Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

To elucidate the role of the rostral ventrolateral medulla (RVLM) in cardiovascular control through the release of central amino acid neurotransmitters, experiments were performed in Sprague-Dawley (normotensive) rats and spontaneously hypertensive rats (SHR) anesthetized with urethane by using microdialysis sampling from the RVLM for determination of amino acid neurotransmitters. The baseline release of the excitatory amino acid neurotransmitter, glutamate (GLU) from the RVLM in SHR was higher and those of the inhibitory amino acid neurotransmitters, glycine (GLY), taurine (TAU), and gamma-aminobutyric acid (GABA), were lower than in normotensive rats. Microinjection of angiotensin II (ANG II) into the RVLM caused a dose-dependent increase in mean arterial pressure (MAP) and heart rate (HR), accompanied by increased release of GLU in the RVLM. In contrast, microinjection of the ANG II type 1 receptor (AT1) antagonist CV 11974 into the RVLM reduced MAP and HR, accompanied by increased release of GLY, TAU and GABA. These changes in MAP and HR after administration of ANG II or AT1 antagonist were partially blocked by the use of the corresponding antagonist of each amino acid neurotransmitter. Furthermore, these effects were more prominently seen in SHR than in normotensive rats. These results suggest that the release of amino acid neurotransmitters mediate the cardiovascular effects of the angiotensin system in the RVLM, which may be involved in the generation of hypertension in SHR.
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PMID:Central amino acids mediate cardiovascular response to angiotensin II in the rat. 944 39

We have recently reported that the cardiovascular responses to excitatory amino acids are augmented in the rostral ventrolateral medulla of spontaneously hypertensive rats (SHR). In the present study, we investigated whether the responsiveness to excitatory amino acids would be normalized by antihypertensive treatment. Thus we treated 4-week-old SHR and age-matched Wistar-Kyoto (WKY) rats with either enalapril (25 mg/kg per day in drinking water) or vehicle for 8 weeks. At 12 weeks of age, systolic blood pressure in the untreated SHR (248+/-9 mm Hg) was significantly (P<.01) higher than that in the enalapril-treated SHR (140+/-4 mm Hg), untreated WKY rats (148+/-4 mm Hg), and enalapril-treated WKY rats (117+/-1 mm Hg). The pressor responses to L-glutamate (2 nmol) microinjected into the rostral ventrolateral medulla were similar in enalapril-treated and untreated SHR (40+/-5 and 47+/-3 mm Hg, respectively, NS), and these responses were significantly greater than that seen in the untreated WKY rats (24+/-2 mm Hg, P<.01). On the other hand, the pressor response to either N-methyl-D-aspartate, an ionotropic glutamate receptor agonist, or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, a metabotropic glutamate receptor agonist, in the enalapril-treated SHR was slightly but significantly smaller than that in the untreated SHR but was still markedly greater than those in untreated and enalapril-treated WKY rats. These results suggest that the augmented responsiveness to excitatory amino acids in the rostral ventrolateral medulla of SHR may be at least partly genetically determined and cannot be normalized by the treatment with enalapril.
Hypertension 1998 Jan
PMID:Antihypertensive treatment and the responsiveness to glutamate in ventrolateral medulla. 944 94

Angiotensin (Ang) II increases substance P (SP) efflux from perfused slices of medulla oblongata, and a peptide antagonist of SP, [Leu11,psiCH2NH10-11]SP, blocks the acute hypotension and bradycardia caused by Ang II injected into the nucleus tractus solitarii (nTS) of Harlan Sprague-Dawley (SD) rats. We investigated whether the same relationships exist in (mRen2)27 renin transgenic (TG) rats, which have chronic elevations of medullary tissue Ang II levels. Ang II increased SP efflux (48% above control; P<0.01) from slices of medulla prepared from 8- to 12-week old male TG rats. Injections of Ang II (250 fmol in 30 nL) into the nTS of chloralose-urethane anesthetized TG rats produced a significant increase in pressure of 7+/-2 mm Hg before a 13+/-3 mm Hg fall in pressure. Ang II induced similar depressor responses in Hannover SD rats but no increase in pressure. After nTS injection of the NK1-selective SP antagonist CP-96,345 (30 pmol in 60 nL), Ang II-induced hypotension was blocked in both groups, as was the pressor component in hypertensive rats. Hypotensive and bradycardic effects of glutamate (0.6 nmol in 30 nL) injected into the nTS were not altered by CP-96,345. In vitro receptor autoradiography showed that the SP antagonist (10 or 100 microM) did not compete for 125I-Ang II binding in the dorsal medulla, a result suggesting that it did not interact directly with Ang II receptors. Thus, the nTS cardiovascular effects of Ang II are mediated by SP in both normotensive rats and a model of hypertension with altered endogenous levels of Ang II. These findings link Ang II-induced effects on SP release from brain slices of the medulla oblongata to acute cardiovascular actions of the peptide through an NK1 receptor.
Hypertension 1998 Jan
PMID:NK1 receptor antagonist blocks angiotensin II responses in renin transgenic rat medulla oblongata. 945 48

