Enhanced serotonin-mediated responses in the nucleus tractus solitarius of spontaneously hypertensive rats

Previous studies have demonstrated that injection of serotonin into the nucleus tractus solitarius (NTS) elicits hypotension and bradycardia in rats. The present study sought to further characterize this response and to examine the role of serotonergic mechanisms in the NTS in cardiovascular regulation in spontaneously hypertensive (SHR) rats. Injections of picomole amounts of serotonin into the NTS of chloralose-anesthetized normotensive Sprague-Dawley (S-D) or Wistar-Kyoto (WKY) rats produced hypotension and bradycardia that were eliminated by prior injection into the NTS of the selective 5HT(2) antagonist sarpogrelate. Bilateral injection of sarpogrelate did not alter blood pressure or reflex changes in heart rate in response to phenylephrine-induced increases in blood pressure or nitroprusside-induced decreases in blood pressure. In SHR rats, the depressor response produced by injection of serotonin into the NTS was markedly larger than in WKY rats, and was larger than depressor responses previously reported for other excitatory substances injected into the NTS. In SHR rats bilateral injection of sarpogrelate produced an increase in blood pressure, although it did not alter baroreceptor-evoked changes in heart rate. These results provide further support for the hypothesis that stimulation of 5HT(2) receptors in the NTS contributes to cardiovascular regulation independent of the baroreceptor reflex. Furthermore, this serotonergic system is altered in SHR rats, apparently acting tonically to reduce blood pressure.     

Cardiovascular responses to blockade of GABA synthesis in the hypothalamus of the spontaneously hypertensive rat

Previous studies have suggested that a decreased inhibitory input onto neurons within the posterior hypothalamus (PH), a known pressor area, may contribute to hypertension in the spontaneously hypertensive rat (SHR). Recent experiments from this laboratory have shown that neurons in the PH of the SHR have an altered and elevated discharge frequency compared to those in the normotensive rat. In addition, biochemical studies have reported that there is a decreased concentration of the inhibitory neurotransmitter, GABA, in the hypothalamus of the SHR. The objective of the present study was to assess any variations in GABAergic modulation of cardiovascular activity in SHRs compared to normotensive Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats. Arterial pressure and heart rate responses to microinjections of the GABA synthesis inhibitor 3-mercaptopropionic acid (3-MP) into the posterior hypothalamic area of anesthetized young (6–8 weeks) and mature (11–16 weeks) hypertensive and normotensive rats were recorded. Microinjection of 3-MP elicited increases in arterial pressure of 17.4 ± 3.9 mmHg, 18.1 ± 7.8 mmHg, 16.9 ± 6.4 mmHg, and 10.4 ± 3.5 mmHg in the mature WKY, mature SD, young WKY, and young SHR, respectively. In addition, heart rate was elevated by 33.2 ± 21.9 beats/min, 70.0 ± 25.3 beats/min, 56.3 ± 15.0 beats/min and, 45.9 ± 10 beats/min in the mature WKY, adult SD, young WKY, and young SHR groups, respectively. In contrast, microinjection of 3-MP into the posterior hypothalamus of adult SHRs produced no significant change in arterial pressure (−5.0 ± 1.8 mmHg) or heart rate (+5.3 ± 6.1 beats/min). In three of the adult SHRs, cardiovascular responses to electrical stimulation in the PH were compared to responses elicited by microinjection of 3-MP into the same PH site. Electrical stimulation produced large increases in both arterial pressure and heart rate; however, microinjection of 3-MP produced no significant changes in cardiovascular activity. These results indicate that spontaneously hypertensive rats have a deficiency in the tonic GABAergic input onto posterior hypothalamic neurons. This alteration may contribute to the maintenance of the elevated blood pressure in spontaneously hypertensive rats.     

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.     

Specific inflammatory condition in nucleus tractus solitarii of the SHR: novel insight for neurogenic hypertension?

