Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that the overexpression of endothelial NO synthase (eNOS) in the rostral ventrolateral medulla (RVLM) decreases blood pressure, heart rate, and sympathetic nerve activity via an increase in gamma-amino butyric acid release in normotensive Wistar-Kyoto rats (WKY). Stroke-prone spontaneously hypertensive rats (SHRSP) appear to have reductions of NO production and GABA release in the RVLM. The aim of this study was to determine whether the effects of the increase in NO production in the RVLM in SHRSP are different from those in WKY. We transfected adenovirus vectors encoding either eNOS (AdeNOS) or beta-galactosidase (Adbetagal) into the RVLM of both strains. In the AdeNOS-treated group, mean arterial blood pressure and heart rate in the conscious state were significantly decreased at day 7 after the gene transfer in both strains. The decreases in mean arterial blood pressure and heart rate were significantly greater in SHRSP than in WKY. Urinary norepinephrine excretion was also decreased to a greater degree in SHRSP than in WKY after the gene transfer. The pressor response evoked by bicuculline into the RVLM of WKY was greater than that of SHRSP in the nontransfected group. However, in the AdeNOS-treated group, the pressor response did not differ between SHRSP and WKY after the gene transfer. These results indicate that the increase in NO production evoked by the overexpression of eNOS in the RVLM causes greater depressor and sympathoinhibitory responses in SHRSP than in WKY by improving an inhibitory action of GABA on the RVLM neurons.
Hypertension 2002 Feb
PMID:Cardiovascular effects of overexpression of endothelial nitric oxide synthase in the rostral ventrolateral medulla in stroke-prone spontaneously hypertensive rats. 1184 95

Experimental evidence indicates that the hypothalamic paraventricular nucleus modulates sympathetic vasomotor tone and blood pressure and that this modulation is altered in some cardiovascular diseases. This study tested the hypothesis that this nucleus exerts a more significant tonic excitatory modulation of basal sympathetic vasomotor activity in spontaneously hypertensive rats. In anesthetized, artificially-ventilated rats, bilateral microinjections of the GABA(A) receptor agonist, muscimol (1 to 1.5 nmoles per side), into the paraventricular nucleus produced a depressor and sympathoinhibitory response that did not recover. When compared with normotensive rats, this response was more marked in spontaneously hypertensive rats, where lumbar sympathetic nerve discharge was reduced by 75 +/- 3% and mean arterial pressure fell from 119 +/- 7 mm Hg to 58 +/- 3 mm Hg. Blockade of excitatory and inhibitory amino acid receptors in the rostral ventrolateral medulla significantly attenuated this response. Microinjections of small volumes (<20 nL) of GABA were used to localize precisely the responsive region of the paraventricular nucleus. Unilateral injections of GABA into the dorsomedial cap of the paraventricular nucleus induced a brisk depressor (decrease of 42 +/- 4 mm Hg), sympathoinhibitory (decrease by 72 +/- 2%), and bradycardic (decrease of 77 +/- 16 bpm) response. The mechanisms underlying the sympathoinhibition after inactivation of the paraventricular nucleus are not elucidated, but evidence discussed suggests the involvement of a supracollicular sympathoinhibitory pathway. The results presented demonstrate that the paraventricular nucleus exerts a powerful, tonic effect on the control of sympathetic vasomotor tone under basal conditions in anesthetized rats and that this is enhanced in spontaneously hypertensive rats.
Hypertension 2002 Feb
PMID:Inhibition of the hypothalamic paraventricular nucleus in spontaneously hypertensive rats dramatically reduces sympathetic vasomotor tone. 1184 97

Neurons in the commissural nucleus of the solitary tract (commNTS) play an important role in certain cardiovascular responses dependent on sympathetic vasoconstrictor activation, including the arterial chemoreceptor reflex. Electrolytic lesions of the commNTS elicit a fall in arterial pressure (AP) in spontaneously hypertensive rats (SHR). To determine whether the latter result 1) arose from elimination of commNTS neuronal activity rather than en passant axons and 2) was accompanied by a reduction in sympathetic nerve activity, we evaluated the effect of inhibition of neurons in the commNTS on basal splanchnic sympathetic nerve activity (SNA), AP, and heart rate (HR) in SHR, Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats. In chloralose-anesthetized, paralyzed, and artificially ventilated SHR, microinjection of GABA into the commNTS markedly decreased splanchnic SNA, AP, and HR. The reductions in SNA and AP following similar microinjections in WKY and SD rats were significantly less than those in SHR. Our findings suggest that tonically active neurons in the commNTS contribute to the maintenance of SNA and the hypertension in SHR. The level of tonic discharge of these commNTS neurons in normotensive WKY and SD rats may be lower than in SHR.
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PMID:Inhibition of neurons in commissural nucleus of solitary tract reduces sympathetic nerve activity in SHR. 1195 31

