Modulation of norepinephrine release by galanin in rat medulla oblongata.

Galanin, a 29-amino acid peptide, is widely distributed in both the central and peripheral nervous systems and is colocalized with catecholamines, although its physiological significance remains to be elucidated. In the present study we investigated the regulatory mechanisms of galanin on norepinephrine release in rat medulla oblongata. In slices of medulla oblongata of Sprague-Dawley rats, galanin inhibited the stimulation-evoked [3H]norepinephrine release in a concentration-dependent manner (fractional release ratio during electrical stimulation: control 0.937 +/- 0.043, mean +/- SEM, n = 6; galanin 1 x 10(-7) M 0.501 +/- 0.037, n = 6, p less than 0.05; and galanin 1 x 10(-6) M 0.299 +/- 0.018 n = 6, p less than 0.05). Galanin potentiated inhibition of [3H]norepinephrine release by the alpha 2-agonists (UK 14,304 and clonidine). The blockade of alpha 2-adrenergic receptors by RX 781094 diminished the inhibition of norepinephrine release by galanin. Pretreatment of pertussis toxin, which interferes with the coupling of inhibitory guanosine triphosphate-binding proteins to adenylate cyclase, significantly attenuated the suppressive effects of galanin on norepinephrine release. In slices of medulla oblongata obtained from spontaneously hypertensive rats (SHR), the inhibitory effect of galanin on norepinephrine release was significantly less than in those from age-matched Wistar-Kyoto rats. These results show that galanin might inhibit the stimulation-evoked norepinephrine release in rat medulla oblongata, at least partially mediated by alpha 2-adrenergic receptors and the pertussis toxin-sensitive guanosine triphosphate-binding proteins. Moreover, less suppression of norepinephrine release by galanin in SHR suggests that galanin might be involved in the regulation of central sympathetic nervous activity in hypertension.     

Role of Brain Dopamine Systems in the Development of Hypertension in the Spontaneously Hypertensive Rat

We studied the role of central dopamine in the development of hypertension. Earlier work had shown that depletion of brain dopamine can inhibit the age related rise in blood pressure in spontaneously hypertensive rats (SHR). In an open field test, locomotor activity of Wistar-Kyoto controls was inhibited by haloperidol, apomorphine and sulpiride, but these drugs had less effect in SHR. The stimulation-evoked release of [³H]-dopamine from slices of the striatum of SHR was smaller than that from slices of WKY. The inhibition of the stimulation-evoked release of [³H]-dopamine by quinpirole was greater in SHR than in WKY. The results from the lesion experiments and from the behavioural activity studies would suggest an enhanced release of central dopamine in SHR, which might contribute to the development of hypertension in these animals. However, the in vitro release experiments (and subsequent in vivo microdialysis experiments) do not support such an enhanced release but rather showed decreased release of striatal dopamine in SHR.     

In Vitro Glutamate-Stimulated Release of Dopamine from Nucleus Accumbens Core and Shell of Spontaneously Hypertensive Rats

Spontaneously hypertensive rats (SHR) are used as a model for attention-deficit hyperactivity disorder (ADHD) since SHR display the major symptoms of ADHD (hyperactivity, impulsivity, inablity to sustain attention during behavioral tasks). We previously showed that electrical and/or K⁺-stimulated release of dopamine (DA) from nerve terminals in the prefrontal cortex, nucleus accumbens, and caudate-putamen of SHR was significantly lower than that of Wistar-Kyoto (WKY) control rats. The aim of the present investigation was to determine whether glutamate-stimulated release of DA from nucleus accumbens core and shell of SHR was significantly different from that of WKY. Using an in vitro superfusion technique, we showed that glutamate-stimulated release of [³H]DA from striatal slices is mediated by glutamate activation of AMPA receptors and that glutamate-stimulated release of [³H]DA from nucleus accumbens core and shell of 4–6-week-old SHR and WKY is not significantly different. Glutamate-stimulated release of [³H]DA from SHR shell is significantly lower than SHR core and there is also a tendency for glutamate-stimulated [³H]DA release from SHR shell to be lower than release from WKY shell.     

Modulation of noradrenergic transmission by neuropeptide Y and presynaptic alpha 2-adrenergic receptors in the hypothalamus of spontaneously hypertensive rats.

