Clonidine action in spontaneously hypertensive rats (SHR) depends on the GABAergic system function

Summary The effect of -aminobutyric acid (GABA)_A antagonists (bicuculline, picrotoxin) on clonidine hypotension in spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats were examined. The GABA turnover changes after clonidine injection in both strains were also studied. Administration of clonidine alone induced the stronger decrease of systolic blood pressure (SBP) in SHR. Co-dosage of clonidine with these agents reduced its hypotensive effect in dose dependent manner and the effectiveness of both antagonists was higher in SHR. We find that clonidine stimulates GABA synthesis in the hypothalamus and the pons-medulla in both strains but the GABA turnover rate is significantly slower in SHR. Therefore, the differences in inhibitory action of GABAA receptor anatgonists between WKY and SHR rats may be explained by central GABAergic system dysfunction in the hypertension. Our results indicate that the down regulation of the GABAergic system observed in hypertension may be compensated by the action of clonidine.     

Role of renal nerves in development of hypertension in DOCA-salt model in rats: a telemetric approach

Centrally mediated hyperactivity of the autonomic nervous system contributes to DOCA hypertension; however, the targeted peripheral vascular bed(s) remain unclear. We propose that if renal sympathetic activity is a factor in the development of DOCA-salt hypertension, then renal denervation (RDNX) should attenuate the hypertensive response. In protocol 1, uninephrectomized RDNX (n = 9) and sham-denervated (n = 6) Sprague-Dawley rats were allowed free access to 0.9% NaCl solution and 0.1% NaCl diet. Mean arterial pressure (MAP) and heart rate were telemetrically recorded for 4 days before and 36 days after DOCA (100 mg/rat) implantation; sodium and water balances were recorded daily. Protocol 2 was similar except that saline intake in sham rats (n = 7) was matched to that observed in RDNX rats of protocol 1 for 30 days; for the last 10 days, the rats were allowed free access to saline. Before DOCA in protocol 1, MAP was lower (P < 0.05) in RDNX rats (99 +/- 1 mmHg) compared with sham rats (111 +/- 3 mmHg); however, heart rate and sodium and water balances were similar between groups. RDNX attenuated the MAP response to DOCA by approximately 50% (DeltaMAP = 22 +/- 3 mmHg, where Delta is change in MAP) when compared with sham rats (DeltaMAP = 38 +/- 6). RDNX rats consumed significantly less saline than sham rats, and cumulative sodium and water balances were reduced by 33% and 23%, respectively. In protocol 2, a similar pattern in MAP elevation was observed in RDNX and saline-restricted, sham-denervated rats even when saline restriction was removed. These results indicate that the renal sympathetic nerves are important in hypertension development but that other factors are also involved.     

Abnormal regulation of the sympathoadrenal system in deoxycorticosterone acetate-salt hypertensive rats

With the use of circulating norepinephrine (NE) and epinephrine (E) levels, the sympathoadrenal activity as well as its local modulation by adrenoceptors were studied in normotensive (NT) and DOCA-salt hypertensive (HT) rats. In anesthetized hypertensive rats, plasma NE levels were higher, whereas in conscious animals both NE and E levels were found to be increased, suggesting an increased basal sympathoadrenal tone in these animals. The finding of a close correlation between blood pressure levels and NE levels suggests that the elevation of blood pressure may be linked to sympathetic system activity in this experimental model of hypertension. The reactivity of the sympathoadrenal system was also found to be increased in DOCA HT rats. Following a bilateral carotid occlusion of 1 min, which specifically activates the adrenal medulla, the elevation of E levels was found to be potentiated in intact or vagotomized HT rats. Moreover, in response to prolonged or acute hypotension in anesthetized and conscious animals, the elevation in plasma NE and E levels was found to be markedly potentiated in DOCA HT rats. The local modulating adrenoceptor-mediated mechanisms of the sympathoadrenal system appeared to be altered in this model of hypertension. Although it was possible to demonstrate that the E response to carotid occlusion can be greatly potentiated by administration of an alpha2-antagonist (yohimbine) and completely abolished by an alpha2-agonist (clonidine) in NT rats, the E response was found to be unaffected by the same treatments in HT rats, suggesting a reduced sensitivity in the alpha2-mediated inhibitory modulation of the adrenal medulla. Moreover, the acute treatment with a beta-blocker (sotalol) lowered circulating NE levels and blood pressure only in HT rats, suggesting the possibility of a more sensitive beta-receptor-mediated presynaptic facilitatory mechanism on sympathetic fibers of these animals. Finally, it was observed that the functional balance which exists between the activities of sympathetic fibers and the adrenal medulla in normotensive animals appears to be impaired in DOCA HT rats. In conclusion, the present studies suggest that the increased sympathoadrenal tone and reactivity may be due, in part, to a variety of dysfunctions in local adrenoceptor modulatory mechanisms of the sympathoadrenal system in DOCA hypertensive rats.     

