous pressure and acute hypertensive disruption of the blood-brain barrier in spontaneous and renal hypertension

The purpose of this study was to determine whether changes in pial venous pressure during acute hypertension account for altered acute hypertensive disruption of the blood-brain barrier in chronic hypertension. We studied 13 normotensive WKY rats, 7 spontaneously hypertensive rats (SHR), and 9 two-kidney, one-clip renal hypertensive rats of the same age. Pial venous pressure (servonull technique) and clearance of fluorescein-labeled dextran from pial vessels (as an estimate of permeability of the blood-brain barrier) were measured before and during acute hypertension produced by i.v. infusion of phenylephrine. Experiments were performed in anesthetized rats (50 mg/kg sodium pentobarbital i.p.). Blood and artificial cerebrospinal fluid pO2, pCO2 and pH were within normal ranges throughout the experiment. The change, time to peak and peak pial venous pressures were the same in all groups. The peak arterial pressure after phenylephrine was greater in the hypertensive rats compared to WKY rats. The time to peak mean arterial pressure was the same in all groups of rats. Clearance of FITC dextran was the same in WKY versus renal hypertensive rats, but less in SHR versus WKY rats (P less than 0.05 by analysis of variance). We conclude that something other than an attenuation of the increase in pial venous pressure protects the blood-brain barrier of SHR against acute hypertensive disruption.     

Regional cerebral blood flow autoregulation in normotensive and spontaneously hypertensive rats--effects of sympathetic denervation

The present study was designed to investigate the effect of acute sympathetic denervation on the regional cerebral blood flow (CBF) autoregulation during acute elevation of blood pressure in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). CBF to the parietal cortex and thalamus was measured by the hydrogen clearance method and, to test autoregulation, systemic arterial blood pressure was elevated by intravenous infusion of phenylephrine. Superior cervical ganglia were removed on both sides to interrupt sympathetic innervation in the deeper structures of the brain. Acute bilateral sympathetic denervation did not alter the resting blood pressure or CBF in either SHR or WKY. In innervated SHR, resting mean arterial pressure (MAP) was 165 +/- 5 mm Hg (mean +/- SEM) and the upper limit of autoregulation in the cortex was 210 +/- 3 mm Hg, which was significantly lower than that in the thalamus (229 +/- 3 mm Hg, p less than 0.02). In bilaterally denervated SHR, the upper limits were lowered to 193 +/- 4 mm Hg in the cortex (p less than 0.02 vs. innervated SHR) and to 207 +/- 5 mm Hg in the thalamus (p less than 0.02 vs. innervated). In WKY, resting MAP was approximately 55 mm Hg lower than that in SHR. Acute denervation reduced the upper limits from 142 +/- 3 mm Hg to 130 +/- 4 in the cortex (p less than 0.05) and from 158 +/- 4 to 145 +/- 4 in the thalamus (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Central ANP attenuates pressor responses to central AVP in WKY and SHR

Blood pressure and heart rate responses to intracerebroventricular (ICV) injections of atrial natriuretic peptide (ANP, 125 ng) arginine vasopressin (AVP, 10 ng), combination of ANP (125 ng) and AVP (10 ng) or artificial cerebrospinal fluid (acsf, 5 microliters) were compared in conscious normotensive (WKY) and spontaneously hypertensive (SHR) rats. In both strains, ICV injection of AVP elicited significant increase of mean blood pressure (MP) and heart rate (HR). Increase of MP but not of HR was significantly greater in SHR than in WKY (p less than 0.05). Injection of acsf or ANP, as well as simultaneous administration of ANP and AVP, did not elicit significant changes of MP either in WKY or in SHR. In SHR, HR was significantly elevated by ICV injections of AVP and ANP + AVP, whereas in WKY HR was increased only after AVP. The data suggest that interaction of ANP and AVP at a central level may result in significant attenuation of central pressor effects of vasopressin.     

Enhanced renal response to intracerebroventricular angiotensins II and III in spontaneously hypertensive rats.

