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)

Evidence is accumulating for the role of metabotropic, as well as ionotropic, glutamate receptors in cardiovascular regulation. We sought to determine whether stimulation of metabotropic glutamate receptors in the rostral ventrolateral medulla would evoke enhanced cardiovascular responses in spontaneously hypertensive rats (SHR). Thus, we microinjected (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD], a selective agonist of metabotropic glutamate receptors, into the rostral ventrolateral medulla of urethane-anesthetized adult SHR and age-matched Wistar-Kyoto (WKY) rats. Microinjection of (1S,3R)-ACPD (1 nmol/50 nL) produced increases in mean arterial pressure and splanchnic sympathetic nerve activity in SHR (+41 +/- 6 mm Hg and +34 +/- 4%, respectively) that were significantly greater than those observed in WKY rats (+18 +/- 3 mm Hg and +22 +/- 3%, P < .005 and P < .05, respectively). The pressor responses evoked by microinjection of L-glutamate (2 nmol), N-methyl-D-aspartate (20 pmol), or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (5 pmol) were also significantly (P < .001) augmented in SHR (+55 +/- 3, +61 +/- 7, and +53 +/- 5 mm Hg, respectively, in SHR versus +31 +/- 1, +30 +/- 3, and +28 +/- 2 mm Hg in WKY rats). Results indicate that stimulation of metabotropic, as well as ionotropic, glutamate receptors in the rostral ventrolateral medulla evokes enhanced cardiovascular responses in SHR, which may contribute to hypertension in this model.
Hypertension 1994 Dec
PMID:Role of metabotropic glutamate receptors in ventrolateral medulla of hypertensive rats. 752 93

alpha-Blockers and calcium antagonists are commonly used in the treatment of hypertension, but few data are available concerning first dose or steady state (SS) hemodynamic and pharmacokinetic effects of these drugs when they are used in combination therapy. To examine these interactions, we measured supine and standing blood pressure (BP), heart rate (HR), and cardiac index (CI) for 6 h in 24 hypertensive patients after 2 weeks of placebo, again after the first dose or 3 weeks of therapy (SS) with either 120 mg verapamil (V) twice a day, or 1 mg terazosin (T) titrated weekly to 5 mg daily, and finally when T was added to V (group VT) or V added to T (group TV), acutely and at SS. Changes in supine hemodynamics when T was added to V or when V was added to T were similar and included a further reduction in BP, a transient increase in HR, and little or no change in CI. Both groups experienced significant decreases in standing blood pressure, especially 0.5 to 2 h following initiation of combination therapy despite significant increases in standing HR and CI. Standing BP tended to be lower in group TV after the first dose, but minimum standing systolic BP was not significantly different between groups (group TV 97 mm Hg at 1 h; group VT 109 mm Hg at 1.5 h, P > .05). Four patients in group TV and two in group VT experienced symptomatic orthostatic hypotension with the first dose of double-agent treatment. Pharmacokinetic interactions, including an increase in the bioavailability of T when V was added, did not correlate with the degree of orthostasis. After 3 weeks of combined therapy, the orthostatic change in BP had attenuated and symptoms had improved in all patients. We conclude that T and V represent an effective combination for the treatment of essential hypertension, but that orthostasis may result when initiating combination therapy. The orthostasis seen in some patients appears to be due to the combined vasodilatory effects rather than negative ionotropic or chronotropic effects.
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PMID:Combined terazosin and verapamil therapy in essential hypertension. Hemodynamic and pharmacokinetic interactions. 775 41