Effects of acute and chronic administration of sotalol on the blood pressure and the sympathoadrenal activity of anesthetized deoxycorticosterone acetate-salt hypertensive rats

Using plasma catecholamine (CA) levels as an index of the sympathoadrenal activity, the effects of chronic and acute beta-blockade on the blood pressure and sympathetic activity were evaluated in deoxycorticosterone acetate (DOCA) - salt hypertensive (HT) rats. The acute administration of one beta-blocker (sotalol, 5 mg/kg) to intact of vagotomized anesthetized HT animals induced a significant decrease in plasma norepinephrine (NE) concentrations and mean arterial pressure (MAP). The amplitude of the decrease of the MAP or NE levels were linearly correlated with the basal NE levels, suggesting that sotalol reduced the blood pressure and sympathetic NE release more efficiently in rats with increased sympathetic activity. Similarly, chronic infusion of sotalol (1.5 mg X day-1 X rat-1) through an osmotic pump for 12 days in DOCA-salt HT rats significantly reduced NE and epinephrine (E) plasma levels compared with those observed in untreated DOCA-salt HT rats. Moreover, the chronic treatment with sotalol significantly reduced the plasma E elevation induced by bilateral carotid occlusion (CO) in vagotomized normotensive (NT) and HT rats. It therefore appears that acute administration of sotalol to HT rats causes a significant reduction in the sympathetic activity which is associated to a decrease in MAP. Although chronic sotalol treatment causes a significant reduction in the sympathoadrenal basal activity and in the adrenal reactivity, this treatment did not prevent the development of DOCA-salt hypertension.     

Chronic infusion of angiotensin-(1-7) into the lateral ventricle of the brain attenuates hypertension in DOCA-salt rats

Angiotensin-(ANG)-(1-7) is known by its central and peripheral actions, which mainly oppose the deleterious effects induced by accumulation of ANG II during pathophysiological conditions. In the present study we evaluated whether a chronic increase in ANG-(1-7) levels in the brain would modify the progression of hypertension. After DOCA-salt hypertension was induced for seven days, Sprague-Dawley rats were subjected to 14 days of intracerebroventricular (ICV) infusion of ANG-(1-7) (200 ng/h, DOCA-A7) or 0.9% sterile saline. As expected, on the 21st day, DOCA rats presented increased mean arterial pressure (MAP) (≈40%), and impaired baroreflex control of heart rate (HR) and baroreflex renal sympathetic nerve activity (RSNA) in comparison with that in normotensive control rats (CTL). These changes were followed by an overactivity of the cardiac sympathetic tone and reduction of the cardiac parasympathetic tone, and exaggerated mRNA expression of collagen type I (≈9-fold) in the left ventricle. In contrast, DOCA rats treated with ANG-(1-7) ICV had an improvement of baroreflex control of HR, which was even higher than that in CTL, and a restoration of the baroreflex control of RSNA, the balance of cardiac autonomic tone, and normalized mRNA expression of collagen type I in the left ventricle. Furthermore, DOCA-A7 had MAP lowered significantly. These effects were not accompanied by significant circulating or cardiac changes in angiotensin levels. Taken together, our data show that chronic increase in ANG-(1-7) in the brain attenuates the development of DOCA-salt hypertension, highlighting the importance of this peptide in the brain for the treatment of cardiovascular diseases.     