The acute effects of intracerebroventricular (i.c.v.) administration of angiotensin III (ANG III) on blood pressure (BP) and renal function were investigated in spontaneously hypertensive rats (SHR, n = 31) and Wistar-Kyoto (WKY) normotensive rats (n = 6). ANG II was also administered to the same rats for comparison of its renal effect. BP and renal clearance responses were measured before and during ANG injections. The results showed that i.c.v. injections of 1, 5 and 50 pmol of ANG III did not significantly alter BP in SHR, but a high dose of ANG III (50 pmol) caused a vasopressor effect (7 +/- 4 mmHg) in WKY rats. There were significant increases in renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow, absolute and fractional excretions of sodium and potassium, osmolar clearance and free water reabsorption rate following i.c.v. administration of ANG III in both SHR and WKY rats. However, the enhancement in renal responsiveness to ANG III was greater in SHR than in the WKY group. At 5 pmol of ANG III, the peak increases in GFR (96 +/- 23%), diuresis (316 +/- 102%) and natriuresis (712 +/- 281%) in SHR were significantly greater than those in WKY rats (40 +/- 13%, 152 +/- 89%, 229 +/- 130%, resp.). The renal effect of central ANG III was blocked by i.c.v. ANG III antagonist, [Ile7]-ANG III, but was enhanced by bestatin, an ANG III metabolic enzyme inhibitor. I.c.v. administration of ANG II at 50 pmol increased BP in both SHR and WKY rats (14 +/- 3 and 10 +/- 3 mmHg, resp.). Greater diuretic and natriuretic responses to ANG II were also noted in SHR than in WKY rats. These results indicate that central ANG III is as active as ANG II in modulating renal function. Furthermore, the enhanced renal response to i.c.v. ANGs II and III in SHR suggests a hyperactive central RAS implicated in BP and body fluid regulation in this genetic hypertensive strain.     

Genetic hypertension and increased susceptibility to cerebral ischemia.

A review of the sensitivity of genetically hypertensive rats to cerebral ischemia was presented together with original data describing the systematic comparison of the effects of focal ischemia (permanent and temporary with reperfusion) performed in hypertensive and normotensive rats (i.e., blood pressures verified in conscious instrumented rats). Microsurgical techniques were used to isolate and occlude the middle cerebral artery (MCAO) of spontaneously hypertensive (SHR), Sprague-Dawley (SD) and Wistar Kyoto (WKY) rats at the level of the inferior cerebral vein. Following permanent (24 h) MCAO, persistent and similar decreases in local microvascular perfusion (i.e., to 15.6 +/- 1.7% of pre-MCAO levels) were verified in the primary ischemic zone of the cortex for all strains using Laser-Doppler flowmetry. A contralateral hemiplegia that occurred following MCAO, evidenced by forelimb flexion and muscle weakness, was greater in SHR (neurological grade = 2.0 +/- 0.1) than SD (1.0 +/- 0.4) or WKY (0.7 +/- 0.4) rats (N = 7-9, p less than 0.05). SHR also exhibited sensory motor deficits following MCAO compared to sham-operation, with decreased normal placement response of the hindlimb (% normal = 20 vs. 83, N = 23-30, p decreased rota-rod (41 +/- 7 vs. 126 +/- 19 on rod, N = 10-15, p less than 0.05) and balance beam (25 +/- 5 vs. 116 +/- 29 s on beam, N = 5-7, p less than 0.05) performance. However, an index of general motor activity was not affected by permanent MCAO. Triphenyltetrazolium-stained forebrain tissue analyzed by planimetry revealed a significantly larger and more consistent cortical infarction in SHR (hemispheric infarction = 27.9 +/- 1.5%) compared to SD (15.4 +/- 4.1%) and WKY (4.0 +/- 2.4%) rats (N = 7-9, p less than 0.05), occupying predominantly the frontal and parietal areas. Also, a significant degree of ipsilateral hemispheric swelling (4.6 +/- 0.9%, N = 7-9, p less than 0.05) and increased brain water content (78.4 +/- 0.3% to 80.4 +/- 0.2%, N = 8-9, p less than 0.05) was identified in SHR that was not observed in SD or WKY rats. A novel model of temporary MCAO also was evaluated in the hypertensive and normotensive rat strains. Initially, the effect of increasing MCAO-time followed by 24 h reperfusion in SHR was studied. During temporary MCAO (20 to 300 min), persistent and stable decreases in local microvascular perfusion (i.e., to 15-20% of pre-MCAO levels) were verified in the primary ischemic zones of the cortex.(ABSTRACT TRUNCATED AT 400 WORDS)     