Experiments were conducted to determine whether the medial amygdala could control hemodynamics through the GABA receptor in anesthetized rats. Bicuculline (10-100pmol), a GABA(A) antagonist, injected into the anterior basomedial amygdala (medial amygdala) produced dose-related increases in blood pressure (BP) and heart rate (HR). Following microinjection of a 100pmol dose, plasma norepinephrine and epinephrine also rose significantly. In a group that had undergone bilateral adrenalectomy, the same dose of bicuculline into the same region of the amygdala caused similar increases in BP and HR to those produced in normal rats. Pretreatment with an intraperitoneal injection of hexamethonium prevented these responses. When bicuculline was given intravenously (100pmol) it failed to effect these cardiovascular changes. Bicuculline-induced hypertension and tachycardia were inhibited by microinjection of muscimol, a GABA agonist, into the anterior basomedial amygdala. The results thus demonstrate that the influence of bicuculline on BP and HR is through action on the anterior basomedial amygdala and direct sympathetic outflow to heart and vascular smooth muscle. There is tonic GABAergic inhibition of sympathetic outflow in the medial amygdala that plays a part in regulating hemodynamics in the limbic system.
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PMID:Role of medial amygdala in controlling hemodynamics via GABA(A) receptor in anesthetized rats. 1199 48

The exact mechanisms by which NO mediates its neuromodulatory effects within the central control of cardiovascular functions are still unclear. Both excitatory and inhibitory actions of NO in different regions of the brainstem have been reported, and that it could be caused by direct actions of NO on neurones and/or by NO-mediated changes in local cerebral blood flow. Microinjection studies suggest that direct modulation of neuronal activity by NO through cyclic 3'-5' guanosine monophosphate (cGMP)-dependent mechanisms predominates. In contrast, endogenous NO produces. only minor changes in local cerebral blood flow, and potentiation of NO-dependent vasodilation with an inhibitor of phosphodiesterase V (PDE5i) has no significant effect on sympathetic activity. Activation of the NO-system in the lower brain stem modulates various central and reflex-activated neuronal pathways. To a large extent, this appears to be mediated by NO-induced GABA- and glutamate-release within the ventrolateral medulla (VLM) and the nucleus of the solitary tract (NTS). In addition, NO has been shown to reduce local generation of angiotensin II (AII) in all areas. Recent studies suggest that the NO-mediated modulation of autonomic function is severely impaired in cardiovascular diseases. Possibly in conjunction with AII, which triggers and promotes superoxide radical generation, chronic oxidative stress (COS) could act as a key mediator of this process. Evidence supporting this hypothesis comes from studies on pigs that were chronically treated with organic nitrates to pharmacologically induce COS. In these animals, microinjection of superoxide dismutase into the rostral VLM (RVLM) diminished sympathetic activity by up to 70%, whereas peroxynitrite, a key mediator of NO-related oxidative stress, had excitotoxic effects. Antagonism of neuronal COS may therefore represent a novel approach to counteract neurohumoral activation in diseases such hypertension, obesity and heart failure.
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PMID:Mechanisms of action of nitric oxide in the brain stem: role of oxidative stress. 1214 34

Heart failure and hypertension are associated with increases in angiotensin II (ANG II) activity. One brain area where ANG II effects may be particularly important in these situations is the nucleus of the solitary tract (NTS). Located in the dorsomedial medulla, the NTS is the termination site of baroreceptor afferents and is essential for mediating the baroreflex. In hypertensive animals the baroreflex is impaired; this may be reversed by antagonizing ANG II AT1 receptors in the NTS. Recently, we showed that the baroreflex depressant action of ANG II in the NTS is mediated by activation of endothelial nitric oxide synthase (eNOS) and enhanced release of GABA. Using conventional pharmacological tools and a range of adenoviral-mediated expression of dominant negative proteins, we have determined the intracellular pathway(s) in the NTS by which ANG II activates eNOS. Our data indicate that ANG II acting in the NTS depresses the baroreflex via a Gq protein-mediated activation of phospholipase C, which through 1,4,5-inositol triphosphate causes release of calcium from the IP3-sensitive intracellular stores and calcium-calmodulin formation. In contrast, multiple site disruption of a pathway leading to eNOS activation via the serine/threonine kinase Akt was ineffective
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PMID:Genetic and pharmacological dissection of pathways involved in the angiotensin II-mediated depression of baroreflex function. 1237 82