Failure of reversal of cardiovascular responses of clonidine by centrally administered naloxone in anaesthetised rats

Central effects of naloxone on the cardiovascular responses of centrally administered clonidine were studied in anaesthetised normotensive, renal DOCA-salt hypertensive and morphine dependent rats. Clonidine (5 micrograms/ICV) produced significant decrease in blood pressure and heart rate in all the groups of rats in a dose dependent manner. Naloxone (2 micrograms/ICV) failed to reverse the responses of clonidine in all the rat groups. In morphine dependent normotensive and morphine dependent renal DOCA-salt hypertensive rats, the responses of clonidine were further enhanced in the presence of naloxone. Our observations clearly indicate that clonidine does not influence endogenous opioid system for producing cardiovascular effects.     

Stimulation of prolactin secretion by L-3,4-dihydroxyphenyl-serine (L-DOPS) via central norepinephrine in the rat

Intracerebroventricular (icv) injection of L-3,4-dihydroxyphenylserine (L-DOPS) (50 and 250 micrograms/rat) raised in a dose-related manner both plasma prolactin (PRL) and CSF norepinephrine (NE) in urethane-anesthetized male rats. Intravenous (iv) injection of larger doses of L-DOPS (5 and 10 mg/100 g BW) slightly but significantly increased plasma PRL and CSF NE. L-DOPS injection (50 micrograms/rat, icv or 5 mg/100 g BW, iv) also raised plasma PRL in conscious rats. There was a good correlation (r = 0.74) between CSF NE and peak plasma PRL in the anesthetized animals. Propranolol (100 micrograms/100 g BW, iv) inhibited plasma PRL responses to L-DOPS (50 micrograms/rat, icv) and NE injection (1 microgram/rat, icv) raised plasma PRL in anesthetized animals. These findings indicate that L-DOPS stimulates PRL secretion via central noradrenergic mechanisms in the rat.     

Vascular responses to sodium arachidonate in experimental hypertension

This study characterizes vascular responsiveness to sodium arachidonate (C 20:4) in four models of hypertension [deoxycorticosterone acetate (DOCA) hypertensive rats, two kidney-one clip (2K-1C) renal hypertensive rats, spontaneously hypertensive rats (SHR), and psychosocial hypertensive mice]. Isolated arterial strips (aorta, mesenteric artery, tail artery) were equilibrated under optimal resting tension in physiological salt solution for measurement of isometric force generation. Dose-response curves to arachidonate (10(-10) to 10(-4) g/ml) in arteries from DOCA and 2K-1C hypertensive rats were shifted to the left compared to those in arteries from control rats. In arteries from SHR and psychosocial hypertensive mice, the dose-response relationships were unchanged compared to normotensive values. Arteries from DOCA hypertensive and 2K-1C hypertensive rats developed greater maximal contractile responses to arachidonate than controls; maximal responses in arteries from SHR and psychosocial hypertensive mice were unchanged compared to normotensive values. Contractions to arachidonate were inhibited by indomethacin (0.5 and 5 micrograms/ml) and by aspirin (5 and 50 micrograms/ml). The fatty acid, oleate (C 18:1), had no effect on the contractile state of the arteries, whereas prostaglandin F2 alpha caused contraction. These results indicate altered responsiveness to exogenous arachidonate in arteries from DOCA and 2K-1C hypertensive rats, but not in arteries from SHR and psychosocial hypertensive mice.     

Critical opening pressure and reactivity of tail vessels in conscious hypertensive rats.