Diminished beta-adrenoceptor-mediated relaxation of femoral arteries from young spontaneously hypertensive rats

A beta-adrenoceptor agonist, norepinephrine (NE)-induced relaxation in the presence of an alpha-adrenoceptor antagonist and indomethacin was investigated in isolated femoral arteries from 5-week-old Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). NE elicited endothelium-dependent and -independent relaxation in WKY. In endothelium-intact WKY artery, the NE-induced relaxation was reduced by nitro L-arginine (L-NA) and methylene blue. The residual response to NE in the presence of L-NA was further reduced by tetraethylammonium (TEA). Glibenclamide attenuated the NE-induced, endothelium-independent relaxation in WKY. In SHR, on the other hand, the relaxation to NE was solely endothelium-independent, unaffected by a combination of L-NA and TEA and inhibited by glibenclamide. The relaxation in response to NE in SHR was less than that in WKY, regardless of the presence and absence of endothelial cells. When WKY and SHR were treated for 10 days with captopril, the response to NE was increased not only in WKY but also in SHR. The relaxation in captopril-treated SHR consisted of endothelium-dependent and -independent components. The former was attenuated by L-NA and to a greater extent by TEA with L-NA. Sodium nitroprusside- and forskolin-induced, endothelium-independent relaxations in SHR were not significantly different from those in WKY. Captopril did not affect the response to these drugs. The present results indicate that the relaxation to NE is in part mediated by NO and a vasorelaxing factor distinct from NO in WKY but not in SHR. It is suggested that NE-induced, endothelium-independent relaxation in both groups is in part mediated by ATP-sensitive K+ channels. It is also suggested that in SHR, captopril increases the response to NE through increases in endothelial production of NO and the non-NO vasorelaxing factor.     

Increased noradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder--the spontaneously hypertensive rat

Spontaneously hypertensive rats (SHR) are used as a model for attention-deficit/hyperactivity disorder (ADHD) since SHR are hyperactive and they show defective sustained attention in behavioral tasks. Using an in vitro superfusion technique we showed that norepinephrine (NE) release from prefrontal cortex slices of SHR was not different from that of their Wistar-Kyoto (WKY) control rats when stimulated either electrically or by exposure to buffer containing 25 mM K(+). The monoamine vesicle transporter is, therefore, unlikely to be responsible for the deficiency in DA observed in SHR, since, in contrast to DA, vesicle stores of NE do not appear to be depleted in SHR. In addition, alpha(2)-adrenoceptor mediated inhibition of NE release was reduced in SHR, suggesting that autoreceptor function was deficient in prefrontal cortex of SHR. So, while DA neurotransmission appears to be down-regulated in SHR, the NE system appears to be under less inhibitory control than in WKY suggesting hypodopaminergic and hypernoradrenergic activity in prefrontal cortex of SHR. These findings are consistent with the hypothesis that the behavioral disturbances of ADHD are the result of an imbalance between NE and DA systems in the prefrontal cortex, with inhibitory DA activity being decreased and NE activity increased relative to controls.     