It is well known that nitric oxide (NO), within the paraventricular nucleus (PVN) of the hypothalamus, mediates sympatho-inhibition via an inhibitory GABA-ergic mechanism. Furthermore, the inhibitory GABA-ergic mechanism is impaired in the spontaneously hypertensive rat (SHR). These data suggest that the NO system, within the PVN, may also be impaired in the SHR. In addition, previous studies have documented that daily exercise attenuates the development of tachycardia, hypertension and blood pressure related cardiovascular disease risk factors in SHR. These data suggest that daily exercise enhances the inhibitory GABA-ergic and/or NO systems. Therefore, this study was designed to test the hypothesis that hypertension, in the SHR, is associated with a lower number of NADPH-diaphorase (a commonly used marker for neuronal NOS activity) positive neurons within the PVN and that daily exercise increases the number of NOS positive neurons. Using a standard histochemical protocol, NOS positive neurons were measured in the PVN, supraoptic nucleus, median preoptic area, lateral hypothalamus, nucleus of the tractus solitarius and rostral ventrolateral medulla. Results document that SHR have significantly fewer NOS-positive neurons in the PVN than their genetic control, the Wistar-Kyoto (WKY) rats (110+/-11 versus 139+/-17). Furthermore, daily exercise increased the number of NOS positive neurons in the SHR to levels seen in the WKY rats. These data demonstrate that hypertension, in the SHR, is associated with a lower number of NOS positive neurons within the PVN and that daily exercise increases the number of NOS positive neurons within the PVN.
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PMID:Daily exercise normalizes the number of diaphorase (NOS) positive neurons in the hypothalamus of hypertensive rats. 1241 31

Intrathecal baclofen is used as a muscle relaxant and antispasmodic in cases of spasticity resulting from central nervous system trauma. The baclofen withdrawal syndrome may include hyperthermia, tachycardia, hypertension, seizures, altered mental status, and psychomotor agitation. We report a case in which the removal of a baclofen pump lead tothe development of severe withdrawal symptoms despite oral baclofen replacement therapy. In order to avoid the development of withdrawal, adequate doses of GABA agonist agents should be administered immediately prior to, and following, baclofen pump removal.
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PMID:Baclofen withdrawal following removal of an intrathecal baclofen pump despite oral baclofen replacement. 1470 58

This study aimed to determine the antihypertensive and metabolic effects of an aqueous extract of Monascus purpureus M9011 on fructose-induced hypertensive rats. After dietary feeding of fructose for 2 weeks, the rats exhibited significantly higher systolic blood pressure (SBP), mean arterial pressure (MAP), and plasma insulin and triglyceride levels, but lower insulin sensitivity than those in control rats on regular diet. The intragastric loading of fructose-fed rats with M9011 containing gamma-aminobutyric acid (GABA, 1 mg.kg(-)(1).day(-)(1)) prevented the development of fructose-induced hypertension. After fructose-induced hypertension had been established, intragastric loading of M9011 reversed the elevated blood pressure to normal level. Administration of pure GABA at the same dose as that contained in M9011 failed to prevent or reverse hypertension due to fructose consumption. Chronic M9011 treatment significantly suppressed the fructose-induced elevation in total cholesterol levels and enhanced the recovery of high-density lipoprotein cholesterol/total cholesterol ratio. However, M9011 treatment did not alter insulin sensitivity or the plasma levels of insulin, glucose, and triglyceride in fructose-fed and control rats. The present results suggest that M9011 is a novel, potent, food-based antihypertensive agent with the capability to improve long-term control of cholesterol metabolism in rats and may be of importance in clinical application for the hypertensive diabetic population.
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PMID:Aqueous extract of Monascus purpureus M9011 prevents and reverses fructose-induced hypertension in rats. 1282 28

The inhibitory amino acid GABA is a potent modulator of the spontaneous discharge and the responses to afferent inputs of neurons in the nucleus of the solitary tract (NTS). To determine if responses to activation of GABA(A) receptors are altered in hypertension, GABA(A) receptor-evoked whole cell currents were measured in enzymatically dispersed NTS neurons from 33 normotensive (NT, 109+/-4 mm Hg, n=7) and 24 hypertensive (HT, 167+/-5 mm Hg, n=24) rats. GABA(A) receptor-evoked currents reversed at the calculated equilibrium potential for chloride and were blocked by bicuculline (n=6). Membrane capacitance was the same in neurons from NT (7.5+/-0.6 pF, n=62) and HT (6.8+/-0.6 pF, n=51) rats. The EC50 for peak GABA-evoked currents cells was significantly greater in neurons from HT (21.0+/-2.6 micromol/L, n=16) compared with NT rats (13.0+/-1.8 micromol/L, n=14, P=0.01). The EC50 of neurons exhibiting DiA labeling of presumptive aortic nerve terminals was no different than that observed in the nonlabeled cells (19.0+/-4.9 micromol/L, n=4). The time constant for desensitization of GABA(A)-evoked currents was the same in neurons from HT (4.5+/-0.3 seconds, n=17) and NT rats (3.8+/-0.3 seconds, n=17, P>0.05). Repetitive pulse application of GABA revealed a more rapid decline in the evoked current in neurons from HT compared with NT rats. The amplitude of the 5th pulse of GABA (5-second duration, 2-second interval) was 21+/-2% the amplitude of the 1st pulse in NT rats (n=10) and 14+/-2% in HT rats (n=11, P<0.05). These alterations in GABAA-receptor evoked currents could render the neurons less sensitive to GABA(A) receptor inhibition and influence afferent integration by NTS neurons in HT.
Hypertension 2003 Oct
PMID:Responses to GABA(A) receptor activation are altered in NTS neurons isolated from renal-wrap hypertensive rats. 1287 97


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