Human essential hypertension is a complex polygenic trait with underlying genetic components that remain unknown. Since the brainstem structure--the nucleus of the solitary tract (NTS)--is a pivotal region for regulating the set-point of arterial pressure, we proposed a role for it in the development of primary hypertension. Using microarray and real-time RT-PCR, we have recently identified that some pro-inflammatory molecules, such as junctional adhesion molecule-1 (JAM-1; a leukocyte/platelet adhesion molecule), were over expressed in endothelial cells in the NTS of an animal model of human essential hypertension--the spontaneously hypertensive rat (SHR) compared to normotensive Wistar Kyoto rats (WKY). Adenoviral mediated over expression of JAM-1 in NTS of WKY rats produced both hypertension and localized leukocyte adherence to the microvasculature. With a known effect of leukocyte adhesion causing cytokine release, we predicted differences in the level of gene expression of cytokines in the NTS of SHR relative to WKY. Gene expression of monocyte chemoattractant protein-1 (MCP-1) was higher in the NTS of SHR while inter-leukin-6 (IL-6) was lower in the NTS of SHR compared to the WKY. Because both inflammatory molecules are known to affect neural functions, our data suggest that the microvasculature of NTS of the SHR exhibits a specific inflammatory state. We propose a new hypothesis that as a consequence of enhanced expression of leukocyte adhesion molecules within the microvasculature of NTS there is a specific inflammatory response that leads to cardiovascular autonomic dysfunction contributing to neurogenic hypertension.     

Gene expression profiles of major cytokines in the nucleus tractus solitarii of the spontaneously hypertensive rat

Since the nucleus of the solitary tract (NTS) is a pivotal region for regulating the set-point of arterial pressure, we proposed a role for it in the development of neurogenic hypertension. Recent studies have suggested that pro-inflammatory molecules are highly expressed in the NTS of an animal model of human essential hypertension--the spontaneously hypertensive rat (SHR), compared to normotensive Wistar-Kyoto rat (WKY). Based on this evidence, we hypothesized that inflammatory mediators such as cytokines are up-regulated in the hypertensive NTS. In the present study, we have assessed the level of gene expression of some cytokines in the NTS of SHR compared to WKY. In addition, for further confirmation of abnormal inflammatory condition within the NTS of SHR, we identified gene expression levels of an inflammatory marker, glycoprotein-39 (gp39) precursor, which is homologous to chitinase 3-like protein 1, human cartilage-gp39 or YKL40. The NTS was micro-dissected from 15-week-old male SHR and WKY rats. Total RNA was extracted and quantitative RT-PCR was performed. Gene expression of gp39 precursor and monocyte chemoattractant protein-1 were higher in the NTS of SHR while inter-leukin-6 was lower in the NTS of SHR compared to the WKY. In contrast, there were no significant differences in the expression of other cytokines including: inter-leukin-1 beta, tumor necrosis factor-alpha and transforming growth factor beta 1. These data together with our previous published finding of an over expression of junctional adhesion molecule-1 suggest that the NTS of the SHR exhibits a specific inflammatory state.     

The blood-brain barrier in young spontaneously hypertensive rats

It has been shown that the blood-brain barrier (BBB) of chronically hypertensive adult spontaneously hypertensive rats (SHR) is less susceptible to disruption during acute superimposed hypertension than normotensive controls. The purpose of this study was to determine if the BBB of young SHR, not yet markedly hypertensive, was similarly protected during superimposed acute hypertension. Spontaneously hypertensive rats (n = 22) and normotensive Wistar-Kyoto rats (WKY) (n = 23) 4–5 weeks of age were anesthetized with secobarbital sodium (50 mg/kg) intraperitoneally and acute hypertension was produced by an intravenous injection of norepinephrine (75 μg). Permeability of the BBB was studied with radioactive iodine serum albumin (RISA) injected intravenously. The ratio of brain-to-blood RISA × 100 was used as an index of permeability of the BBB expressed as % protein transfer. In WKY exposed to acute hypertension mean arterial pressure increased by 52 ± 2 mmHg and in SHR the increase was 49 ± 3 mmHg. The protein transfer of the cerebral hemispheres was 1.17 ± 0.30% in WKY and 0.90 ± 0.20% in SHR ( P < 0.40). These data indicate that BBB protein transfer during acute superimposed hypertension does not differ between young SHR and WKY. Thus, the reduced susceptibility to BBB disruption in chronically hypertensive adult SHR is not present in young SHR, making them as susceptible as WKY to cerebral complications related to protein transfer during acute hypertension.     

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.     

Is neurogenic hypertension related to vascular inflammation of the brainstem?