Association between sympathetic nerve activity and cerebrovascular protection in young spontaneously hypertensive rats

The purpose of this study was to determine resting and maximal superior cervical sympathetic nerve activity in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) at five and ten weeks of age as hypertension was developing. Basal cervical sympathetic nerve activity (SNA) of five week SHR was 58 +/- 3 muv* which was significantly elevated over age-matched WKY (SNA = 30 +/- 4 muv, *p less than 0.001) and ten week SHR (SNA = 30 +/- 4 muv, *p less than 0.001) as well as ten week WKY (SNA = 24 +/- 4 muv, *p less than 0.001). Thus, during basal conditions five week SHR nerve traffic was approximately two times that found in age-matched WKY as well as in ten week SHR and WKY. The peak sympathetic nerve activity in response to rapid hemorrhage in five week SHR (215 +/- 16 muv*) was significantly elevated over the maximal response of WKY (140 +/- 23 muv) (*p less than 0.02). Ten week SHR also reached a maximal sympathetic nerve activity (187 +/- 28 muv*) that was significantly elevated over WKY (100 +/- 15 muv) (*p less than 0.02). Thus, both five and ten week SHR had a greater capacity for elevated nerve activity following rapid hemorrhage than age-matched WKY. The elevation in resting cervical sympathetic activity in five week SHR, and the elevated capacity for sympathetic neural response in both five as well as ten week SHR, are consistent with a central nervous system abnormality in SHR that could relate to the previously described protective influence of sympathetic nerves on SHR cerebral blood vessels as hypertension is developing.     

Alpha2-adrenoceptor-mediated restraint of norepinephrine synthesis, release, and turnover during immobilization in rats

Stress-related release of norepinephrine (NE) in the brain and periphery probably underlies several neuroendocrine and neurocirculatory responses. NE might influence its own synthesis, release, and turnover, by negative feedback regulation via alpha2-adrenoceptors. We examined central and peripheral noradrenergic function by measuring concentrations of NE, dihydroxyphenylglycol (DHPG), and dihydroxyphenylacetic acid (DOPAC) in hypothalamic paraventricular nucleus (PVN) microdialysate and arterial plasma simultaneously during immobilization (IMMO) in conscious rats. The alpha2-adrenoceptor antagonist yohimbine (YOH) was injected i.p. or perfused locally into the PVN via the microdialysis probe. The i.p. YOH increased plasma NE, epinephrine (EPI), DHPG, dihydroxyphenylalanine, and DOPAC levels by 4.3, 7.3, 2.5, 0.6 and 1.8-fold and PVN microdialysate NE, DHPG, and DOPAC by 1. 2, 0.6 and 0.5-fold. The i.p. YOH also enhanced effects of IMMO on plasma and microdialysate NE, DHPG, and DOPAC. YOH delivered via the PVN microdialysis probe did not affect microdialysate or plasma levels of the analytes at baseline and only slightly augmented microdialysate NE responses to IMMO. The results indicate that alpha2-adrenoceptors tonically restrain NE synthesis, release, and turnover in sympathetic nerves and limit IMMO-induced peripheral noradrenergic activation. In the PVN, alpha2-adrenoceptors do not appear to contribute to these processes tonically and exert relatively little restraint on IMMO-induced local noradrenergic activation.     

The effect of alpha-adrenergic receptor blockers prazosin and yohimbine on cerebral metabolism and biogenic amine content of traumatized brain.

Widespread decrease in local cerebral glucose utilization (LCGU) previously shown to occur 3 days after a local freezing lesion was interpreted as reflecting a depression of functional activity in the affected areas. In parallel experiments, cortical norepinephrine (NE) content of traumatized brain was found to be decreased. The effects of prazosin (PZ), an alpha 1-adrenergic receptor blocker, and yohimbine (YOH), an alpha 2-blocker, on glucose use and biogenic amine content of lesioned rat brain were studied to determine if the changes in the noradrenergic system associated with injury are of functional importance, to identify the receptors that may be involved in mediating the action of NE in injured brain, and to look for evidence of interaction between the noradrenergic and the serotonergic systems in traumatized brain. PZ (1 mg/kg) given 30 min before the lesion ameliorated the subsequent metabolic cortical depression seen in untreated animals. PZ given for 3 days starting before the lesion (3 mg/kg/day) was also effective in normalizing LCGU in areas where it was depressed by lesioning, despite the fact that this regimen induced significant global decrease in LCGU in normal animals. Once cortical metabolic depression had developed 3 days after the lesion, it could not be modified by PZ. YOH was less effective than PZ and was so only when given for 3 days (22.5 mg/kg/day in three divided doses). PZ (3 mg/kg/day in three divided doses) slightly but significantly decreased the accumulation of the serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid in the traumatized hemisphere. These results provide evidence that blockage of alpha 1-adrenergic receptors prevents the development of cortical dysfunction associated with brain trauma. This implies that the noradrenergic system plays a role in the functional consequences of injury and that this effect is, at least in part, mediated by alpha 1-adrenergic receptors. Furthermore, alpha 1-adrenergic receptor blockage appears to modulate cortical turnover of 5-HT, previously also implicated in functional consequences of brain injury. The data are compatible with inhibitory effects of NE in the cortex and suggest a potential of alpha 1-adrenergic blockage in development of novel therapeutic approaches to brain injury.     

