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

Microinjection of N-methyl-D-aspartate (NMDA) (0.068 to 6.8 nmol) into the periaqueductal gray area (PAG) of anaesthetized rats caused dose-dependent increases in blood pressure. Preinjection (10 min before) of FR 139317 (an ETA receptor selective antagonist; 5 nmol) or SB 209670 (an ETA/ETB receptor non-selective antagonist; 5 nmol) to the PAG reduced the pressor response to NMDA whereas BQ-788 (an ETB receptor selective antagonist; 5 nmol) did not affect the NMDA-induced hypertension. Pretreatment with DL-2-amino-5-phosphono valeric acid (2-APV) (an NMDA receptor selective antagonist, 5 nmol) also abolished the pressor response induced by NMDA. Dose-dependent increases in blood pressure induced by injection of angiotensin II (0.1-10 nmol) to the PAG were unaffected by FR 139317 or SB 209670. Thus, our data indicate that endogenous ET-1, via an action on ETA receptors, contributes to the pressor effects of NMDA within the brain.
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PMID:Involvement of endothelin in the pressor response following injection of NMDA to the periaqueductal gray area of rats. 868 Jul 7

In anesthetized and ventilated rats, activation of carotid chemoreceptors with intracarotid administration of 100 nmol sodium cyanide rapidly excited the spinal cord-projecting vasomotor neurons in the rostroventrolateral reticular nucleus (RVL) of the medulla oblongata and sympathetic nerves and increased arterial pressure. The chemoreflex sympathoexcitatory pressor responses were attenuated by an acute systemic administration of ethanol at 0.45 g/kg, but not at 45 mg/kg. The ethanol effects were observed at the level of RVL-spinal vasomotor neurons, in attenuating the neuronal responses to the chemoreflex excitation and direct iontophoresis of N-methyl-D-aspartic acid (NMDA) but without altering responses of the carotid sinus nerves to intracarotid cyanide. The effect of ethanol on the RVL neurons was further defined as blocking NMDA-evoked inward current in the corresponding spontaneously active RVL neurons in vitro. The results indicate that acute ethanol intoxication markedly influences NMDA receptor activation and arterial chemoreflexes. The relevance of the type of action to clinical hypertension in chronic and heavy drinkers is discussed.
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PMID:Ethanol inhibits chemoreflex excitation of reticulospinal vasomotor neurons. 888 2

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

Biochemical, electrophysiological and behavioural studies have provided evidence that activation of N-methyl-D-aspartate (NMDA) receptors contributes to the hyperactivity of noradrenergic neurons of the locus coeruleus (LC) in precipitated opioid withdrawal. Recently, it was demonstrated that central administration of nitric oxide (NO) synthase inhibitors suppresses this hyperactivity suggesting that NO mediates the NMDA receptor activation of LC in opioid withdrawal. Using a combination of microdialysis and in vivo voltammetry, this study examined whether local application of NMDA to the LC in opioid naive animals mimics the NO-dependent LC response seen in opioid withdrawal. In the urethane anaesthetized rat, perfusion of the LC (2 microliters min-1) with a solution of NMDA (5 mmol) via a microdialysis probe for 9 min resulted in a rapid and robust increase (290.1 +/- 32.2% above baseline) in the catechol oxidation current (CA.OC) recorded from the LC using differential normal pulse voltammetry (DNPV). The NMDA microdialysis also produced a large increase in the blood pressure (150.4 +/- 6.9% above baseline). An injection of the non-competitive NMDA receptor antagonist (+)MK-801 (0.5 mg kg-1 i.v.), given 45 min after the start of NMDA application, rapidly returned both the CA.OC signal and the blood pressure response to baseline levels. Pretreatment of animals with intraventricular nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME) (100 micrograms) significantly inhibited NOS activity in the LC, PAG-PVG and cerebellum. This dose of L-NAME, administered prior to application of NMDA by microdialysis abolished the NMDA-induced rise in the CA.OC recorded in the LC and the increase in systolic blood pressure. The results show that in voltammetry experiments, NMDA produces hyperactivity of LC and hypertension, responses that are dependent upon the synthesis of NO. Thus, in opioid naive rats, regional NMDA application via microdialysis mimics characteristics of the LC response that occur during the antagonist-precipitated opioid withdrawal.
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PMID:Excitatory action of N-methyl-D-aspartate on the rat locus coeruleus is mediated by nitric oxide: an in vivo voltammetric study. 968 68