We investigated the hypothesis that stimulation of metabotropic excitatory amino acid receptors in the ventrolateral medulla evokes cardiovascular responses. Thus, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD], a selective agonist of metabotropic excitatory amino acid receptors, was microinjected into the rostral or caudal ventrolateral medulla of halothane-anesthetized Sprague-Dawley rats. Microinjections of (1S,3R)-ACPD (100 pmol-1 nmol) into the rostral ventrolateral medulla produced dose-dependent increases in mean arterial pressure (+20 +/- 4 mm Hg by 100 pmol and +35 +/- 2 mm Hg by 1 nmol, p < 0.01 versus artificial cerebrospinal fluid) and integrated splanchnic sympathetic nerve activity (+17 +/- 3% and +46 +/- 4%, respectively, p < 0.01), whereas (1S,3+)-ACPD microinjected into the caudal ventrolateral medulla decreased mean arterial pressure (-28 +/- 2 mm Hg by 100 pmol and -48 +/- 6 mm Hg by 1 nmol, p < 0.01 versus artificial cerebrospinal fluid) and splanchnic sympathetic nerve activity (-24 +/- 4% and -49 +/- 5%, p < 0.01). The blockade of ionotropic excitatory amino acid receptors by the combined injection of 2-amino-7-phosphonoheptanoic acid (200 pmol) and 6,7-dinitroquinoxaline-2,3-dione (200 pmol), which effectively blocked the responses elicited by either N-methyl-D-aspartate (20 pmol) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (5 pmol), failed to affect the responses evoked by either (1S,3R)-ACPD (100 pmol) or L-glutamate (2 nmol) microinjected in the rostral and caudal ventrolateral medulla. These results suggest that metabotropic receptors are present and mediate cardiovascular responses evoked by L-glutamate injections into the rostral and caudal ventrolateral medulla.
Hypertension 1993 May
PMID:Metabotropic glutamate receptors in the ventrolateral medulla of rats. 849 9

The microinjection of L-glutamate (1-6 nmol/rat) and N-methyl-D-aspartate (NMDA 1-10 nmol/rat), ionotropic glutamate receptor (iGluR) agonists, into the nucleus raphe obscurus caused a concentration -dependent increase of arterial blood pressure. In contrast, (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD, 14-42 nmol/rat), a metabotropic glutamate receptor (mGluRs) agonist, caused a concentration-dependent decrease in blood pressure. Pretreatment with D,L-2-amino-phosphono valeric acid (2-APV, 5 nmol/rat) a selective NMDA iGluR antagonist, and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b] cyclohepten-5,10-imine hydrogen maleate (MK801, 0.9 nmol/rat), a noncompetitive NMDA iGluR antagonist, blocked both the glutamate and NMDA pressor responses, while pretreatment with (+)-alpha-methyl-4-carboxyphenylglycine (MCPG, 0.05 nmol/rat), a mGluR1 antagonist, increased the glutamate-induced pressor effects and blocked the fall in blood pressure induced by t-ACPD. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX, 0.4 nmol/rat) a non-NMDA iGluR antagonist, did not affected the glutamate-induced hypertension. These observations indicate opposing roles for ionotropic and metabotropic receptors in the glutamate-induced blood pressure changes elicited from the nucleus raphe obscurus. Moreover, we suggest that the glutamate-induced hypertension may be due to the activation of NMDA ionotropic receptor subtypes and the metabotropic receptors may influence this activation through a reduction of excitability at level of synapses.
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PMID:Opposing effects on blood pressure following the activation of metabotropic and ionotropic glutamate receptors in raphe obscurus in the anaesthetized rat. 869 85

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 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

We investigated the role of calcium/calmodulin-dependent protein kinases in the phosphorylation of cyclic AMP response element binding protein and subsequent induction of c-fos gene elicited by sustained hypertension in neurons of the nucleus tractus solitarii of anesthetized rats. Activation of glutamate receptors in the nucleus tractus solitarii significantly increased the number of neurons that were immunoreactive to phosphorylated cyclic AMP response element binding protein and Fos protein. Microinjection bilaterally into the nucleus tractus solitarii of the calcium/calmodulin-dependent protein kinase inhibitor, 1-[N,O-bis(5-isoquinolinesulfonyl-N-methyl-L-tyrosyl]-4-phenylpiperazine , appreciably blunted such an increase. This inhibitor also attenuated the augmented immunoreactivity for phosphorylated cyclic AMP response element binding protein or Fos protein in the same nucleus induced by sustained hypertension. These results were comparable to those observed after blockade of either N-methyl-D-aspartate or non-N-methyl-D-aspartate ionotropic glutamate receptors in the nucleus tractus solitarii. Reverse transcription-polymerase chain reaction further indicated that the calcium/calmodulin-dependent protein kinase blocker attenuated the expression of Fos protein induced by sustained hypertension in the nucleus tractus solitarii by suppressing the transcription of c-fos messenger RNA. The present results suggest that activation of calcium/calmodulin-dependent protein kinases may represent an important step in the cascade of intracellular events that leads to phosphorylation of cyclic AMP response element binding protein and subsequent induction of c-fos gene after activation of ionotropic glutamate receptors by baroceptive signals in the nucleus tractus solitarii.
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PMID:Role of calcium/calmodulin-dependent protein kinases in expression of Fos protein in the nucleus tractus solitarii after sustained hypertension. 1061 71