Neuropeptide Y (NPY) has a wide and specific distribution in the central nervous system, and is colocalized with catecholamines in specific neuronal systems. In this study, in order to investigate the regulatory mechanisms of NPY and presynaptic alpha 2-adrenergic receptors on central noradrenergic transmission in hypertension, we have examined the effects of NPY and the alpha 2-agonist, UK 14,304, on (3H)-noradrenaline (NA) release from hypothalamic slices of spontaneously hypertensive rats (SHR). Electrical stimulation (1 Hz)-evoked (3H)-NA release was significantly greater in the hypothalamic slices of SHR than in those of Wistar Kyoto rats (WKY). NPY and the alpha 2-agonist, UK 14,304, inhibited the stimulation-evoked (3H)-NA release in a dose-related manner. The inhibitory effects of NPY and UK 14,304 on NA release were significantly attenuated in SHR compared with WKY. These results suggest that NPY and alpha 2-adrenoceptors might be involved in the regulation of central sympathetic nervous activity in hypertension.     

Central alpha-adrenoceptors during the development of hypertension in rats on high and low salt intake

Our purpose was to investigate the binding characteristics of central alpha-adrenoceptors during the early stages of the development of hypertension in rats on high and low salt (NaCl) intake. We measured alpha 1-[( 3H]prazosin) and alpha 2-[( 3H]rauwolscine) binding in membranes of the hypothalamus and medulla oblongata of six groups of young Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and subtotally nephrectomized WKY (SN) rats with mean arterial blood pressure (MAP) ranging from normotensive to hypertensive levels after 1 week of salt restriction or loading. In the hypothalamus the SN-high salt rats and both SHR groups had elevated alpha 1-number but there was no change in alpha 2-number. Moreover, MAP was positively correlated with mean hypothalamic alpha 1-number in the six groups. In the medulla oblongata alpha 1-number was unaffected. However, high salt diet influenced medullary alpha 2-binding in the opposite manner in WKY rats versus SN rats and SHR. In these latter groups the affinity was increased and the number decreased in response to high salt intake. Furthermore, a positive correlation between MAP and mean alpha 1:alpha 2 ratio existed in both the hypothalamus and the medulla of the six groups. The data suggest that hypothalamic alpha 1-binding capacity was increased in SHR due principally to a genetic condition which is mimicked by salt loading in the SN rats. Medullary alpha 2-adrenoceptors of WKY, which remained normotensive despite salt loading, responded differently to high salt intake than those of the SN and SHR, whose blood pressure rose significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional brain concentrations of calcitonin gene-related peptide in spontaneously hypertensive and normotensive Wistar-Kyoto rats

The regional brain and spinal cord concentrations of calcitonin gene-related peptide (CGRP) were measured in age-matched (22-23-week-old) spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The highest concentration of CGRP in the WKY rats was in the spinal cord (172 +/- 9 pmol/g), followed by the medulla oblongata/pons (88 +/- 5 pmol/g). The relative order of distribution in the remaining regions was: hypothalamus (12.6 +/- 0.8 pmol/g) = striatum greater than thalamus greater than midbrain = hippocampus greater than cortex (2.1 +/- 0.3 pmol/g). The concentration of CGRP in the cerebellum was at the level of the assay's sensitivity (0.5 pmol/g). The relative order of distribution in the SHR strain was essentially the same. However, in comparison with the WKY rats, the SHR had significantly lower levels of CGRP in the hippocampus (-47%), striatum (-49%) and medulla oblongata/pons (-24%), and in the spinal cord (-24%). In younger age-matched (16-17-week-old) rats, the spinal cord and medulla oblongata/pons concentrations of CGRP were also lower in SHR than in WKY rats. CGRP is a putative neurotransmitter which, when administered centrally or peripherally, has potent cardiovascular effects. The reduced levels of this peptide may be an important factor in the cardiovascular and/or behavioural abnormalities of the SHR strain.     

