UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. L-DOPA as a probable neurotransmitter of baroreceptor afferents functions as a tonic to mediate cardiodepressor control in the nucleus tractus solitarii (NTS). We attempted to clarify further whether a transmitter-like L-DOPA system is altered in NTS of adult spontaneously hypertensive rats (SHR). 2. By microdialysis of left NTS area, the basal L-DOPA release was lower in SHR than in Wistar-Kyoto (WKY) rats. This release was partially inhibited by tetrodotoxin (TTX, 1 mu mol/L) to a similar degree in both strains. TTX-sensitive L-DOPA release was lower in SHR than in WKY. 3. L-DOPA (10-300 ng) and L-glutamate (3-100 ng) microinjected into left NTS produced dose-dependent hypotension and bradycardia. No difference of responses to L-glutamate was seen in either strain. However, depressor but not bradycardic responses to L-DOPA at higher doses were slightly greater in SHR than in WKY. 4. In caudal dorsomedial medulla including NTS, tyrosine hydroxylase activity was increased in SHR compared to WKY, while there was no difference in either strain of L-aromatic amino acid decarboxylase activity. 5. Impaired tonic neuronal activity to release L-DOPA in NTS may be involved in the maintenance of hypertension in SHR. An increase in sensitivity of a recognition site for L-DOPA seems to occur as a compensatory mechanism for impairment of the neuronal activity.
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PMID:Altered basal release and depressor effect of L-DOPA in the nucleus tractus solitarii of spontaneously hypertensive rats. 907 20

1. Transmitter-like L-DOPA functions as a tonic to produce postsynaptic cardiopressor responses in the rostral ventrolateral medulla (RVLM) of rats. We attempted to clarify whether a transmitter-like L-DOPA system is altered in the RVLM of spontaneously hypertensive rats (SHR) to maintain the hypertension. 2. By microdialysis of left RVLM area, the basal L-DOPA release was higher in SHR than in Wistar-Kyoto (WKY) rats. This release was partially inhibited by tetrodotoxin (TTX, 1 mu mol/L) to a similar degree in both strains. TTX-sensitive L-DOPA release was higher in SHR than in WKY. 3. L-DOPA (10-600 ng) and L-glutamate (10-300 ng) microinjected into left RVLM produced dose-dependent hypertension and tachycardia. Pressor but not tachycardiac responses to L-DOPA at lower doses were slightly greater in SHR than in WKY, whereas no difference to L-glutamate was observed in either strain. 4. In RVLM regions, there was no difference of tyrosine hydroxylase activity in SHR or WKY; however, L-aromatic amino acid decarboxylase activity was lower in SHR than in WKY. 5. Enhanced presynaptic neuronal L-DOPA release, including a decrease in decarboxylation and sensitization of postsynaptic pressor sites to L-DOPA in RVLM, may be involved in the maintenance of hypertension in SHR.
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PMID:Altered basal release and pressor effect of L-DOPA in the rostral ventrolateral medulla of spontaneously hypertensive rats. 907 38

The gigantocellular depressor area (GiDA) is a functionally defined subdivision of the medullary gigantocellular reticular formation where vasodepressor responses are evoked by glutamate microinjections (Aicher, S. A., D. J. Reis, D. A. Ruggiero, and T. A. Milner. Neuroscience 60: 761-779, 1994). The present experiments sought to determine whether the GiDA 1) tonically inhibits the sympathetic nervous system; 2) is necessary for baroreflex function; and 3) is functionally distinct from adjacent vasodepressor regions in the medullary reticular formation, including the midline raphe nuclei and the caudal ventrolateral medulla (CVL). Excitotoxic lesions of the GiDA abolished the baroreflex and significantly increased sympathetic nerve activity in anesthetized rats. Equivalent injections into the midline raphe nuclei elevated sympathetic activity but did not alter baroreflex responses. Therefore, the GiDA is functionally distinct from the raphe nuclei, although both contain tonically active sympathoinhibitory neurons. Because the effects of GiDA lesions were identical to those seen after lesions of the CVL, further studies were required to demonstrate that the GiDA and CVL are functionally and anatomically distinct. First, intramedullary injections of kynurenic acid produced hypertension and blocked the baroreflex when placed in the CVL, but not when placed in the GiDA. Second, muscimol inactivation of the RVL blocked the hypertension produced by excitotoxic lesions of the CVL, but failed to block the hypertension produced by similar lesions of the GiDA. Third, CVL neurons project to the RVL but not the spinal cord, whereas GiDA neurons project to the spinal cord but not the RVL. These studies show that the CVL and GiDA are both tonically sympathoinhibitory regions, but they are distinct with regard to their functional connectivity with other autonomic regions.
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PMID:Gigantocellular vasodepressor area is tonically active and distinct from caudal ventrolateral vasodepressor area. 908 34