Differential effects of naloxone on the release of neurohypophysial hormones in normotensive and spontaneously hypertensive rats

The hypothalamo-neurohypophysial system is altered in the spontaneously hypertensive rat (SHR). We hypothesized that an aberrant regulation of vasopressin (VP) and oxytocin (OT) release by endogenous opioid peptides alters this neuroendocrine system in the SHR. Concentrations of the neurohypophysial hormones in plasma and the pituitary were measured in 17-week-old SHRs and two strains of normotensive controls. Wistar Kyoto (WKY) and Sprague-Dawley rats. Animals were decapitated 20 min after s.c. injection of saline (1 ml/kg) or naloxone hydrochloride (1 or 10 mg/kg). In addition, neurohypophysial hormones excreted during the day (08.00-17.30 h) and night (17.30-08.00 h) were determined in urine from 16-week-old animals kept in metabolic cages for 5 days. VP at extrahypothalamic sites was also measured as [VP] in acid extracts of the subfornical organ area, hippocampal commissure-fornix and choroid plexus. Hormones were quantified by radioimmunoassay. The pituitary content, plasma concentration, and urinary excretion of OT were reduced (P less than 0.05) in SHRs, whereas VP content was increased (P less than 0.05) in the pituitary and plasma, but unchanged in urine, of hypertensive animals. In extrahypothalamic tissues, [VP] in the hippocampal commissure-fornix was increased in the SHR. Naloxone elevated (P less than 0.05) the plasma concentration of OT in WKY animals and VP in SHRs. Neither [VP] nor [OT] in plasma was changed by naloxone in Sprague-Dawley rats. Pituitary stores of the neurohypophysial hormones were not altered by naloxone in either hypertensive or normotensive rats. In conclusion, endogenous opioid peptides tonically inhibit OT release in WKY rats, whereas VP release is decreased by opioid peptides in SHRs, 16-17 weeks of age. The neuromodulatory role of opioid peptides in the release of neurohypophysial hormones appears to be altered in the SHR such that VP release is suppressed and OT release is augmented.     

Sympathetic nerve activity: a link to stroke?

Spontaneously hypertensive rats (SHR) have been shown to have an increased capacity for superior cervical sympathetic nerve activity which may protect against stroke (Mueller et al: Stroke 13: 115, 1982). Sympathetic nerve activity has never been examined in the stroke-prone substrain of SHR (SP). In this study we measured superior cervical sympathetic nerve activity during rest and during a maximal sympathetic response in SHR, SP, and their normotensive controls, Wistar-Kyoto (WKY). The resting superior cervical sympathetic nerve activity of SP was significantly less than SHR (p less than 0.02) but not different from WKY. During central ischemia, used to induce maximal sympathetic response, the increase in SP sympathetic nerve activity was significantly less than SHR (p less than 0.001) but was not different from WKY. This diminished capacity for elevated superior cervical sympathetic nerve activity in stroke-prone SHR may relate to their increased predisposition to stroke because sympathetic hyperactivity cannot protect cerebral vessels during acute hypertension.     