Sympathetic nerves and adrenal medulla: contributions to cardiovascular-conditioned emotional responses in spontaneously hypertensive rats

This report investigates the contributions of the sympathetic nerves and adrenal medulla to resting mean arterial pressure (MAP) and to emotionally conditioned MAP and heart rate (HR) responses in unrestrained spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive control rats (WKY). Resting MAP (in mm Hg), which was higher in SHR (WKY = 120 +/- 4; SHR = 163 +/- 4; p less than 0.01), did not differ in the two strains following chemosympathectomy (WKY = 105 +/- 2; SHR = 101 +/- 2; n.s.). Adrenal medullectomy did not affect resting MAP in WKY (125 +/- 6; n.s.) but lowered it in SHR (146 +/- 5; p less than 0.05), relative to controls (see above). The conditioned pressor response (in mm Hg) in controls consisted of two peaks (I, II) in both strains, but was exaggerated in SHR (I = WKY, 13 +/- 1; SHR, 25 +/- 2; p less than 0.01; II = WKY 10 +/- 2; SHR 20 +/- 2; p less than 0.01). Chemosympathectomy suppressed (relative to controls) the first peak, but not the second, in both strains (WKY: I = 4 +/- 1, p less than 0.01; II = 12 +/- 2, n.s.; SHR: I = 6 +/- 1, p less than 0.01; II = 15 +/- 2, n.s.). Adrenal medullectomy alone had little effect on the pressor response, but when combined with chemosympathectomy both peaks were largely eliminated (WKY: I = 2 +/- I; II = 5 +/- 1; SHR: I = 1 +/- 0; II = 2 +/- 0). These data indicate that: 1) hypertension in conscious, freely behaving SHR is largely sustained by the sympathetic vasomotor nerves but that the adrenal medulla contributes to the magnitude of the elevation; 2) the early component of the exaggerated pressor response during aversive stimulation is mediated by sympathetic vasomotor excitation; and 3) the later component of the exaggerated pressor response reflects coactivation of the sympathetic vasomotor nerves and the adrenal medulla.     

Effects of a Protein Kinase C Inhibitor (H-7) on Norepinephrine Release from Vascular Adrenergic Neurons in Spontaneously Hypertensive Rats

This study was performed to investigate the effects of a specific protein kinase C inhibitor (H-7) on vascular adrenergic transmission in hypertension. In the isolated mesenteric vasculature of spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY), we have examined the effects of H-7 on norepinephrine (NE) release from vascular adrenergic neurons. Endogenous NE release during periarterial nerve stimulation was inhibited by H-7 in a dose-dependent manner with a concomitant reduction of pressor responses of the preparation. The inhibition of NE release was not affected by an uptake blocker of NE (desipramine). In SHR, the stimulation-evoked NE release and pressor responses were significantly greater than in age-matched WKY. The suppressive magnitude of stimulation-evoked NE release and pressor responses by H-7 were pronounced in SHR compared with WKY. These results demonstrate that endogenous NE release and pressor responses were increased in the mesenteric vasculature of SHR. Furthermore, the marked inhibition of NE release and pressor responses by H-7 in SHR may suggest the presence of enhanced protein kinase C-dependent regulation of vascular adrenergic transmission, which may contribute to the calcium-related abnormalities in this form of hypertension.     

Renal alpha 1-adrenergic receptor response coupling in spontaneously hypertensive rats

Renal sympathetic antidiuretic, antinatriuretic, and vasoconstrictor responses are mediated by alpha 1-adrenergic receptors in the normal rat. Since the renal nerve has been implicated in the pathogenesis of rat genetic hypertension, we investigated renal alpha 1-adrenergic receptor coupling to phosphoinositide turnover in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). In cortical slices from adult (13-week-old) SHR and WKY, stimulation with norepinephrine (10(-7)-10(-3) M) caused a concentration-dependent increase in accumulation of [3H]inositol phosphates. However, dose-response curves for SHR characteristically displayed a depression of the maximum response as compared with those for WKY. Baseline accumulation of [3H]inositol phosphates was not different between strains (39.4 +/- 2.2 cpm/mg tissue/hr for WKY and 34.4 +/- 2.1 cpm/mg tissue/hr for SHR slices; n = 5 rats/group, determined in triplicate). Antagonist competition studies revealed that norepinephrine-stimulated (10(-4) M) [3H]inositol phosphate accumulation was mediated by alpha 1-adrenergic receptors (IC50) for prazosin: 65 +/- 11 nM for SHR and 64 +/- 5 nM for WKY). The reduction in norepinephrine-stimulated [3H]inositol phosphate accumulation in SHR cortex was not the result of the hypertension, since it was also present in cortical slices from young (4-week-old) SHR in which the blood pressure was not yet significantly different from that in WKY and since [3H]inositol phosphate accumulation was unchanged from control values in rats made hypertensive by treatment with deoxycorticosterone acetate. Scatchard analysis of [3H]prazosin binding in renal cortical membranes of young and adult SHR and WKY revealed no significant differences in alpha 1-adrenergic receptor density or affinity between strains at either age. Our results suggest that renal alpha 1-adrenergic receptor coupling to phospholipase C is less efficient in SHR than in WKY. This impaired response is not the result of hypertension or changes in receptor density; this defect may play a role in increased renal sympathetic nerve activity and in the development or maintenance of hypertension in SHR.     