We assessed the pressor and sympathetic responses to microinjection of excitatory amino acids (EAA) into the rostral ventrolateral medulla (RVLM) to see whether the response would be augmented in salt-induced hypertension. Seven-week-old Dahl-Iwai salt-sensitive rats were fed either a high- (8%, n = 10) or a low- (0.3%, n = 12) salt diet for 3 weeks. Then, L-glutamate (2 nmol), N-methyl-D-aspartate (NMDA; ionotropic EAA receptor agonist, 20 pmol) or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD; metabotropic EAA receptor agonist, 1 nmol] was microinjected into the RVLM of urethane-anesthetized, artifically ventilated rats. The rats fed a high-salt diet showed a significantly (P < 0.001) higher mean arterial pressure (123 +/- 3 mmHg) than those fed a low-salt diet (99 +/- 2 mmHg). We found similar increases in mean arterial pressure and splanchnic sympathetic nerve activity elicited by microinjection of L-glutamate into the RVLM in the high- (33 +/- 2 mmHg and 52 +/- 10%) and low- (35 +/- 3 mmHg and 46 +/- 8%) salt groups. Similarly, pressor and sympathoexcitatory responses to either NMDA or (1S,3R)-ACPD did not differ between the groups. Microinjections of the lower doses of L-glutamate, NMDA and (1S,3R)-ACPD also showed comparable pressor responses between the groups. These results indicate that salt-induced hypertension in Dahl salt-sensitive rats is not associated with enhanced responsiveness of the RVLM to EAA. This is in contrast with our previous findings that pressor and sympathetic responses to EAA are enhanced in spontaneously hypertensive rats.
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PMID:Pressor and sympathetic responses to excitatory amino acids are not augmented in the ventrolateral medulla of Dahl salt-sensitive rats. 909 45

We have recently demonstrated in a rat model that traumatic brain injury induces perturbation of cellular calcium homeostasis with an overload of cytosolic calcium and excessive calcium adsorbed on the mitochondrial membrane, consequently the mitochondrial respiratory chain-linked oxidative phosphorylation was impaired. We report the effect of a selective N-type calcium channel blocker, SNX-111 on mitochondrial dysfunction induced by a controlled cortical impact. Intravenous administration of SNX-111 at varying times post injury was made. The concentration titration profile revealed SNX-111 at 4 mg kg-1 to be optimal, and the time window to be administration at 4 h post-injury, in line with that reported on the effect of SNX-111 in experimental stroke. Under optimal conditions, SNX-111 significantly improved the mitochondrial respiratory chain-linked functions, such as the electron transfer activities with both succinate and NAD-linked substrates, and the accompanied energy coupling capacities measured as respiratory control indices (RCI) and ATP synthesis (P/O ratio), and the energy linked Ca2+ transport. In order to assess the applicability of these data to the clinical setting, we have initiated studies with brain tissue which has to be resected during surgical treatment. Five patients suffered from brain trauma, one from intracranial hypertension due to stroke (noninfarcted tissue was taken), and one from epilepsy. Our data revealed that brain mitochondria derived from the patient with intracranial hypertension and the patient with epilepsy were tightly coupled with good respiratory rates with glutamate and malate as substrates, and high P/O ratios. The rates of respiration and ATP synthesis were severely impaired in the brain mitochondria isolated from traumatized patients. These results indicate that investigation of brain mitochondrial functions can be used as a measure for trauma-induced impairment of brain energy metabolism. The time window for the effect of SNX-111 in mitochondrial function and the (preliminary) similarity between mitochondrial dysfunction in experimental animals and humans make the drug appear to be well suited for clinical trials in severe head injury.
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PMID:Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111). 919 88