Essential hypertension is idiopathic although it is accepted as a complex polygenic trait with underlying genetic components, which remain unknown. Our supposition is that hypertension involves activation of the sympathetic nervous system. One pivotal region controlling arterial pressure set point is nucleus tractus solitarii (NTS). We recently identified that pro-inflammatory molecules, such as junctional adhesion molecule-1 (JAM-1), were over expressed in endothelial cells of the microvasculature supplying the NTS in an animal model of human hypertension (the spontaneously hypertensive rat) compared to normotensive Wistar-Kyoto rats (WKY). Over expression of JAM-1 in NTS of WKY rats was pro-hypertensive and induced leukocyte adherence to the microvasculature. Since leukocyte adhesion causes cytokine release, we found expression of monocyte chemoattractant protein-1 (MCP-1) was higher in the NTS of SHR while inter-leukin-6 (IL-6) was lower compared to the WKY rat. Inflammation of the brainstem microvasculature may increase vascular resistance within the brainstem. High brainstem vascular resistance and its inflammation may release pathological paracrine signaling molecules affecting central neural cardiovascular activity conducive to neurogenic hypertension.     

Localization of vasopressin-neurophysin and norepinephrine in the supraoptic nucleus of spontaneously hypertensive rats

Histological analysis of the catecholaminergic innervation of vasopressin neurons in the supraoptic nucleus (SON) was performed using catecholamine histofluorescence and immunocytochemistry of vasopressin specific neurophysin (VP-NP) in order to determine if spontaneously hypertensive rats (SHR) demonstrate alterations in the relationship between these two types of chemically defined neurons. Chronically hypertensive SHRs showed an increased density of catecholamine fluorescence particularly in the dorsal part of the SON in comparison to age-matched, normotensive, Wistar-Kyoto (WKY) rats, but not in comparison to age-matched Wistar rats. In addition, there was an increase in the area of distribution of VP-NP immunopositive neurons such that they extended into the dorsal portion of the nucleus in the SHR compared to the WKY. Comparator bridge analysis of immunocytochemical staining and catecholamine histofluorescence revealed a precise overlap of the two patterns in SHR. Thus, the more extensive distribution of catecholamine fluorescence in the dorsal SON in the SHR compared to WKY paralleled the more extensive distribution of VP neurons in this region. Quantitative analysis of the relative percentage of SON neurons which were VP-NP positive indicated that the increased representation of VP-NP positive neurons in the dorsal portion of the nucleus reflected a greater distribution of the VP-NP cell population throughout the SON rather than an increase in the number of VP-NP neurons in the SHR. In young SHRs (5 weeks old) the catecholamine fluorescence pattern in the SON was considerably smaller than that observed in older SHRs. This low density pattern, however, was comparable to that observed in young WKYs. Thus, the catecholamine fluorescence in the SON apparently increases in the SHR in parallel with the development of the hypertension. This observation and the finding of comparable catecholamine fluorescence in Wistars and SHRs suggest that the altered catecholamine innervation of VP neurons observed in chronically hypertensive SHRs is not causal to the hypertension but may reflect a response to the elevated blood pressure. A marked increase in the catecholamine innervation of cerebral arteries was also noted.     

Paramedian reticular nucleus--sympathetic inhibition in spontaneously hypertensive rats

The cardiovascular reactivity of various areas in the medulla related to sympathetic or parasympathetic activation, or to sympathetic inhibition, was compared in spontaneously hypertensive rats (SHR) and in normotensive rats Wistar-Kyoto (WKY) or Sprague-Dawley (SD). In SHR, which has an elevated resting systemic arterial blood pressure (SAP), the sympathetic pressor responses elicited from electrical stimulation of the dorsomedial medulla (DMM), parvocellular lateral nucleus (PVC) or ventrolateral medulla (VLM) were more profound than those in WKY and SD. The depressor and bradycardia responses elicited from electrical stimulation of the paramedian reticular nucleus (PRN) (which exerts both sympathetic and parasympathetic inhibitions) or from the area of the solitary nucleus/dorsomotor nucleus of vagus (NTS/DMV) (where stimulation leads to both parasympathetic activation and sympathetic inhibition) were also more intensive in SHR than in WKY and SD. The elicited pressor and depressor responses, however, were not significantly different between WKY and SD. Our results are consistent with previous findings (15) that in SHR an increased sympathetic activity of the pressor areas of medulla contributes to the pathogenesis of hypertension. Sympathetic inhibition (PRN and NTS/DMV areas) and parasympathetic activation (NTS/DMV area) from these areas, however, may not be critically involved.     

