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)

Rats with chronic inhibition of GABA synthesis and consequently enhanced glutamatergic excitation in the dorsomedial hypothalamus (DMH) develop panic-like responses, defined as tachycardia, tachypnea, hypertension, and increased anxiety as measured by a social interaction (SI) test, after intravenous sodium lactate infusions, a phenomenon similar to patients with panic disorder. Therefore, the present studies tested the role of the postsynaptic NMDA and AMPA type glutamatergic receptors in the lactate-induced panic-like responses in these rats. Rats were fit with femoral arterial and venous catheters and Alzet pumps [filled with the GABA synthesis inhibitor L-allylglycine (L-AG; 3.5 nmol/0.5 microl per hour) or its inactive isomer D-AG] into the DMH. After 4-5 d of recovery only those rats with L-AG pumps exhibited panic-like responses to lactate infusions. Using double immunocytochemistry, we found that rats exhibiting panic-like responses (e.g., L-AG plus lactate) had increased c-Fos immunoreactivity in DMH neurons expressing the NMDA receptor 1 (NR1) subunit, but not those expressing the glutamate receptor 2 and 3 subunits of the AMPA receptors. To confirm this pharmacologically, we tested another group of rats implanted with l-AG pumps with intravenous lactate infusions preceded by injections of either NMDA [aminophosphonopentanoic acid (AP-5) or (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801)] or non-NMDA [CNQX or 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodazepin-5-yl)-benzenamine dihydrochloride (GYKI52466)] antagonists into the DMH. Injections of NMDA, but not non-NMDA, antagonists into the DMH resulted in dose-dependent blockade of the tachycardia, tachypnea, hypertension, and SI responses after lactate infusions. These results suggest that NMDA, and not non-NMDA, type glutamate receptors regulate lactate-induced panic-like responses in rats with GABA dysfunction in the DMH.
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PMID:Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors. 1680 38

Intravenous sodium lactate infusions or the noradrenergic agent yohimbine reliably induce panic attacks in humans with panic disorder but not in healthy controls. However, the exact mechanism of lactate eliciting a panic attack is still unknown. In rats with chronic disruption of GABA-mediated inhibition in the dorsomedial hypothalamus (DMH), achieved by chronic microinfusion of the glutamic acid decarboxylase inhibitor L-allylglycine, sodium lactate infusions or yohimbine elicits panic-like responses (i.e., anxiety, tachycardia, hypertension, and tachypnea). In the present study, previous injections of the angiotensin-II (A-II) type 1 receptor antagonist losartan and the nonspecific A-II receptor antagonist saralasin into the DMH of "panic-prone" rats blocked the anxiety-like and physiological components of lactate-induced panic-like responses. In addition, direct injections of A-II into the DMH of these panic-prone rats also elicited panic-like responses that were blocked by pretreatment with saralasin. Microinjections of saralasin into the DMH did not block the panic-like responses elicited by intravenous infusions of the noradrenergic agent yohimbine or by direct injections of NMDA into the DMH. The presence of the A-II type 1 receptors in the region of the DMH was demonstrated using immunohistochemistry. Thus, these results implicate A-II pathways and the A-II receptors in the hypothalamus as putative substrates for sodium lactate-induced panic-like responses in vulnerable subjects.
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PMID:Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus. 1695 77

Precise control of cellular Cl(-) transport is necessary for many fundamental physiological processes. For example, the intracellular concentration of Cl(-), fine-tuned through the coordinated action of cellular Cl(-) influx and efflux mechanisms, determines whether a neuron's response to GABA is excitatory or inhibitory. In epithelia, synchrony between apical and basolateral Cl(-) flux, and transcellular and paracellular Cl(-) transport, is necessary for efficient transepithelial Cl(-) reabsorption or secretion. In cells throughout the body, coordination of Cl(-) entry and exit mechanisms help defend against changes in cell volume. The Na-K-Cl and K-Cl cotransporters of the SLC12 gene family are important molecular determinants of Cl(-) entry and exit, respectively, in these systems. The WNK serine-threonine kinase family, members of which are mutated in an inherited form of human hypertension, are components of a signaling pathway that coordinates Cl(-) influx and efflux through SLC12 cotransporters to dynamically regulate intracellular Cl(-) activity.
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PMID:WNK protein kinases modulate cellular Cl- flux by altering the phosphorylation state of the Na-K-Cl and K-Cl cotransporters. 1699 Apr 53