Norepinephrine and serotonin in central autonomic nuclei in the spontaneously hypertensive rat and two normotensive control rats

Neurochemical analysis of norepinephrine and serotonin with high performance liquid chromatography with electrochemical detection (LCEC) in several microdissected central autonomic nuclei of 4 week old and 16 week old spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and control normotensive Wistar rats (WIS), revealed some differences among these strains, but only one change that correlated with the hypertensive state. Norepinephrine levels in the 4 week old SHR were greater in the parabrachial nuclei and the dorsal motor nucleus of X than in the WKY, but levels in the WIS normotensive also were greater than in the WKY, and equalled levels in the SHR. In the 16 week old rats, no difference was noted between NE levels in the SHR and WKY strains, but levels in the locus coeruleus and parabrachial nuclei of the WIS were greater than in both the SHR and WKY. Serotonin levels in the 4 week old SHR and WKY rats did not differ, while levels in the paraventricular nucleus, locus coeruleus, parabrachial nuclei, and medullary raphe nuclei of the WIS rat were greater than one or both of these inbred strains. In the dorsal motor nucleus of X in 16 week old rats, serotonin levels were greater in the SHR than in either the WKY or WIS controls, suggesting one possible transmitter action that should be explored further for its potential relationship to the hypertensive state.(ABSTRACT TRUNCATED AT 250 WORDS)     

Two genetic rat models of arterial hypertension show different mechanisms by which adult hippocampal neurogenesis is increased

To investigate strain differences and genetic effects on different aspects of neurogenesis, we compared young adult spontaneously hypertensive/hyperactive rats (SHR) and stroke-prone SHR (SHRSP) with the genetic control WKY strain. In both hypertensive/hyperactive strains, the number of newly generated neurons and the number of lineage-determined cells as detected by doublecortin (DCX) immunoreactivity were significantly increased. SHRSP had significantly more DCX-positive cells than the other groups. Whereas cell proliferation as measured by Ki67 expression was increased in SHR, we found no difference between SHRSP and WKY. In summary, we found increased net neurogenesis in both hypertensive/hyperactive strains. However, this phenotype was based on different mechanisms in the course of neuronal development: cell proliferation in SHR and cell survival in SHRSP. In addition, we found that within strains the number of DCX-positive cells was not predictive of the net number of new neurons and that the increase in neurogenesis was not significantly correlated with blood pressure in SHR and WKY. However, in both SHR and SHRSP, cell proliferation showed an association with blood pressure recordings.     

Sympathetic inhibition and attenuation of spontaneous hypertension by PVN lesions in rats

To determine whether the paraventricular nucleus (PVN) contributes to the development of hypertension in spontaneously hypertensive rats (SHR), we compared cardiovascular responses to ganglionic blockade with hexamethonium or vasopressin antagonism with dPVAVP in sham-operated or PVN lesioned SHR and Wistar-Kyoto rats (WKY). Lesions were produced electrolytically when the rats were 5 weeks old. During the next 3 weeks, tail-cuff measurements showed that the development of hypertension in SHR was inhibited, while systolic pressure in WKY was unaffected. Mean pressures recorded directly from the femoral artery at 8 weeks of age were lower in lesioned than in sham-operated SHR (141 +/- 5 vs 110 +/- 3 mm Hg, P less than 0.05), but did not differ in corresponding WKY groups (110 +/- 4 vs 112 +/- 5 mm Hg). Depressor responses to ganglionic blockade induced by i.v. injection of hexamethonium (25 mg/kg) were significantly larger in sham-operated than in lesioned SHR (-41 +/- 4% vs -28 +/- 3%, P less than 0.05). By contrast, vasopressin antagonism with dPVAVP did not alter blood pressure in all rat groups. In 24-h urine samples, excretion of vasopressin was unaffected, but that of norepinephrine was significantly reduced in lesioned SHR. These findings suggest that the PVN contributes to the development of spontaneous hypertension by sympathetic activation without increasing vasopressin secretion.     

Role of central serotonergic systems in the development of hypertension in spontaneously hypertensive rats.