Autonomic and cardiovascular effects of corticotropin-releasing factor in the spontaneously hypertensive rat

Corticotropin-releasing factor (CRF) administered intracerebroventricularly (i.c.v.) produced a greater increase of plasma epinephrine and glucose concentrations in spontaneously hypertensive rats (SHR) than in Wistar-Kyoto (WKY) or Sprague-Dawley (SD) rats. In contrast, CRF given i.c.v. produced significant elevations of mean arterial pressure (MAP) and heart rate (HR) in WKY and SD rats, but not in SHRs. To determine whether the prominent rise of plasma epinephrine levels following CRF administration to SHRs was a unique response to this peptide, two other stimuli for epinephrine secretion were evaluated, i.e. bombesin given i.c.v., and insulin given intravenously (i.v.). In contrast to the apparent enhanced responsiveness of the SHR to CRF, plasma epinephrine levels following either bombesin or insulin administration were similar in SHR, WKY and SD rats. These results demonstrate that the adrenomedullary response to CRF administration in the SHR is of greater magnitude than in WKY or SD rats. In an effort to identify the mechanisms responsible for the differential cardiovascular and adrenomedullary responses to CRF in the SHR versus WKY rat, CRF binding studies were performed. No difference in binding affinity of [125I]CRF or CRF receptor number could be identified in brains from SHR and WKY rats. Thus, CRF influences cardiovascular and adrenomedullary functions in a qualitatively dissimilar fashion in SHR and WKY rats. These differences are not secondary to any measurable alteration in CRF receptor affinity and number in SHR and WKY rats.     

Yohimbine-induced alterations of monoamine metabolism in the spontaneously hypertensive rat. I. The peripheral nervous system

The effects of alpha 2 adrenoreceptor blockade with YOH on blood pressure, plasma catecholamines and norepinephrine (NE) stores in kidney, adrenal and spleen of spontaneously hypertensive rats of the Okamoto strain (SHR) and Wistar-Kyoto (WKY) control animals were examined. YOH administration resulted in a significant (p less than 0.001) reduction in arterial pressure in both SHR and WKY. Plasma NE and EPI were significantly (p less than 0.05) elevated by YOH treatment in both SHR and WKY, but SHR exhibited a significantly (p less than 0.05) greater percent increase in plasma NE than WKY. YOH produced significant decreases in splenic NE content in both SHR and WKY but reduced renal NE content in the SHR only. SHR had significantly higher basal renal NE and DA content and fewer NE uptake (3H-desmethylimipramine binding) sites (p less than 0.05) than WKY. Treatment of SHR or WKY with either the alpha 2-adrenergic antagonist, idazoxan, or the alpha 1-antagonist, prazosin, failed to significantly alter renal NE levels from those found after saline injection. The enhanced YOH-induced renal NE depletion in SHR suggests an alteration in the presynaptic control of NE release in the genetically hypertensive rat, however, the effects of YOH in the SHR may be mediated by mechanisms unrelated to alpha 2-adrenergic receptors.     

Enhanced angiotensin-mediated responses in the nucleus tractus solitarii of spontaneously hypertensive rats

Studies using an AT(1) receptor antagonist, losartan, demonstrated that depressor and bradycardic responses to angiotensin II (Ang II) injection into the nucleus tractus solitarii (NTS) are mediated via those receptors. We further characterized Ang II-evoked cardiovascular responses in this nucleus in spontaneously hypertensive rats (SHR) using a new, selective AT(1) receptor antagonist, valsartan. In alpha-chloralose-anesthetized Sprague-Dawley (S-D) rats, Wistar-Kyoto (WKY) rats, and SHR, unilateral injection of Ang II into the NTS decreased arterial pressure (AP) and heart rate (HR). This response was eliminated by preinjection of valsartan. Depressor responses were much greater in SHR than in WKY rats. In normotensive rats, bilateral valsartan injection did not alter baseline AP or HR, or baroreceptor reflex index (BRI) calculated as the maximal change in HR (bpm) divided by phenylephrine- or nitroprusside-induced maximal change in mean AP (mmHg). In SHR, this treatment did not alter baseline HR and BRI, but significantly increased AP. Preinjection of valsartan did not alter injected glutamate effects in any strain. Thus, stimulation of AT(1) receptors within the NTS contributes to cardiovascular regulation independently of the baroreceptor reflex and the glutamatergic system. This angiotensinergic system in SHR acts tonically to reduce AP.     