The paraventricular nucleus (PVN) of the hypothalamus is involved in tonic regulation of sympathetic outflow. Impaired GABAergic control of PVN neurons may contribute to the elevated sympathetic drive in hypertension. In this study, we examined the function of GABA(A) and GABA(B) receptors in the PVN in control of sympathetic nerve activity and arterial blood pressure (ABP) in normotensive and hypertensive rats. Lumbar sympathetic activity (LSNA) and ABP were recorded from anesthetized spontaneously hypertensive rats (SHRs), Sprague-Dawley (SD) rats, and Wistar-Kyoto (WKY) rats. Bilateral microinjection of bicuculline (0.01-0.15 nmol), a GABA(A) receptor antagonist, into the PVN increased LSNA and ABP in normotensive WKY and SD rats in a dose-dependent manner. This response was significantly attenuated in SHRs. Furthermore, the decrease in LSNA and ABP induced by a GABA(A) receptor agonist, muscimol (0.05-1.5 nmol), in the PVN was significantly less in SHRs than in normotensive controls. In contrast, microinjection of the GABA(B) receptor agonist baclofen (0.3-4.5 nmol) into the PVN decreased LSNA and ABP in SHRs. However, in WKY and SD rats, baclofen only decreased LSNA and ABP at the highest dose tested. In addition, blockade of GABA(B) receptors in the PVN with CGP52432 (3-[[(3,4-dichlorophenyl)methyl]amino]propyl]diethoxymethyl)phosphinic acid) (0.15-3.0 nmol) dose-dependently increased LSNA and ABP in SHRs but not in normotensive controls. Collectively, this study provides new evidence that GABA(A) receptor function is attenuated, whereas the function of GABA(B) receptors is enhanced, in the PVN of SHRs.
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PMID:Role of gamma-aminobutyric acid (GABA)A and GABAB receptors in paraventricular nucleus in control of sympathetic vasomotor tone in hypertension. 1707 18

Mutations in the serine-threonine kinases WNK1 and WNK4 cause a Mendelian disease featuring hypertension and hyperkalemia. In vitro and in vivo studies have revealed that these proteins are molecular switches that have discrete functional states that impart different effects on downstream ion channels, transporters, and the paracellular pathway. These effects enable the distal nephron to allow either maximal NaCl reabsorption or maximal K+ secretion in response to hypovolemia or hyperkalemia, respectively. The related kinase WNK3 has reciprocal actions on the primary mediators of cellular Cl(-) influx and efflux, effects that can serve to regulate cell volume during growth and in response to osmotic stress as well as to modulate neuronal responses to GABA. These findings define a versatile new family of kinases that coordinate the activities of diverse ion transport pathways to achieve and maintain fluid and electrolyte homeostasis.
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PMID:Molecular physiology of the WNK kinases. 1796 Oct 84

The current study tested the hypothesis that chronic loss of inhibitory GABAergic tone in the bed nucleus of the stria terminalis (BNST), a region implicated in anxiety behavior, results in generalized anxiety disorder-like behaviors without panic-like responses (i.e., tachycardia, hypertension and tachypnea) following panicogenic stimuli (e.g., sodium lactate infusions). To test this hypothesis, the GABA synthesis inhibitor L-allylglycine (L-AG) or its inactive isomer D-AG was chronically infused into the BNST of male rats via osmotic mini-pumps. L-AG, but not D-AG, treated rats had increased anxiety-like behavior as measured by social interaction (SI) and elevated-plus maze paradigms. Restoring GABAergic tone, with 100pmoles/100nl of muscimol (a GABA(A) receptor agonist), in the BNST of L-AG treated rats attenuated L-AG-induced anxiety-like behavior in the SI test. To assess panic-like states, L-AG treated rats were intravenously infused with 0.5 M sodium lactate, a panicogenic agent, prior to assessing SI and cardiorespiratory responses. L-AG decreased SI duration again; however, sodium lactate did not induce panic-like cardiorespiratory responses. These findings demonstrate that GABA inhibition in the BNST elicits anxiety-like behavior without increasing sensitivity to lactate, thus suggesting a behavioral profile similar to that of generalized anxiety-like behavior rather than that of panic.
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PMID:Chronic inhibition of GABA synthesis in the bed nucleus of the stria terminalis elicits anxiety-like behavior. 1830 97