The possible role of increased vascular reactivity in the mechanism of experimental hypertension was studied by measurements of the critical opening pressure (COP) of tail vessels in conscious rats. In hypertension induced by administration of desoxycorticosterone acetate (DOCA) and replacement of the drinking water by 1% NaCl solution (DOCA-NaCl hypertension), and in one-kidney Goldblatt renovascular hypertension, the raised level of blood pressure was associated with an increased COP of the tail vessels when measured both before and after ganglionic blockade. In rats treated with either DOCA alone or 1% NaCl alone there was no significant increase in systolic blood pressure (SBP) or COP relative to the corresponding controls. In all four experimental series intravenous infusion of angiotensin or norepinephrine in conscious ganglion-blocked rats produced dose-dependent increases in SBP and COP. In DOCA-NaCl hypertensive rats but not in renovascular hypertensives, nor in rats treated with DOCA alone or 1% NaCl alone, the increase in COP for a given increment in dose of angiotensin or norepinephrine was significantly greater than in the control rats. It is concluded that in DOCA-NaCl hypertension there is a true increase in the reactivity of the smooth muscle of the resistance vessels to angiotensin and norepinephrine. In renovascular hypertension this is not the case and other factors must therefore be involved in causing the increased blood pressure and COP.     

GABA receptor binding and hemodynamic responses to ICV GABA in adult spontaneously hypertensive rats

Blood pressure and heart rate responses after central administration of GABA (100-1000 micrograms, ICV) and after ganglionic blockade with hexamethonium (25 mg/kg, i.a.) were compared in conscious 12 week-old spontaneously hypertensive (SH) and age-matched Wistar-Kyoto (WKY) rats. Ganglionic blockade produced an equivalent change in mean arterial pressure between SH and WKY rats. Thus, the total functional sympathetic nervous system contribution to blood pressure is equivalent in these two strains. Intraventricularly-administered GABA produced a greater absolute decrease in mean arterial pressure in the SHR compared to the WKY. However, the percent changes in arterial pressure produced by GABA were not different between these strains. This greater absolute depressor effect of GABA does not appear to be due to differences in GABA receptor binding constants since GABA receptor affinity and number of binding sites were not significantly different in the forebrain, cerebellum or pons-medulla between SH and WKY rats.     

Effect of Ganglion Blockade on Cerebrospinal Fluid Norepinephrine

The source of norepinephrine (NE) in CSF has been unclear. It has been suggested that CSF NE indicates central neural noradrenergic tone and is determined differently from plasma NE. If CSF NE depended specifically on NE release in the CNS, then interference with ganglionic neurotransmission would be expected to decrease plasma NE but not CSF NE. Hypotension caused by ganglionic blockade might be expected to increase CSF NE reflexively. We infused the ganglion blocker, trimethaphan, intravenously into anesthetized dogs and measured the effects on mean arterial blood pressure (MAP) and on cisterna magna CSF levels of NE. The results were compared with those obtained on administration of saline, clonidine (2 micrograms/kg), yohimbine (0.25 mg/kg), or nitroprusside and with those obtained when hypotension during ganglion blockade was prevented by concurrent treatment with phenylephrine. Trimethaphan decreased MAP by 40%, arterial NE by 64%, and CSF NE by 61%. Nitroprusside administered intravenously to produce the same 40% depressor response increased arterial NE by 612% and CSF NE by 155%. Prevention of ganglion blockade-induced hypotension using phenylephrine did not prevent the decrease in CSF NE caused by trimethaphan, and when phenylephrine was discontinued, the resulting hypotension was not associated with increases in CSF NE. The similar decreases in plasma NE and CSF NE during ganglionic blockade, and the abolition of reflexive increases in CSF NE during hypotension in ganglion-blocked subjects, cast doubt on the hypothesis that CSF NE indicates central noradrenergic tone and are consistent instead with at least partial derivation of CSF NE from postganglionic sympathetic nerve endings.     