We investigated the role of glutamatergic synapses in the expression of Fos protein at the nucleus tractus solitarii following baroreceptor activation in rats anaesthetized with pentobarbital sodium. Microinjection of L-glutamate (1 nmol) bilaterally into the nucleus tractus solitarii elicited significant hypotension and bradycardia. There was a concurrent increase, as determined immunohistochemically, in the expression of Fos protein at the commissural, medial and dorsomedial subnuclei of the caudal nucleus tractus solitarii. These effects were blunted when L-glutamate was co-administered with either the selective N-methyl-D-aspartate or non-N-methyl-D-aspartate glutamate receptor antagonist, dizocilpine maleate (200 pmol) or 6-cyano-7-nitroquinoxaline-2,3-dione (8 pmol), into the caudal nucleus tractus solitarii. Repeated and scheduled transient hypertension evoked by phenylephrine (2.5, 5.0 or 10.0 microg/kg, i.v.) also appreciably increased the number of Fos-immunoreactive neurons at the commissural, medial and dorsomedial subnuclei of the caudal nucleus tractus solitarii. The expression of Fos protein in this fashion was reduced, simultaneous with a discernible depression in baroreceptor reflex response, when baroreceptor activation was coupled with microinjection bilaterally of dizocilpine maleate (200 pmol) or 6-cyano-7-nitroquinoxaline-2,3-dione (8 pmol) into the nucleus tractus solitarii. Regression analysis showed that the depressive action on the baroreceptor reflex response by both glutamate receptor antagonists correlated positively to the reduction in Fos-immunoreactivity in the nucleus tractus solitarii after baroreceptor activation. Double immunohistochemical staining revealed that nucleus tractus solitarii neurons that showed Fos immunoreactivity were generally also immunoreactive to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor subunit 1. On the other hand, Fos immunoreactivity was usually absent from neurons in the nucleus tractus solitarii that were immunoreactive to N-methyl-D-aspartate receptor subunit 1. These results suggest that glutamatergic neurotransmission plays an active role, via comparable contributions from both N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors, in the expression of Fos protein at the caudal nucleus tractus solitarii in response to baroreceptor activation.
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PMID:Mediation by N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors in the expression of Fos protein at the nucleus tractus solitarii in response to baroreceptor activation in the rat. 946 1

The present study was designed to develop an animal model of multiple risk factors, including obesity, hypertension, non-insulin-dependent diabetes mellitus, and hyperlipidemia. Hypothalamic obesity was induced by neonatal monosodium glutamate (MSG) treatment in spontaneously hypertensive rats (SHR). Female newborn SHR were treated intraperitoneally with 2 or 4 mg/kg body weight of MSG for 5 days. Obesity developed in SHR treated with 4 mg/kg of MSG but not in SHR treated with 2 mg/kg of MSG. Obese SHR had impaired glucose tolerance, hyperinsulinemia, and hypertriglyceridemia. However, the severity of hypertension was attenuated in obese SHR as compared with control SHR. The degree of obesity was closely related to the metabolic abnormalities, but inversely correlated with the blood pressure level. Macrovascular changes were investigated in obese SHR at 14 months of age. Intimal thickening was accelerated in the carotid artery of obese SHR as compared with that of nonobese SHR. Aortic contents of DNA and total cholesterol were significantly increased in obese SHR. SHR associated with MSG-induced obesity showed major manifestations of metabolic syndrome X. This animal model may be useful to study the clustering of risk factors for the development of macrovascular diseases.
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PMID:Obesity induced by neonatal monosodium glutamate treatment in spontaneously hypertensive rats: an animal model of multiple risk factors. 958 1