Spinal cord injury destroys bulbospinal amino acid-containing pathways to sympathetic preganglionic neurons and severely disrupts blood pressure control, resulting in resting or postural hypotension and episodic hypertension. Almost all immunoreactivity for the excitatory amino acid L-glutamate has been reported to disappear from autonomic areas of the cord caudal to a transection, apparently depriving autonomic neurons of their major excitatory input. However, the magnitude of the neurogenic episodic hypertension after cord injury suggests that excitatory inputs to sympathetic preganglionic neurons must still be present. Moreover, the hypotension associated with high spinal injuries may reflect a enhanced role for inhibitory transmitters, such as GABA. This apparent contradiction regarding the presence of glutamate and lack of information about GABA prompted the present investigation. In rats seven days after spinal cord transection, we examined identified sympathetic preganglionic neurons caudal to the injury for the presence of synapses or direct contacts from varicosities that were immunoreactive for the amino acids, L-glutamate and GABA. Adrenal sympathetic preganglionic neurons were retrogradely labelled with cholera toxin B subunit and amino acid immunoreactivity was revealed with post-embedding immunogold labelling. In single ultrathin sections, 46% (98/212) of the synapses or direct contacts on adrenal sympathetic preganglionic neurons were immunoreactive for glutamate and 39% (83/214) were immunoreactive for GABA. Analysis of inputs with the physical disector yielded similar results for the two amino acids. The proportions of glutamatergic or GABAergic synapses on cell bodies and dendrites were similar. When alternate ultrathin sections were stained to reveal glutamate or GABA immunoreactivity, either one or the other amino acid occurred in 78.4% (116/148) of inputs; 4.1% (6/148) of inputs contained both amino acids and 17.5% (26/148) of inputs contained neither. These results demonstrate that nerve fibres immunoreactive for the neurotransmitter amino acids, glutamate and GABA, provide most of the input to sympathetic preganglionic neurons caudal to a spinal cord transection. Synapses containing glutamate and GABA could provide the anatomical substrate for the exaggerated sympathetic reflexes and the low sympathetic tone that result from spinal cord injury.
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PMID:Glutamate- and GABA-immunoreactive synapses on sympathetic preganglionic neurons caudal to a spinal cord transection in rats. 928 72

Hypertension in the conscious rat, elicited by i.v. infusion of phenylephrine, evoked expression of the immediate early gene c-fos in discrete groups of brain stem neurons. Fos-immunoreactive neurons were located in the caudal ventrolateral medulla (CVLM); others were located in the nucleus of the tractus solitarius (NTS). Because of their sensitivity to alterations in arterial pressure, these neurons are likely to subserve the arterial baroreceptor reflex. The aim of this study was to identify the brain stem projections and the neurotransmitter content of the barosensitive CVLM neurons using neuronal tracing and immunohistochemistry. Some of the barosensitive CVLM neurons projected directly to the rostral ventrolateral medulla (RVLM), and many contained the GABA synthesizing enzyme, glutamic acid decarboxylase (GAD). Other CVLM neurons, containing markers of glutamate or catecholamine synthesis, were insensitive to baroreceptor stimulation. This study delineates neuronal pathways acting in the arterial baroreceptor reflex and identifies precisely GABA-synthesizing CVLM neurons as the source of inhibitory input to the RVLM.
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PMID:c-fos identifies GABA-synthesizing barosensitive neurons in caudal ventrolateral medulla. 933 8