Clonidine and morphine increase atrial natriuretic peptide secretion in anesthetized rats

In order to determine whether the activity of central alpha 2-adrenergic and opioid receptors influence plasma atrial natriuretic peptide (ANP) levels, clonidine and morphine were infused into the lateral cerebral ventricle for 45 min in anesthetized Sprague-Dawley rats. The central administration of a low dose of clonidine (10 ng/min) caused a significant increase in plasma ANP without changing arterial blood pressure or central venous pressure. Pretreatment with yohimbine (5 micrograms/min) completely blocked the effect of clonidine. Central infusion of morphine (100 ng/min) also elevated plasma ANP levels and naloxone (5 micrograms/min) blunted this effect. Intravenous infusion of the same dose of clonidine or morphine did not affect plasma ANP levels. Moreover, the effect of clonidine on plasma ANP was partially blocked by pretreatment with naloxone (5 micrograms/min). These results suggest that central alpha 2-adrenergic and opioid receptors may be involved in ANP secretion.     

Splanchnic sympathetic nerves in the development of mild DOCA-salt hypertension

We previously reported that mild deoxycorticosterone acetate (DOCA)-salt hypertension develops in the absence of generalized sympathoexcitation. However, sympathetic nervous system activity (SNA) is regionally heterogeneous, so we began to investigate the role of sympathetic nerves to specific regions. Our first study on that possibility revealed no contribution of renal nerves to hypertension development. The splanchnic sympathetic nerves are implicated in blood pressure (BP) regulation because splanchnic denervation effectively lowers BP in human hypertension. Here we tested the hypothesis that splanchnic SNA contributes to the development of mild DOCA-salt hypertension. Splanchnic denervation was achieved by celiac ganglionectomy (CGX) in one group of rats while another group underwent sham surgery (SHAM-GX). After DOCA treatment (50 mg/kg) in rats with both kidneys intact, CGX rats exhibited a significantly attenuated increase in BP compared with SHAM-GX rats (15.6 ± 2.2 vs. 25.6 ± 2.2 mmHg, day 28 after DOCA treatment). In other rats, whole body norepinephrine (NE) spillover, measured to determine if CGX attenuated hypertension development by reducing global SNA, was not found to be different between SHAM-GX and CGX rats. In a third group, nonhepatic splanchnic NE spillover was measured as an index of splanchnic SNA, but this was not different between SHAM (non-DOCA-treated) and DOCA rats during hypertension development. In a final group, CGX effectively abolished nonhepatic splanchnic NE spillover. These data suggest that an intact splanchnic innervation is necessary for mild DOCA-salt hypertension development but not increased splanchnic SNA or NE release. Increased splanchnic vascular reactivity to NE during DOCA-salt treatment is one possible explanation.     

Effect of intracerebroventricular benzamil on cardiovascular and central autonomic responses to DOCA-salt treatment

DOCA-salt treatment increases mean arterial pressure (MAP), while central infusion of benzamil attenuates this effect. The present study used c-Fos immunoreactivity to assess the role of benzamil-sensitive proteins in the brain on neural activity following chronic DOCA-salt treatment. Uninephrectomized rats were instrumented with telemetry transmitters for measurement of MAP and with an intracerebroventricular (ICV) cannula for benzamil administration. Groups included rats receiving DOCA-salt treatment alone, rats receiving DOCA-salt treatment with ICV benzamil, and appropriate controls. At study completion, MAP in vehicle-treated DOCA-salt rats reached 142 ± 4 mmHg. In contrast DOCA-salt rats receiving ICV benzamil had lower MAP (124 ± 3 mmHg). MAP in normotensive controls was 102 ± 3 mmHg. c-Fos immunoreactivity was quantified in the supraoptic nucleus (SON) and across subnuclei of the hypothalamic paraventricular nucleus (PVN), as well as other cardiovascular regulatory sites. Compared with vehicle-treated normotensive controls, c-Fos expression was increased in the SON and all subnuclei of the PVN, but not in other key autonomic nuclei, such as the rostroventrolateral medulla. Moreover, benzamil treatment decreased c-Fos immunoreactivity in the SON and in medial parvocellular and posterior magnocellular neurons of the PVN in DOCA-salt rats but not areas associated with regulation of sympathetic activity. Our results do not support the hypothesis that DOCA-salt increases neuronal activity (as indicated by c-Fos immunoreactivity) of other key regions that regulate sympathetic activity. These results suggest that ICV benzamil attenuates DOCA-salt hypertension by modulation of neuroendocrine-related PVN nuclei rather than inhibition of PVN sympathetic premotor neurons in the PVN and rostroventrolateral medulla.     