The spontaneously hypertensive rat (SHR) maintained a higher blood pressure level at and after 8 weeks old than the genetical control Wistar-Kyoto strain (WKY). At 10 weeks old, the turnover rate of 5-hydroxytryptamine (5-HT) was lower in the hypothalamus of SHR than of WKY. Following portacaval anastomosis (PCA) in SHR, the blood pressure was significantly decreased in comparison with that of sham-operated control SHR. In WKY, no significant change in the blood pressure response was observed. PCA treatment increased the 5-HT turnover including that in SHR. If the SHR with PCA was bred with food pellets containing higher concentrations of leucine and isoleucine, the blood pressure increased and the 5-HT turnover decreased. These findings suggest that the central serotonergic system is involved in the development of hypertension.     

Angiotensin II binding sites in the superior cervical ganglia of spontaneously hypertensive and Wistar-Kyoto rats after preganglionic denervation

Angiotensin II binding was higher in superior cervical ganglia of adult spontaneously hypertensive rats (SHR) when compared to ganglia of Wistar-Kyoto (WKY) rats (571 +/- 29 and 375 +/- 9 fmol/mg protein, SHR and WKY, respectively, P less than 0.05). Unilateral preganglionic denervation reduced binding site density in ganglia of WKY (-39%, P less than 0.05 vs sham operated ganglia in WKY), and the decrease of binding sites was larger in SHR (-59%, P less than 0.01, operated vs sham operated ganglia in SHR). Part of the binding sites in the superior cervical ganglia may be present in or be associated to preganglionic nerves, and the number of these sites is higher in SHR.     

Central amygdaloid nucleus lesion attenuates exaggerated hemodynamic responses to noise stress in the spontaneously hypertensive rat

The regional hemodynamic basis of the cardiovascular response to acute noise stress in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats and the role of the central amygdaloid nucleus in mediating this response was investigated. Using the pulsed Doppler flow probe technique it was determined that in response to noise, SHR exhibit a significantly greater percent increase in renal and mesenteric vascular resistance than WKY. Vascular responses in the hindquarter were similar in both groups. Bilateral lesion of the central amygdaloid nucleus or its output pathways to the brainstem decreased the cardiovascular response to noise in both SHR and WKY, with SHR and WKY lesion rats responding similarly. The central amygdaloid nucleus appears to participate in the cardiovascular response to acute noise stress in SHR and WKY. Although other structures in the limbic system network may contribute to integration of responses that involve the amygdala the present data suggest that this structure may play a central role in mediating the exaggerated cardiovascular responsiveness of SHR to environmental stress.     

Increased expression of alpha 1-adrenergic receptors in the hypothalamus of spontaneously hypertensive rats

The specificity and molecular weights of alpha 1-adrenergic receptors in various tissues of spontaneously hypertensive (SH) rat were compared with normotensive controls (Wistar-Kyoto; WKY) with the use of [125I]HEAT and [125I]azidoprazosin, specific alpha 1-adrenergic receptor antagonists. Binding of [125I]HEAT to membranes prepared from SH rat brain hypothalamus was significantly higher, due to a 75% increase in the Bmax, than the WKY control. In contrast, the Bmax and Kd of [125I]HEAT binding to brainstem and liver membranes from SH rats were not significantly different from those of WKY controls. Competition-inhibition data suggested similar pharmacological specificity with potencies in the order of prazosin greater than yohimbine greater than propranolol for both WKY and SH rat membranes prepared from liver, hypothalamus, brainstem and neuronal cultures. Photoaffinity labeling of alpha 1-adrenergic receptors from hypothalamus, brainstem and neuronal cultures using [125I]azidoprazosin followed by SDS-PAGE and autoradiography showed the presence of one major band with a molecular weight (MW) of 105,000 Da for both WKY and SH rats. In contrast, labeling of liver alpha 1-adrenergic receptors revealed one major band with a MW of 60,000 Da. Quantitation of the 105,000-Da band from SH rat hypothalamic membranes demonstrated a 52% higher intensity compared with WKY controls. Neuronal cultures prepared from 1-day-old SH rats showed a similarly greater intensity of the 105,000-Da band compared with WKY controls.(ABSTRACT TRUNCATED AT 250 WORDS)