Agonists of the GABA-A receptor are neuroprotective after experimental stroke, but studies of GABA-B agonists have contradicted each other. To further investigate whether GABA-B agonists may be neuroprotective, we devised a quantal bioassay using the intraluminal occlusion method of inducing reversible cerebral ischemia. Subjects underwent middle cerebral artery occlusion for varying amounts of time, ranging from 5 to 90 min. Behavioral outcome was measured 48 h later with a quantal observational scale: score of abnormal given for any one of asymmetric forepaw flexion on tail lift, asymmetric grip, circling, reduced exploration, seizures, or death. To the grouped response data the logistic equation was used to find the ED50, the duration of occlusion that caused one-half of the subjects to be abnormal. To find the potency ratio for each drug, we divided the ED50 for treatment by that for vehicle. We administered baclofen, a GABA-B agonist, intraperitoneally 5 min after the onset ofischemia. Baclofen (20 mg/kg) was neuroprotective (potency ratio of 3.0, P < 0.05), but a lower dose (10 mg/kg) was not. However, both doses of baclofen caused significantly more intracerebral hemorrhages than control. In awake animals, both baclofen doses caused significant increases in mean arterial pressure, but no changes in other cardiorespiratory variables. The glutamate antagonist MK-801, the GABA-A agonist muscimol, and hypothermia were all protective using the bioassay (potency ratios ranging from 1.5 to 3.0). We conclude that although baclofen (20 mg/kg) may be neuroprotective, its utility is complicated by postischemic hypertension and cerebral hemorrhages.
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PMID:High dose baclofen is neuroprotective but also causes intracerebral hemorrhage: a quantal bioassay study using the intraluminal suture occlusion method. 934 59

A wealth of experimental evidence demonstrates that cerebral ischemia causes excessive release of glutamate and that glutamate contributes to ischemic injury. Glutamate antagonism by any of several mechanisms can ameliorate the extent of infarction. These antagonists comprise noncompetitive blockers of the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor [e.g., aptiganel (Cerestat)], competitive antagonists of the glutamate recognition site of the NMDA receptor (e.g., selfotel) or of the glycine recognition site (e.g., ACEA 1021, GV150526), antagonists at the polyamine site (e.g., eliprodil), and drugs that may interfere with glutamate release by sodium channel blockade as well as having other actions (e.g., lubeluzole, 619C89). Clinical experience suggests that although some NMDA antagonists are poorly tolerated at putative neuroprotective doses (e.g., selfotel), potentially neuroprotective plasma concentrations can be achieved in humans with others (e.g., aptiganel), though tolerable adverse effects are frequently observed. These clinical effects include hypertension (which is probably preferable to the hypotension seen with nimodipine and lifarizine), sedation, confusion or hallucinations and, at high doses, catatonia. Glycine antagonists may be associated with fewer adverse effects, but preclinical studies suggest that brain penetration may be low. Although recent studies with selfotel and eliprodil have been discontinued because of insufficient evidence for a satisfactory risk/benefit ratio, encouraging experience with aptiganel, magnesium, and glycine antagonists has prompted continued clinical trials with these agents. To be of sufficient size to detect a clinically useful improvement in outcome, these trials need to be large (600-1,000 patients). Present trials with aptiganel (Cerestat) are comparing the efficacy and tolerability of two doses vs. placebo in patients treated within 6 hours of ischemic stroke. Outcome is assessed by the modified Rankin Scale at 3 months.
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PMID:Cerestat and other NMDA antagonists in ischemic stroke. 937 Nov 55

Nitric oxide (NO) is an endogenously synthesized effector molecule that acts as a neurotransmitter with novel properties in both the central and peripheral nervous systems. We previously reported that NO was involved in central cardiovascular regulation and modulated the baroreflex in the nucleus tractus solitarii (NTS) of rats. The aim of the present study was to determine whether NO and excitatory amino acids reciprocally release each other in the NTS. In normotensive Sprague-Dawley rats, intra-NTS microinjection of L-arginine (1 to 100 nmol/60 nL) produced a dose-dependent decrease in blood pressure and heart rate. Microinjection of excitatory amino acids L-glutamate and NMDA also produced depressor and bradycardic effects. These effects of L-glutamate or NMDA were blocked by prior administration of NO synthase inhibitor N(G)-methyl-L-arginine or N(G)-nitro-L-arginine methyl ester. Similarly, prior administration of N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione significantly attenuated the depressor and bradycardic effect of L-arginine. These results demonstrated a reciprocal attenuation of NO synthase inhibitor and NMDA receptor antagonist on NMDA and L-arginine responses, respectively, in the NTS and suggest that NO and NMDA receptors may interact in central cardiovascular regulation.
Hypertension 1997 Dec
PMID:Cardiovascular effects of nitric oxide and N-methyl-D-aspartate receptors in the nucleus tractus solitarii of rats. 940 73

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