Clonidine reduces elevated cerebrospinal fluid catecholamine levels in patients with essential hypertension

Cerebrospinal fluid (CSF) catecholamines were measured in normotensive patients and in patients with mild to moderate essential hypertension. CSF-norepinephrine (NE) concentrations were 50% lower in the normotensive individuals (127 ± 28 vs. 240 ± 23 pg/m1) (P<0.01). In hypertensive patients, CSF-NE was inversely related to age (r =-0.68; P<0.01) and directly related to plasma NE (r = 0.61; P<0.05). Clonidine (450 mcg/day for 2 weeks) significantly reduced CSF-NE (?40%) in hypertensive patients. In addition, it decreased blood pressure, plasma and urinary NE. Urinary VMA was not affected by clonidine. No correlation was observed between clonidine effects on BP and on plasma or CSF catecholamines. This study indicates that patients with essential hypertension have elevated levels of CSF-NE which are reduced after treatment with clonidine. The elevation of CSF-NE suggests that central (spinal?) noradrenergic activity may be increased in patients with mild to moderate essential hypertension, and that can be reduced by treatment with clonidine.     

心房钠尿肽的中枢性心血管和肾效应

在麻醉大鼠观察了颈动脉、脊髓蛛网膜下腔和侧脑室内注射心房钠尿肽(Atrial natri-uretic peptide,ANP)后,血压,心率或/和尿量、尿钠和尿钾的变化,并观察了 ANP 对血管紧张素Ⅱ(AGⅡ)中枢效应的影响。结果如下:(1)在大鼠头部交叉循环条件下,经受血鼠颈总动脉内注射α-人心房钠尿多肽(α-human atrial natriurctic polypeptide,α-hANP)(15μg/kg)后,受血鼠平均动脉压(MAP)无改变,而供血鼠的 MAP 降低,⊿MAP为-2.4±0.84kPa(-18±6.3mmHg,P<0.05),(2)脊髓蛛网膜下腔注射心房肽,Ⅱ(AtriopeptinⅡ,APⅡ)(5μg/kg)对血压、心率和尿量无明显影响;(3)侧脑室注射 APⅡ(20μg/kg)后血压和心率无显著改变,尿量仅在注射后第30至50min 时显著增加,而尿钠无改变;(4)侧脑室注射 AGⅡ(1μg/kg),血压升高,⊿MAP 为1.3±0.17kPa(10±1.3mmHg,n=10,P<0.001)。注射1h 后,尿量增加106%(P<0.01),尿钠增加642%(P<0.01);(5)事先侧脑室注射 APⅡ(20μg/kg),2min 后再注入 AGⅡ(1μg/kg),AGⅡ的中枢升压效应不受影响,⊿MAP为1.5±0.25kPa(11±1.9mmHg,n=7,P<0.01),而尿量和尿钠的增值明显减小。以上结果表明,ANP 难于透过血脑脑脊血屏障,可能与其分子量较大有关。在静脉注射 ANP 所致降压效应中,似无中枢机制的参与。ANP 对 AGⅡ     

Physiological and behavioral studies with muscimol

Muscimol has been used to increase our knowledge of central GABAergic systems, CNS physiology, and behavior. Some studies concerning the neurophysiological and behavioral effects of muscimol and its analogs have been reviewed and analyzed. In vivo iontophoretic studies have greatly increased our knowledge of the active conformation(s) adopted by GABA during its interaction with neuronal synaptic (or extrasynaptic) receptors, and behaviors. studies have supported the notion that central GABAergic systems might be involved in convulsions, extrapyramidal functions, and other behaviors. However, behavioral studies with muscimol remain difficult to interpret in terms of central GABAergic systems, especially since muscimol is extensively metabolized and since it appears to interact with membrane sites other than GABA receptors. Muscimol does not appear to be useful for reversing human neurologic-psychiatric disorders.     