Increased anti-apoptotic conditions in the nucleus tractus solitarii of spontaneously hypertensive rat

Since the nucleus tractus solitarii (NTS) is a pivotal region for regulating the set-point of arterial pressure, we propose here its role in the development of neurogenic hypertension. Given the findings of recent studies suggesting that the NTS of spontaneously hypertensive rats (SHR) exhibits a specific inflammatory state characterized by leukocyte accumulation within the NTS microvasculature, we hypothesized that gene expression levels of apoptotic factors are altered in the NTS of SHR compared to normotensive Wistar-Kyoto rats (WKY). To test this hypothesis, we used RT(2) Profiler PCR arrays targeting apoptosis-related factors. We found that gene expression of the death receptor Fas (tumor necrosis factor receptor superfamily, member 6) and the cysteine-aspartic acid protease caspase 12 were down-regulated in the NTS of both adult hypertensive and young pre-hypertensive SHR compared to age-matched WKY. On the other hand, an anti-apoptotic factor, neuronal apoptosis inhibitory protein, was highly increased in the NTS of SHR. These results suggest that the NTS of SHR exhibits an anti-apoptotic condition. Furthermore, this profile appears not to be secondary to hypertension. Whether this differential gene expression in the NTS contributes to the hypertensive state of the SHR via alteration of neuronal circuitry regulating cardiovascular autonomic activity awaits elucidation.     

Volume loading hypoalgesia in SHR, WKY and F1 offspring of a SHR × WKY cross

The effects of volume loading on a nociceptive reflex, arterial blood pressure and heart rate were studied in spontaneously hypertensive rats (SHRs), Wistar Kyoto normotensive rats (WKYs) and the F₁ offspring of a SHR × WKY cross. Volume loading resulted in significantly greater inhibition of the tail-flick reflex to painful radiant heat in SHRs compared to WKYs. The F₁ offspring of a SHR × WKY cross showed levels of hypoalgesia to volume loading that were intermediate to those of SHRs and WKYs. There were no differences between these strains in their hypotensive and bradycardic responses to volume loading. These findings are discussed in terms of cardiovascular-somatosensory interactions.     

Functional subdivisions of the nucleus tractus solitarii of the rat as determined by circulatory and respiratory responses to electrical stimulation of the nucleus

We have recently identified two functional subdivisions of the nucleus tractus solitarii (NTS) in the cat: the pressor and apneustic (inspiratory) response zone, and the depressor and apneic (hypopneic) response zone. The presence of such functional subdivisions in the NTS of the rat was explored. The circulatory and respiratory responses to electrical stimulation of a small part of the NTS were surveyed in all regions of the NTS in rats anesthetized with urethane (500 mg/kg, i.p.). A set of depressor, bradycardiac and apneic responses was elicited in the dorsomedial portions, whereas a pressor response with or without an apneic (hypopneic) response was elicited in the ventral and lateral portions. The presence of a difference in the functional subdivisions between spontaneously hypertensive rats (SHR) and normotensive rats (WKY) was also explored. The SHR group showed significantly larger pressor responses than the WKY group (P less than 0.001), despite its higher basal level of arterial blood pressure, but significantly fewer bradycardiac responses (P less than 0.001). This suggests the SHR group is more sensitive in terms of sympathetic vasomotor activity but less sensitive in parasympathetic cardioinhibitory activity. There was no significant difference in the distribution of the pressor and depressor response zones between the two strains.     