Angiotensin II (AngII) is a major culprit in essential hypertension. Based on a genetic rodent model of hypertension, we review here evidence that AngII may signal across the blood brain barrier to affect neuronal circuits within the nucleus tractus solitarii (NTS) of the brainstem, a pivotal region regulating both the baroreceptor reflex and set point control of arterial pressure. We have termed this form of signalling as vascular-neuronal signalling. We describe that the depressant action of AngII in NTS on the baroreceptor reflex is mediated via activation of endothelial nitric oxide synthase (eNOS) releasing NO that promotes release of the inhibitory transmitter-GABA. This could shunt the incoming excitatory baroreceptor afferent traffic impinging on NTS neurones. Chronic studies recording arterial pressure in conscious unrestrained rats using radio-telemetry have revealed that eNOS in NTS plays an endogenous physiological role in the homeostatic regulation of the gain of the cardiac baroreceptor reflex. However, in the spontaneously hypertensive rat, eNOS mRNA was higher (compared to normotensive rats), and its chronic blockade in NTS restored the abnormally depressed cardiac baroreceptor reflex to levels akin to normotensive rats, improved heart rate variability and lowered arterial pressure. Hence, it seems that excessive eNOS activity in NTS of the SHR contributes to the pathological state of this animal model's cardiovascular autonomic nervous system. We speculate on why eNOS activity may be up regulated in the NTS of the SHR and propose that it is a consequence of high cerebral vascular resistance and inadequate blood perfusion of the brainstem.
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PMID:Signalling across the blood brain barrier by angiotensin II: novel implications for neurogenic hypertension. 1844 53

GABA(B) receptor function is upregulated in the paraventricular nucleus (PVN) of the hypothalamus in spontaneously hypertensive rats (SHR), but it is unclear whether this upregulation occurs pre- or postsynaptically. We therefore determined pre- and postsynaptic GABA(B) receptor function in retrogradely labeled spinally projecting PVN neurons using whole cell patch-clamp recording in brain slices in SHR and Wistar-Kyoto (WKY) rats. Bath application of the GABA(B) receptor agonist baclofen significantly decreased the spontaneous firing activity of labeled PVN neurons in both SHR and WKY rats. However, the magnitude of reduction in the firing rate was significantly greater in SHR than in WKY rats. Furthermore, baclofen produced larger membrane hyperpolarization and outward currents in labeled PVN neurons in SHR than in WKY rats. The baclofen-induced current was abolished by either including G protein inhibitor GDPbetaS in the pipette solution or bath application of the GABA(B) receptor antagonist in both SHR and WKY rats. Blocking N-methyl-d-aspartic acid receptors had no significant effect on baclofen-elicited outward currents in SHR. In addition, baclofen caused significantly greater inhibition of glutamatergic excitatory postsynaptic currents (EPSCs) in labeled PVN neurons in brain slices from SHR than WKY rats. By contrast, baclofen produced significantly less inhibition of GABAergic inhibitory postsynaptic currents (IPSCs) in labeled PVN neurons in SHR than in WKY rats. Although microinjection of the GABA(B) antagonist into the PVN increases sympathetic vasomotor tone in SHR, the GABA(B) antagonist did not affect EPSCs and IPSCs of the PVN neurons in vitro. These findings suggest that postsynaptic GABA(B) receptor function is upregulated in PVN presympathetic neurons in SHR. Whereas presynaptic GABA(B) receptor control of glutamatergic synaptic inputs is enhanced, presynaptic GABA(B) receptor control of GABAergic inputs in the PVN is attenuated in SHR. Changes in both pre- and postsynaptic GABA(B) receptors in the PVN may contribute to the control of sympathetic outflow in hypertension.
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PMID:Plasticity of pre- and postsynaptic GABAB receptor function in the paraventricular nucleus in spontaneously hypertensive rats. 1856 9