Neuropeptide Y and galanin enhance the inhibitory effects of clonidine on norepinephrine release from medulla oblongata of rats.

The medulla oblongata is thought to play an important role in the central regulation of blood pressure. Neuropeptide Y (NPY) and galanin (Gal) coexist with norepinephrine (NE) and may have a functional interaction in this region. The aim of the present study was to investigate whether NPY and Gal could modulate the presynaptic neuronal mechanisms, especially the alpha-adrenoceptor function, inhibiting NE release in medulla oblongata. In slices of rat medulla oblongata, clonidine, an alpha-adrenoceptor agonist, inhibited the NE release elicited by electrical stimulation in a concentration-dependent manner. A combination of clonidine and low concentration of NPY (1 X 10(-9) mol/L) resulted in an increase in the inhibitory action of clonidine on stimulation-evoked NE release. The inhibitory action of clonidine was also potentiated by Gal (1 X 10(-8) mol/L). These results indicate the existence of the presynaptic NPY- and Gal-receptors on noradrenergic nerve terminals, which may enhance the presynaptic alpha-adrenoceptor function to inhibit NE release. This suggests a possible involvement of NPY and Gal in the regulation of sympathetic nerve activity in medulla oblongata.     

Decreased hypothalamic and medullary GABA turnover in spontaneously hypertensive rats.

OBJECTIVE: The aim was to assess whether Gamma-aminobutyric acid (GABA) neurone activities in the central nervous system, especially in the hypothalamus and medulla oblangata, are altered in hypertension. METHODS: Central GABA content and turnover rate were measured in spontaneously hypertensive rats (SHR) and their normotensive Wistar Kyoto controls (WKY). GABA content was determined with high performance liquid chromatography, and in vivo GABA turnover rates were estimated by GABA accumulation after injection of amino-oxyacetic acid, a selective inhibitor of GABA degrading system. Two groups of nine week old male rats (32 SHR and 32 WKY) were used. RESULTS: GABA concentrations in cerebrospinal fluid were lower in SHR than in WKY. Since hypothalamus and medulla oblongata are the possible active sites of this system, basal GABA contents and in vivo GABA turnover rates were measured in hypothalamus and medulla oblongata. Basal GABA content in the medulla oblongata and hypothalamus was almost equal in SHR and WKY. On the other hand, GABA turnover rates were significantly lower in SHR than in WKY in both the hypothalamus and the medulla. CONCLUSIONS: Since it is known that GABA is an inhibitory neurotransmitter in the central nervous system and that it controls autonomic and cardiovascular activities, the findings suggest that the decreased hypothalamic and medullary GABAergic activities may permit sympathetic hyperactivity to contribute to the increase in blood pressure in SHR.     