Reaction of pial arteries and veins to hypercapnia in hypertensive and normotensive rats

The lumen diameters of the main cortical surface arteries were continuously monitored through a closed cranial window in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). The arterial diameter was significantly smaller in SHR (55 +/- 1 micron) than in WKY (87 +/- 1 micron) during resting conditions as well as during hypercapnic dilatation (87 +/- 2 micron compared to 117 +/- 5 micron). The per cent increase in diameter induced by hypercapnia was larger in SHR (54%) than in WKY (36%), presumably a consequence of the altered vascular wall to lumen ratio. Alpha-adrenoreceptor blockade with yohimbine and phenoxybenzamine had no significant effect on arterial diameter during hypercapnia. The diameters of the largest pial surface veins increased to the same extent in SHR and WKY during hypercapnia (about 10%).     

Ultrastructural studies on catecholaminergic terminals and GABAergic neurons in nucleus tractus solitarius of the rat medulla oblongata

Synaptogenesis of catecholamine (CA) boutons in the nucleus tractus solitarius (NTS) was compared between spontaneously hypertensive (SHR) rats and Wistar-Kyoto (WKY) rats at different ages. On the average, there were about 32 CA varicosities per 2200 μm² area of the NTS in both SHR and WKY rats as revealed by glyoxylic acid fluorescence microscopic (FM) morphometric study. The FM analysis indicated that there were no significant changes in the CA varicosity density between SHR and WKY rats.The CA boutons were labeled with 5-hydroxydopamine and appeared to contain small granular vesicles at the electron microscopic (EM) level. A total of 1402 CA boutons were studied in a 540, 000 μm² area of the NTS. The number of CA boutons involved in synaptic contacts vs the number of total CA boutons was used to obtain synaptic frequency which was taken as an index for synaptogenesis. A reduction of approximately 18% and 14% of synaptogenesis of CA boutons was observed in the NTS of SHR rats at 4 weeks (prehypertensive stage) and 12 weeks (early hypertensive stage) of age respectively, as compared to age-matched WKY rats. No significant difference of synaptogenesis of CA neurons was found between SHR and WKY rats at 16 weeks of age, a stage in which hypertension is well established and maintained in SHR rats. These results suggest that CA neurons with fewer synaptic contacts in the NTS may play a more important role in the initiation than in the maintenance of hypertension in the SHR rats.In addition to CA terminals, there were numerous GABAergic cell bodies in the NTS which were identified by immunocytochemistry using antibodies to the GABA synthesizing enzyme,l-glutamate decar☐ylase (GAD). GABAergic dendrites with GAD-positive reaction were often seen to receive several GAD-negative synapses at EM random profiles. In the text, a viewpoint is thus discussed that emphasizes that a synaptic abnormality of CA terminals with fewer synaptic contacts affecting GABAergic neurons may participate in the pathogenesis of hypertension. However, it remains to be determined as to whether or not there is a direct contact between CA boutons and GABAergic dendrites.     

Effects of aging and chronic arterial hypertension on the cell populations in the neocortex and archicortex of the rat

Summary Quantitative histological techniques were used to evaluate the effects of chronic arterial hypertension on the changes which occur during aging of the cerebral cortex and hippocampus. Normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were killed at 3 or 22–27 months of age. In the cerebral cortex, the numerical density of neurons decreased by 29.7% in aged WKY (mean age: 25.5 months) and by 31.6% in aged SHR (mean age: 23.3 months). The volume density of neuronal cell bodies decreased from 3.54% in young WKY and 3.68% in young SHR to 2.74% in the aged rats of both strains. No significant alterations in the population of cortical neuroglial cells were observed as a result of either aging or hypertension. No differences in the number of capillaries, volume density of blood vessels or number of pericytes were observed among the four experimental groups. The normotensive rats exhibited an increase in the number of venules with age. Aged hypertensive rats had significantly (23.3%) fewer endothelial cells than young SHR, while the 9.1% loss of endothelial cells in aged WKY was not statistically significant. In the CA1 zone of the hippocampus, the number of pyramidal neurons per millimeter decreased by 32.0% in aged (mean age: 25.0 months) WKY and by 34.1% in aged (mean age: 23.0 months) SHR as compared with their corresponding values at 3 months of age. These results indicate that the numerical density of neurons in the neocortex and archicortex decreases by nearly onethird between 3 and 23–25 months of age in both normotensive and hypertensive strains of rats. Chronic hypertension does not significantly alter the apparent loss of neurons from the cerebral cortex and hippocampus with advancing age.Supported by the American Heart Association, Louisiana, Inc.