Carvedilol is a vasodilating beta-blocker and antioxidant approved for treatment of mild to moderate hypertension, angina, and congestive heart failure. SB 211475 (4-[2-hydroxyl-3-[[2-(2-methoxyphenoxy)ethyl]amino]propoxyl]-9H-++ +carbazol-3-ol), a hydroxylated carvedilol analogue, is an even more potent antioxidant in several assay systems. Carvedilol also has neuroprotective capacity with modulatory actions at N-methyl-D-aspartate (NMDA) receptors and Na+ channels. In the present study, we demonstrated that in cultured rat cerebellar neurons, SB 211475 has 28-fold greater antioxidant activity than carvedilol, but is 2- to 6-fold less potent, respectively, at inhibiting neurotoxic activities at Na+ channels and at NMDA receptor channels. To determine a biophysical rationale for these differential activities, small angle x-ray scattering data were obtained from model lipid and brain membrane bilayers containing either carvedilol, SB 211475, or dihydropyridine calcium channel blockers. Electron density profiles revealed that the location of SB 211475 was restricted to the glycerol backbone/hydrocarbon interface and significantly reduced membrane width by 5%, whereas the time-averaged location for carvedilol and flunarizine also extended to the hydrated surface of the bilayer. Comparison of carvedilol with several dihydropyridines showed a correlation between high ClogP values (lipophilicity), Na+ channel inhibitory potency, and bilayer localization. The antioxidant activity of SB 211475 could be explained by restricted intercalation into the glycerol phosphate/hydrocarbon interface, creating an increase in volume associated with the phospholipid acyl chains, which would then become resistant to lipid peroxidation. Differential channel modulation may also be explained by these membrane structural results, which indicate that carvedilol and the less spatially restricted dihydropyridine molecules are more likely to inhibit transmembrane receptor channels.
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PMID:Neuroprotective activities of carvedilol and a hydroxylated derivative: role of membrane biophysical interactions. 997 86

Neurologic deterioration observed following head injury is recognized as having a deleterious effect on outcome. The present study examines this occurrence in detail to determine the frequency of these episodes, their antecedent events and causal relationships in order to identify patients who are at risk. Data was collected prospectively from a consecutive series of 427 patients entered into the international trial of the NMDA receptor antagonist Selfotel. Using a definition of neurologic worsening based upon objective criteria, 117 patients were identified who suffered 164 episodes of deterioration. The occurrence of a single episode of neurologic worsening increased mortality by more than five-fold and reduced favorable outcomes (good or moderate on the Glasgow Outcome Scale), by more than 50%. Increased intracranial volume resulting in intracranial hypertension was the single most frequent cause of neurologic worsening. This serves to emphasize the importance of more adequate treatments of intracranial hypertension in improving the outcome of patients with severe head injury.
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PMID:The frequency, antecedent events, and causal relationships of neurologic worsening following severe head injury. Executive Committee of the international Selfotel Trial. 1049 50