Specific changes in hypothalamic alpha-adrenoceptors in young spontaneously hypertensive rats

Changes in the activity of hypothalamic and brain-stem adrenergic neurons have been reported in young spontaneously hypertensive rats (SHR) prior to the development of hypertension. We have measured central alpha- and beta-adrenoceptor concentrations in 4-week-old SHR and Wistar-Kyoto (WKY) controls by direct radioligand binding studies using [3H]prazosin (alpha 1), [3H]clonidine (alpha 2), and [125I]iodohydroxybenzlpindolol (beta). The concentration of alpha 2-adrenoceptors was significantly elevated in the hypothalamus of the SHR, 156.9 +/- 10.4 compared with WKY, 119.4 +/- 10.0 fmole/mg protein (n = 7, mean +/- SEM, p less than 0.0125). Alpha 2-adrenoceptor concentrations in both the brain stem and cerebral cortex were similar in the two groups of animals. The increase in hypothalamic adrenoceptors was specific for alpha 2-adrenoceptors, since similar concentrations of alpha 2- and beta-adrenoceptors were found in this region.     

Renal sympathetic nerve responses to tempol in spontaneously hypertensive rats

Recent studies have implicated a contribution of oxidative stress to the development of hypertension. Studies were performed to determine the effects of the superoxide dismutase (SOD) mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol) on vascular superoxide production and renal sympathetic nerve activity (RSNA) in anesthetized Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Compared with WKY rats (n=6), SHR showed a doubled vascular superoxide production, which was normalized by treatment with Tempol (3 mmol/L, n=7). In WKY rats (n=6), Tempol (30 mg/kg IV) significantly decreased mean arterial pressure (MAP) from 108+/-5 to 88+/-6 mm Hg and HR from 304+/-9 to 282+/-6 beats/min. In SHR (n=6), Tempol significantly decreased MAP from 166+/-4 to 123+/-9 mm Hg and HR from 380+/-7 to 329+/-12 beats/min. Furthermore, Tempol significantly decreased RSNA in both WKY rats and SHR. On the basis of group comparisons, the percentage decreases in MAP (-28+/-4%), HR (-16+/-3%) and integrated RSNA (-63+/-6%) in SHR were significantly greater than in WKY rats (-17+/-3%, -9+/-2%, and -30+/-4%, respectively). In SHR, changes in integrated RSNA were highly correlated with changes in MAP (r=0.85, P<0.0001) during administration of Tempol (3, 10, and 30 mg/kg IV). In both WKY rats and SHR (n=4, respectively), intracerebroventricular injection of Tempol (300 micro g/1 micro L) did not alter MAP, HR, or RSNA. Intravenous administration of a SOD inhibitor, diethyldithio-carbamic acid (30 mg/kg), significantly increased MAP, HR, and integrated RSNA in both WKY rats and SHR (n=6, respectively). These results suggest that augmented superoxide production contributes to the development of hypertension through activation of the sympathetic nervous system.     

Facilitatory effects of diltiazem on dopamine release in the central nervous system. Focus on interactions with D2 autoreceptors and guanosine triphosphate binding proteins.

The purpose of the present study was to investigate the effects of a Ca antagonist (diltiazem) on dopamine release in the central nervous system. Rat striatal slices prelabeled with [3H]dopamine (DA) and superfused with Krebs-Ringer solution were stimulated electrically at a frequency of 1 Hz. Exposure to diltiazem (3.3 x 10(-7) to 1 x 10(-5) mol/L) significantly increased both the basal and stimulation-evoked [3H]DA release in a dose-dependent manner. Exogenously applied unlabeled DA inhibited the stimulation-evoked [3H]DA release. Diltiazem significantly antagonized the capacity of the unlabeled DA to inhibit stimulation-evoked [3H]DA release. The blockade of D2 receptors by a preferential D2 antagonist, sulpiride, reduced the facilitatory effect of diltiazem on stimulation-evoked [3H]DA release. Pretreatment with pertussis toxin, which interferes with the coupling of the inhibitory guanosine triphosphate-binding proteins to adenylate cyclase, significantly diminished the effects of diltiazem on stimulation-evoked [3H]DA release. These results show that diltiazem increased DA release in rat striatum, at least partially by interactions with the D2 autoreceptors and pertussis toxin-sensitive guanosine triphosphate-binding proteins.     

Effects of chronic oral treatment with imidapril and TCV-116 on the responsiveness to angiotensin II in ventrolateral medulla of SHR.