Melatonin, acting through its receptors, is involved in numerous physiological processes, including blood pressure (BP) regulation. In present study, the effect of melatonin inhibition on stress-induced hypertension was investigated. The hypertensive model consisted of male Sprague-Dawley rats subjected to electrical foot-shock combined with noise. Microinjection of melatonin (0.1 and 1.0 mmol/L) into the anterior hypothalamic area (AHA) produced a fall in BP in nomortensive rats and stress-induced hypertensive rats (SIHR). Luzindole (10 mmol/L), a competitive antagonist of melatonin MT1 and MT2 receptors, almost completely abolished the depressor effect of melatonin, the MT2 receptor-specific antagonist 4-phenyl-2-propionamidotetralin (10 mmol/L) partially blocked (by approximately 60%) the depressor effect of melatonin, whereas the MT3 receptor-selective antagonist prazosin (10 mmol/L) failed to antagonize the effects of melatonin. Brain microdialysis was performed in the AHA and the rostral ventrolateral medulla (RVLM). Melatonin and amino acids in the dialysate samples collected were detected by high-performance liquid chromatography combined with fluorescence detection. The results indicated that melatonin concentrations in the AHA were reduced in SIHR. Microinjection of melatonin into the AHA decreased glutamate release and increased GABA and taurine release in the RVLM, which were paralleled by a decrease in arterial pressure. The mRNA expression of MT2 in the AHA of SIHR was higher than that in normotensive control rats, whereas there was no significant difference in MT1 mRNA expressin between the two groups. The results of the present study suggest that both a decrease of melatonin and an increase in the MT2 receptor in the AHA are involved in the manifestation of stress-induced hypertension. Both MT1 and MT2 receptors participated in the antihypertensive effect of melatonin in the AHA. The antihypertensive effect of melatonin was related to the decreases in the excitatory amino acid glutamate and increases in the inhibitory amino acids taurine and GABA in the RVLM.
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PMID:Effects of melatonin on blood pressure in stress-induced hypertension in rats. 1863 16

1. Several groups have reported that melatonin produces a significant decrease in blood pressure in mammals and that pinealectomy in rats causes hypertension. The purpose of the present study was to investigate the effects of melatonin and bicuculline methiodide on the blood pressure of rats, both in the developing and fully developed stage of stress-induced hypertension (SIH). 2. Rats with SIH were generated by mild electric foot shocks for 15 days, after which tail arterial systolic pressure and plasma angiotensin (Ang) II levels were measured. The effects of melatonin injections (i.p. or i.c.v.) on mean arterial pressure (MAP) in rats with SIH were also determined. 3. Pretreatment with 1 mg/kg, i.p., melatonin significantly diminished the elevated tail arterial systolic pressure and plasma AngII levels caused by 15 days stress. The suppressive effects of melatonin were blocked by i.p. injection of 1 mg/kg bicuculline methiodide, an antagonist of the GABA(A) receptor. 4. Intraperitoneal (0.2, 0.5 and 1 mg/kg) or i.c.v. (0.15 and 1.5 microg/3 microL) injection of melatonin produced a dose-dependent lowering of MAP in rats with SIH. The antihypertensive response induced by melatonin was blocked by injection of both 1 mg/kg, i.p., and 1.5 x 10(6) microg/3 microL, i.c.v., bicuculline methiodide. 5. In conclusion, melatonin not only prevents increases in blood pressure during the developing stage of SIH, but can also reduce the blood pressure of rats that have already developed SIH. The antihypertensive effect of melatonin may be mediated by GABA(A) receptors through inhibition of plasma AngII levels.
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PMID:Melatonin reduces blood pressure in rats with stress-induced hypertension via GABAA receptors. 1901 3


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