We evaluated the relationship between the area under the concentration versus time curve (AUC) of cyclosporin A (CsA) and several other clinical factors, because the clinical utility of AUC monitoring has been ambiguous. Fifty-four clinical time courses from 14 Japanese renal transplant patients during hospitalization, in the period from April 1990 to March 1997, were examined. In a bivariate regression analysis there was no correlation between the AUC and the daily dose of CsA (mg/kg/day) when the individual data or total series data were analyzed. In a chi-square test, the donor type of kidney (chi(2) = 25.254, df = 1, p = 0.0000) and renal function-related episodes, i.e. acute tubular necrosis, hemodialysis, hypertension, nephrotoxicity, or rejection (chi(2) = 13.982, df = 1, p = 0.0002) directly affected posttransplant renal function assessed by creatinine clearance, while episodes of hepatic function as assessed by the glutamate-pyruvate transaminase (GPT) activity level had no correlation with the posttransplant renal function evaluated according to creatinine clearance. In contrast, the renal function-related episodes significantly affected the AUC after renal transplantation (chi(2) = 4.934, df = 1, p = 0.0263), while hepatic function assessed by GPT did not. In a multivariate analysis, the creatinine clearance and obesity had significant positive correlations with the AUC, whereas the hematocrit had a significant negative correlation with the AUC. From these observations, we concluded that the dosage adjustment of CsA cannot be performed using the linear relationship between the daily oral dose and the AUC, and that renal function, obesity, and the CsA blood distribution properties affect the CsA pharmacokinetics after renal transplantation. Posttransplant renal function as well as obesity and CsA blood distribution properties are important factors to be considered when therapeutic monitoring is performed.
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PMID:Relationship between area under the concentration versus time curve of cyclosporin A, creatinine clearance, hematocrit value, and other clinical factors in Japanese renal transplant patients. 958 46

Hypercholesterolemia is known to affect the responsiveness of various blood vessels to endogenous and to exogenous vasoactive agents. Of particular interest is the increased responsiveness to vasoconstrictors, e.g., 5-hydroxy tryptamine and noradrenaline, and the decreased reactivity towards vasodilators, e.g., acetylcholine. This, together with the development of arteriosclerosis, could play an important role in the progression of many vascular complications, such as hypertension and coronary heart disease. Magnesium pyridoxal 5-phosphate glutamate (MPPG) has been shown to effectively reduce serum lipids in animals and in man, and to retard the progression of atherosclerotic lesions in experimental animals. It was therefore considered of interest to investigate the reactivity of both the aorta and the renal artery to different vasoactive substances in hypercholesterolemic rabbits under the influence of MPPG as well as the effect of such substances on the blood pressure of the anesthetized animals. The rabbits were fed a high cholesterol diet for 2 months, followed by MPPG for 1 month, while keeping the rabbits on the same diet. One batch of animals was used for blood pressure recording and testing drug effects, and another was used for testing the responsiveness of their aortae and renal arteries to the different mediators. In hypercholesterolemic rabbits, treatment with MPPG tended to normalize the increased responsiveness of the blood pressure to the vasoconstrictors: noradrenaline and angiotensin and the diminished sensitivity to histamine and acetylcholine. For the isolated arteries, however, MPPG did not significantly affect the responses to noradrenaline nor potassium chloride, but tended to normalize responses to clonidine and acetylcholine. It could be concluded from the present findings that the high cholesterol diet induces changes in vascular reactivity which are possibly related to endothelial and/or receptor sensitivity changes. Treatment with MPPG helps to reverse these changes and to restore normal vascular reactivity, a fact that could have important clinical implications in the management of cardiovascular diseases.
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PMID:Effect of magnesium pyridoxal 5-phosphate glutamate on vascular reactivity in experimental hypercholesterolemia. 960 46