OBJECTIVE: To examine whether chronic oral treatment with an angiotensin-converting enzyme inhibitor imidapril and an angiotensin II type 1 receptor antagonist TCV-116 would alter the response to angiotensin II in the rostral ventrolateral medulla. METHODS: Twelve-week-old spontaneously hypertensive rats (SHR) were treated with imidapril (20 mg/kg per day, n = 7), TCV-116 (5 mg/kg per day, n = 8) or vehicle (n = 8) for 4 weeks. Wistar- Kyoto rats (WKY) (n = 8) served as normotensive controls. At 16 weeks of age, angiotensin II (100 pmol) was microinjected into the rostral ventrolateral medulla of anaesthetized rats. RESULTS: Blood pressure decreased significantly in the rats treated with either imidapril or TCV-116. Pressor responses to angiotensin II microinjected into the rostral ventrolateral medulla were comparable in the untreated SHR, the imidapril-treated SHR and WKY (12 +/- 2, 15 +/- 4 and 10 +/- 1 mmHg, respectively), but were abolished in SHR treated with TCV-116 (0 +/- 2 mmHg, P< 0.01). Angiotensin-converting enzyme activity in the brain stem was significantly lower in SHR treated with imidapril (0.70 +/- 0.06 nmol/mg per h), but significantly higher in SHR treated with TCV-116 (1.62 +/- 0.04 nmol/mg per h) than in the untreated SHR (1.37 +/- 0.05 nmol/mg per h). CONCLUSIONS: Chronic oral treatment with imidapril and TCV-116 may have divergent influences on the renin-angiotensin system within the brain stem. TCV-116, but not imidapril, abolishes the pressor effect of angiotensin II in the rostral ventrolateral medulla.     

Neuropeptide Y and galanin in norepinephrine release in hypothalamic slices

Noradrenergic neurons in the locus ceruleus contain neuropeptide Y and galanin, which project to the hypothalamic region. We have investigated the regulatory mechanisms of these peptides on norepinephrine release in rat hypothalamic slices in vitro. Neuropeptide Y and galanin significantly inhibited the stimulation-evoked [3H]norepinephrine release in a dose-dependent manner (1 Hz: S2/S1 ratio (mean +/- SEM), control 0.947 +/- 0.040, n = 11, neuropeptide Y 1 x 10(-8) M 0.509 +/- 0.013, n = 8, p less than 0.01, neuropeptide Y 1 x 10(-7) M 0.283 +/- 0.021, n = 8, p less than 0.01; galanin 1 x 10(-7) M 0.448 +/- 0.026, n = 8, p less than 0.01, galanin 1 x 10(-6) M 0.261 +/- 0.023, n = 8, p less than 0.01). The inhibition of norepinephrine release by the alpha-2 agonist UK 14,304 was potentiated by neuropeptide Y and galanin. The blockade of the alpha 2-adrenergic receptors by RX 781094 diminished the inhibitory effects of neuropeptide Y and galanin on norepinephrine release. Pretreatment of hypothalamic slices with islet activating protein (a toxin that interferes with the coupling of inhibitory receptors to adenylate cyclase) attenuated the suppression of norepinephrine release by UK 14,304, neuropeptide Y, and galanin. These results support the idea that neuropeptide Y and galanin are involved in the regulation of central adrenergic transmission partially mediated by alpha 2-adrenergic receptors and islet-activating protein-sensitive guanosine triphosphate-binding proteins in rat hypothalamus.     

Reflex cardiovascular responses to somatic stimulation in spontaneously hypertensive rats