To develop effective gene therapy techniques that target populations of neurons in the spinal cord, suitable vectors must be developed that will undergo efficient, retrograde transport from an appropriate peripheral site and will not be cytotoxic. Our previous work (LeVatte et al, 1998a) has demonstrated that a replication defective herpes simplex virus vector 14Hdelta3vhsZ, that has been substantially detoxified, is retrogradely transported from peripheral sites and can infect large numbers of the targeted spinal neurons. We plan to develop targeted gene therapy approaches designed to modulate the excitatory glutamatergic methyl-D-aspartate (NMDA) receptor in spinal cord neurons as a means of ameliorating a form of episodic high blood pressure that occurs after spinal cord injury. In this report, we demonstrate that, in differentiated PC12 cells, a neuronal-like cell line, the virus vector does not appear to alter aspects of the cytoskeletal architecture important to the proper distribution of the NMDA receptor. In turn, the distribution of endogenous NMDA receptor 1 subunit protein (NMDAR1) or a transfected NMDAR1-green fluorescent fusion protein was also found to be unaltered after vector infection. However, whereas endogenous NMDAR1 distribution was maintained, vector infection did tend to reduce the level of its expression. This drop in endogenous NMDAR1 expression coincided with the expression of the HSV immediate early genes ICP0 and ICP27 over the first 24-48 h. These results indicate that the 14Hdelta3vhsZ herpes simplex virus vector is suitable to use in future strategies to alter the level of gene expression in targeted populations of spinal cord neurons.
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PMID:A multi-mutant herpes simplex virus vector has minimal cytotoxic effects on the distribution of filamentous actin, alpha-actinin 2 and a glutamate receptor in differentiated PC12 cells. 1078 95

The involvement of glutamatergic neurotransmission in the rostral ventrolateral medulla (RVLM) in the suppression of baroreflex bradycardia by the parabrachial nucleus (PBN) was investigated. Repeated electrical activation of the PBN increased the concentration of glutamate in the dialysate collected from the RVLM. The same stimulation also suppressed baroreflex bradycardia in response to transient hypertension evoked by phenylephrine (5 microg/kg, intravenously). Microinfusion of L-glutamate (10, 50 or 100 microM) via the microdialysis probe into the RVLM dose-dependently elicited a significant inhibition of baroreflex bradycardia that paralleled the concentration and time course of the PBN-elicited elevation in extracellular glutamate in the RVLM. The suppression of baroreflex bradycardia elicited by microinjection of L-glutamate (1 nmol) into the RVLM was appreciably reversed by coinjection of the NMDA receptor antagonist, dizocilpine (500 pmol), or the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2, 3-dione (50 pmol). These results suggest that an increase in the extracellular concentration of glutamate and activation of both NMDA and non-NMDA receptors in the RVLM may mediate the suppression of baroreflex bradycardia by activation of the PBN.
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PMID:Parabrachial nucleus induces suppression of baroreflex bradycardia by the release of glutamate in the rostral ventrolateral medulla of the rat. 1097 Nov 38

N-methyl D-aspartate (NMDA) receptor stimulation is known to activate nitric oxide (NO) synthase, an enzyme present in a high proportion of sympathetic preganglionic neurons. In this study, we have examined the possibility that NO modulates the pressor responses elicited by NMDA receptor stimulation in the spinal cord. In experiments on anesthetized rats, we determined whether intrathecal administration of either 3-morpholinylsydnoneimine chloride (SIN-1), an NO donor, or N:(G)-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, affected the response to stimulation of spinal NMDA receptors by NMDA (1 pmol to 1 micromol in 10-microL intrathecal administration). Intrathecal NMDA resulted in dose-dependent increases in blood pressure. SIN-1 (100 nmol) attenuated the pressor responses to NMDA (F(1,70)=12, P=0.001). Conversely, L-NAME (1 nmol to 1 micromol) augmented the pressor response to NMDA in a dose-dependent manner (F(3,161)=28.3, P<0.001). The effect of L-NAME to amplify the pressor response to NMDA was reversed by L-arginine but not by D-arginine. These results indicate that endogenous synthesis of NO in the spinal cord limits the pressor response to stimulation of spinal NMDA receptors.
Hypertension 2000 Dec
PMID:Nitric oxide limits pressor responses to sympathetic activation in rat spinal cord. 1111 30


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