Central and peripheral noradrenergic tone in primary hypertension

The contents of norepinephrine (NE), epinephrine (E), dopamine (DA), normetanephrine (NMN), and 4-hydroxy-3-methoxyphenylethylene glycol (MHPG) were measured in the plasma and cerebrospinal fluid (CSF) of 66 patients with primary hypertension and 24 patients with normal blood pressure and minor neurological disorders. Plasma and CSF NE and NMN concentrations were raised in the hypertensive patients. The plasma and CSF NE levels and arterial blood pressure of a small subset of hypertensive patients were normalized after clonidine therapy. In hypertensive patients the content of DA was lower and the ratio of NE/DA was greater; CSF and plasma NE contents were related to the level of arterial blood pressure; and the content of MHPG in CSF was linked strongly with NE content in plasma and CSF and to the level of arterial blood pressure. Thus both central sympathetic nerve tone and peripheral sympathetic nerve tone were enhanced in young patients with uncomplicated hypertension. The elevated levels of neurohormones and their metabolites in some patients with primary hypertension may be related to increased synthesis and release of neural NE and may be pathogenic in the blood pressure elevation.     

Whole body norepinephrine kinetics in ANG II-salt hypertension in the rat

The purpose of this study was to investigate total body norepinephrine (NE) kinetics as an index of global sympathetic nervous system (SNS) outflow in a rat model of chronic ANG II-salt hypertension. Male Sprague-Dawley rats fed a 0.4% (normal salt, NS) or 2% (HS) NaCl diet were instrumented with arterial and venous catheters. After 5 days of recovery and a 3-day control period, ANG II (150 ng.kg(-1).min(-1)) was given subcutaneously by minipump for 14 days. Plasma NE levels and total body NE spillover and clearance were determined on control day 3 and ANG II infusion days 7 and 14 using radioisotope dilution principles. To perform this analysis, 3H-NE and NE were measured in arterial plasma after a 90-min infusion of tracer amounts of 3H-NE. Mean arterial pressure (MAP) was similar during the control period in NS and HS rats; however, MAP increased to a higher level in HS rats. During the control period, plasma NE tended to be lower in rats on HS, whereas NE clearance tended to be higher in HS rats. As a result NE spillover was similar in NS and HS rats during the control period. In NS rats, plasma NE, NE spillover, and NE clearance were unchanged by ANG II. In contrast, in rats on the HS diet, plasma NE and NE spillover increased during ANG II infusion, whereas NE clearance was unchanged. In conclusion, a HS diet alone or ANG II infusion in animals fed NS do not affect global sympathetic outflow. However, the additional hypertensive response to ANG II in animals fed HS is accompanied by SNS activation.     

Noradrenergic and GABAergic systems in the medial hypothalamus are activated during hypoglycemia

Noradrenergic and GABAergic systems in the medial hypothalamus influence plasma glucose and may be activated during glucoprivation. Microdialysis probes were placed into the ventromedial nucleus (VMH), lateral hypothalamus (LHA), and paraventricular nucleus (PVH) of male Sprague-Dawley rats to monitor extracellular concentrations of norepinephrine (NE) and GABA. During systemic hypoglycemia, induced by insulin (1.0 U/kg), NE concentrations increased in the VMH (P < 0.05) and PVH (P = 0.06) in a bimodal fashion during the first 10 min and 20-30 min after insulin administration. In the VMH, GABA concentrations increased (P < 0.05) in a similar manner as NE. Extracellular NE concentrations in the LHA were slightly lower (P = 0.13), and GABA levels remained at baseline. The increases in NE and GABA in the VMH were absent during euglycemic clamp; however, NE in the PVH still increased, reflecting a direct response to hyperinsulinemia. On the basis of these data, we propose that the activity of noradrenergic afferents to the medial hypothalamus is increased during hypoglycemia and influences the activity of local GABAergic systems to activate appropriate physiological compensatory mechanisms.