OBJECTIVES: This study aimed to test whether the cardiovascular responses to somatic stimulation in spontaneously hypertensive rats (SHR) were enhanced compared with those in normotensive Wistar-Kyoto (WKY) rats, and to examine any role of the impaired baroreflex function in the hypertensive rats. METHODS: Experiments were done in anaesthetized SHR (n = 34) and WKY (n = 31). Baroreceptor reflexes were assessed by continuous infusion of incremental doses (5-30 microg/kg per min) of phenylephrine over a 3 min infusion period. Cardiovascular responses to sciatic nerve stimulation (5 s trains, 1 ms pulse duration, 400 microA intensity) were studied before and after baroreceptor deactivation. The latter was achieved either by carotid occlusion and cutting the vagi and aortic nerves (SHR, n = 28 and WKY rats, n = 27), or by complete baroreceptor denervation (SHR, n = 6 and WKY rats, n = 4). RESULTS: We confirmed that baroreceptor sensitivity was significantly lower in SHR (0.40 +/- 0.05 ms/mmHg) than in WKY rats (0.90 +/- 0.04 ms/mmHg). Sciatic nerve stimulation elicited significantly greater increases in mean arterial pressure (MAP) and in heart rate in SHR than in WKY rats (+32.5 +/- 1.9 mmHg versus +20.2 +/- 1.1 mmHg and +13.5 +/- 1.5 bpm versus +8.0 +/- 1.1 bpm, respectively). Following baroreceptor deactivation, the responses to the same sciatic nerve stimulation of MAP and heart rate in SHR (+38.5 +/- 2.4 mmHg and +15.5 +/- 1.5 bpm) were still significantly greater than those in WKY rats (+29.5 +/- 1.3 mmHg and +11.6 +/- 1.2 bpm). CONCLUSIONS: These results show that cardiovascular responses to sciatic nerve stimulation are increased in SHR compared to WKY rats, and that this increased reactivity to somatic stimuli in hypertensive rats does not depend upon the impairment in baroreflex function demonstrated in this strain.     

Dissociation of hypertension and genetically enhanced cell growth capacity in skin fibroblasts of F2 hybrid spontaneously hypertensive rats/Wistar-Kyoto rats.

Skin fibroblasts from newborn spontaneously hypertensive rats (SHR) grow faster in culture than Wistar-Kyoto rat (WKY) cells. Similar results have been described for vascular smooth muscle cells from prehypertensive and adult SHR. This suggests the existence of an intrinsic abnormality in vascular and nonvascular cells of mesodermal origin affecting cell growth control in those rats. In an attempt to determine the relation between high blood pressure and this trait, we cultured skin fibroblasts from adult SHR, WKY, F1, and F2 hybrid SHR/WKY populations by explant technique. Their growth capacity was determined by culture well DNA doubling time and by [3H]thymidine incorporation. Adult SHR fibroblasts grew more quickly (doubling time [DT] = 37.2 +/- 2.3 h, n = 8) than WKY ones (DT = 53.9 +/- 3.6 h, n = 6). Female SHR were crossed with male WKY to produce an F1 and an F2 hybrid generation presenting a Mendelian distribution of blood pressure. Skin fibroblasts were cultured from 21 rats belonging to the highest and the lowest blood pressure groups. No difference was observed between the two groups in either growth (DT = 47.5 +/- 4.1 h, n = 11 v DT = 44.6 +/- 3.2 h, n = 10) or epidermal growth factor-induced [3H]thymidine incorporation. These observations suggest that the increased growth capacity observed in SHR is not a determinant of high blood pressure initiation but may be involved in early cardiovascular enlargement.     

Rostral ventrolateral medulla neurons of neonatal Wistar-Kyoto and spontaneously hypertensive rats

We compared the electrophysiological properties of neurons in the rostral ventrolateral medulla (RVLM) of neonatal Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), and responses to angiotensin II and its type 1 receptor antagonist candesartan. Using the whole-cell patch-clamp technique, we examined the characteristics of RVLM neurons in brainstem-spinal cord preparations with a preserved sympathetic neuronal network. The baseline membrane potential of irregularly firing neurons was less negative (-50.1+/-0.6 versus -52.0+/-0.6 mV) and the firing rate was faster (3.0+/-0.2 versus 2.0+/-0.2 Hz) in SHR (n=56) than in WKY (n=38). Superfusion with angiotensin II (6 micromol/L) significantly depolarized the RVLM bulbospinal neurons in SHR (5.4+/-1.1 mV, n=15) but not in WKY. In contrast, candesartan (0.12 micromol/L) induced a significant membrane hyperpolarization (-3.7+/-0.4 mV; n=14) and a decrease in the firing rate in RVLM bulbospinal neurons of SHR but not of WKY. These results suggest that endogenously generated angiotensin II binds to type 1 receptors on RVLM bulbospinal neurons, thus tonically contributing to a higher membrane potential and a faster firing rate in SHR. The electrophysiological properties of RVLM neurons and their responses to angiotensin II and candesartan differ between neonatal WKY and SHR. These differences in RVLM neurons suggest a mechanism that possibly leads to elevation in blood pressure.