This study investigated the relationship between brain tissue oxygen tension (PbtO2) and cerebral microdialysate concentrations of several compounds in five patients with refractory intracranial hypertension after severe head injury. The following substances were assayed: lactate and glucose; the excitatory amino acids glutamate and aspartate; and the cations potassium, calcium, and magnesium. Glucose concentrations did not correlate with PbtO2, but lactate increased as PbtO2 decreased. The lactate/glucose ratio exhibited a close relationship to PbtO2, increasing sharply only when oxygen tension reached zero. Although glucose and oxygen eventually reached very low levels and zero, respectively, in these fatally head-injured patients, the terminal decrease in PbtO2 slightly preceded that of glucose in four of the five patients. This time lag is the cause of the poor correlation between glucose and PbtO2. Glutamate and aspartate concentrations both demonstrated a close relationship to PbtO2, with sharp increases not occurring until PbtO2 was zero. Concentrations of these amino acids exhibited a similar pattern in response to decreasing glucose concentrations. Potassium concentrations began increasing at a PbtO2 of 35 mm Hg, which is not generally considered indicative of hypoxia. Sharper increases began occurring once PbtO2 dropped below 15 mm Hg, with a slight rise in the minimum potassium concentrations recorded at these low PbtO2 values. Calcium and magnesium concentrations did not vary in response to PbtO2. In summary, the most robust biochemical indicators of cerebral anoxia were elevations in the lactate/glucose ratio and in the concentrations of lactate and of the excitatory amino acids glutamate and aspartate. Furthermore, the fact that glucose concentrations continue to decrease for a short period after oxygen levels reach zero suggests that cells continue to utilize glucose anaerobically for such functions as maintenance of cellular integrity, with collapse of the cell membrane as evidenced by increases of extracellular glutamate and aspartate not occurring until both oxygen and glucose concentrations reach zero.
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PMID:Comparison of brain tissue oxygen tension to microdialysis-based measures of cerebral ischemia in fatally head-injured humans. 967 54

In atherosclerosis and hypertension, vascular smooth muscle cells (SMCs) are stimulated to proliferate and exhibit enhanced gap junction protein expression. Our goal was to determine whether gap junction function differs in proliferating vs. growth-arrested SMCs. A7r5 cells (embryonic rat aortic SMCs) did not proliferate in media with reduced serum ( approximately 90% of cells in G0/G1 phase after 48-96 h in 1% fetal bovine serum). Dye coupling was less but electrical coupling was comparable in proliferating vs. growth-arrested A7r5 cells, suggesting differences in junctional permselectivity. In growth-arrested cells, junctional conductances measured with potassium glutamate, tetraethylammonium chloride, and KCl were well predicted by the conductivities of these solutions. In contrast, junctional conductances measured with potassium glutamate and tetraethylammonium chloride in proliferating cells were significantly greater than predicted by the conductivities of these solutions. These results suggest that junctions between growth-arrested cells are permeated equally well and simultaneously by anions and cations, whereas junctions between proliferating cells are poorly permeated by large molecules of either charge and equally well but not simultaneously by small anions and cations. The data indicate that A7r5 cells regulate chemical coupling independent of electrical coupling, a capacity that could facilitate growth control while protecting vasomotor responsiveness of vessels.
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PMID:Gap junction permeability is diminished in proliferating vascular smooth muscle cells. 984 30

It has been shown that nitric oxide (NO) is synthesized in the central nervous system as well as in vascular endothelial cells. We recently reported that NO was involved in central cardiovascular regulation, modulated the baroreflex, and was involved in a reciprocal release with excitatory amino acids in the nucleus tractus solitarii (NTS) of rats. We also reported previously that adenosine increased the release of glutamate in the NTS. The purpose of the present study was to investigate the possible interaction of NO and adenosine in the NTS. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Unilateral microinjection of L-arginine (3.3 nmol/60 nL) into the NTS produced decreases in blood pressure and heart rate. Microinjection of adenosine (2.3 nmol/60 nL) also produced depressive and bradycardic effects. These cardiovascular effects were attenuated by prior administration of the specific adenosine receptor antagonist DPSPX (0.92 nmol). Similarly, prior administration of NO synthase inhibitor NG-monomethyl-L-arginine or NG-nitro-L-arginine methyl ester significantly attenuated the depressive and bradycardic effects of adenosine. These results demonstrate a reciprocal attenuation of adenosine receptor antagonist and NO synthase inhibitor on L-arginine and adenosine responses, respectively, in the NTS and implicate an interaction between NO and adenosine in central cardiovascular regulation.
Hypertension 1998 Dec
PMID:Cardiovascular effects of nitric oxide and adenosine in the nucleus tractus solitarii of rats. 985 69


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