The effect of blockade of ionotropic GABA and glutamate receptors in the rostral ventrolateral medulla (RVLM) on the relationship between phrenic nerve, splanchnic sympathetic nerve and lumbar sympathetic nerve activities was examined in urethane anesthetized, paralyzed and vagotomized Sprague-Dawley rats. Bilateral microinjection of the GABA-A receptor antagonist, bicuculline (4 mM, 100 nl), into the RVLM dramatically, and almost exclusively, increased the post-inspiratory related discharge in both splanchnic sympathetic nerve and lumbar sympathetic nerve activities and elicited hypertension with fluctuations of arterial pressure phase locked to the discharge of the phrenic nerve. Subsequent bilateral microinjection of kynurenate, a non-selective ionotropic excitatory amino acid receptor antagonist (50 mM, 100 nl), into the RVLM significantly attenuated the sympathoexcitation and hypertension evoked by injection of bicuculline. This was accompanied by an abolition of the post-inspiratory related burst discharge of splanchnic sympathetic nerve and lumbar sympathetic nerve activities. These data suggest that the GABAergic inputs to RVLM tonically inhibit glutamatergic inputs from central respiratory neurons that normally act to increase the firing of presympathetic neurons in the RVLM. Inputs from post-inspiratory neurons appear to be an especially potent excitatory synaptic drive to the presympathetic neurons in the absence of the GABAergic inhibition.
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PMID:Evidence for a tonic GABA-ergic inhibition of excitatory respiratory-related afferents to presympathetic neurons in the rostral ventrolateral medulla. 1174 95

1. Excitatory amino acid (EAA)-mediated neural transmission in the rostral ventrolateral medulla (RVLM) is important for many cardiovascular reflexes, although the receptor subtypes involved vary depending on the specific response. 2. Although injection of the EAA ionotropic receptor antagonist kynurenic acid into the RVLM has no effect on baseline arterial pressure, this lack of effect appears to result from EAA inputs to RVLM exciting both excitatory and inhibitory mechanisms within the RVLM. 3. The balance between EAA-mediated excitation and inhibition of RVLM neurons may be shifted to excitation in experimental models of hypertension. 4. The excitatory influence that EAA inputs to the RVLM have on vasomotor neurons in the RVLM may involve a sarthran-sensitive intermediary in the RVLM.
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PMID:Role of excitatory amino acid inputs to the rostral ventrolateral medulla in cardiovascular regulation. 1201 Jan 99

Acute blockade of gamma-aminobutyric acid (GABA)-A receptors in the hypothalamic paraventricular nucleus (PVN) increases mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). However, the underlying neural mechanisms have not been fully determined. We tested the hypothesis that responses to GABA-A receptor blockade in the PVN require activation of local ionotropic excitatory amino acid (EAA) receptors. MAP, HR, and renal SNA responses to unilateral PVN microinjection of bicuculline methobromide (BIC, 0.1 nmol) were recorded before and after ipsilateral PVN injection of either vehicle (saline), the nonselective ionotropic EAA receptor antagonist kynurenate (KYN), the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5), or the non-NMDA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium (NBQX). Responses to PVN-injected BIC were unaltered by vehicle injection. In contrast, injection of KYN (7.2 nmol; n=4) nearly abolished ABP and renal SNA responses to BIC (P<0.01) and significantly attenuated (P<0.05) HR responses as well. Similarly, graded doses of AP5 (0.6, 3, and 6 nmol) and NBQX (0.26, 1.3, and 2.6 nmol) reduced responses to PVN-injected BIC in a dose-related manner, with the 3 nmol (n=7) and 1.3 nmol (n=6) doses producing maximal effects (P<0.05). KYN, AP5, and NBQX did not affect baseline parameters. Effects of a cocktail containing AP5 (3 nmol) and NBQX (1.3 nmol) were greater (P<0.01) than either antagonist alone and were not statistically different from KYN. These data indicate that cardiovascular and renal sympathetic responses to acute GABA-A receptor blockade in the PVN require local actions of EAAs at both NMDA and non-NMDA receptors.
Hypertension 2003 Oct
PMID:Sympathoexcitation by PVN-injected bicuculline requires activation of excitatory amino acid receptors. 1290 Apr 39


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