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)

The dorsomedial hypothalamus (DMH) is critically implicated in the cardiovascular response to emotional stress. This study aimed to determine whether the DMH is also important in cardiovascular arousal associated with appetitive feeding behavior and, if so, whether locally released angiotensin II and glutamate are important in this arousal. Emotional (air-jet) stress and feeding elicited similar tachycardic (+51 and +45 beats/min, respectively) and pressor (+16 and +9 mmHg, respectively) responses in conscious rabbits. Bilateral microinjection of GABA(A) agonist muscimol (500 pmol) into the DMH, but not nearby hypothalamic regions, attenuated pressor and tachycardic responses to air-jet by 56-63% and evoked anorexia. Conversely, stimulation of the DMH with the glutamate analog kainic acid (250 pmol) elicited hypertension (+25 mmHg) and tachycardia (+114 beats/min) and activated feeding behavior. Local microinjection of a glutamate receptor antagonist, kynurenic acid (10 nmol), decreased pressor responses to stress and eating by 46 and 72%, respectively, without affecting feeding behavior. Bilateral microinjection of a selective AT(1)-receptor antagonist, candesartan (500 pmol), into the DMH, but not nearby sites, attenuated pressor and tachycardic stress responses by 31 and 33%, respectively. Candesartan did not alter feeding behavior or circulatory response to feeding. These results indicate that, in addition to its role in mediating stress responses, the DMH may be important in regulating cardiovascular arousal associated with feeding. Local glutamatergic inputs appear to regulate cardiovascular response to both stress and feeding. Conversely, angiotensin II, acting via AT1 receptors, may selectively modulate, in the DMH, cardiovascular response to stress, but not feeding.
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PMID:Angiotensin II in dorsomedial hypothalamus modulates cardiovascular arousal caused by stress but not feeding in rabbits. 1614 7

Male Sprague-Dawley rats underwent sinoaortic denervation (SAD) or sham operation. We examined changes in the release rates of GABA, glutamate and arginine in the locus coeruleus (LC) elicited by experimental blood pressure increases (i.v. noradrenaline infusion for 3 min, 4 microg kg(-1)min(-1)) or decreases (i.v. sodium nitroprusside infusion for 3 min, 150 microg kg(-1)min(-1)). The release of the neurotransmitters was monitored by the push-pull superfusion technique. Mean blood pressure did not differ between sham-operated and SAD rats but blood pressure lability was greatly enhanced in SAD rats and accompanied by increased basal release of glutamate in the LC. GABA release was not affected. A rise in blood pressure induced by noradrenaline enhanced GABA release in the LC of sham-operated rats. This effect was abolished by SAD. Glutamate release did not respond to hypertension either in SAD or in sham-operated rats. Nitroprusside led to a fall in blood pressure which was more pronounced and lasted longer in SAD than in sham-operated rats. In SAD rats, glutamate release was enhanced by nitroprusside. The depressor response had no effect on glutamate release in sham-operated rats. GABA release did not respond to this stimulus in either SAD or sham-operated rats. SAD and blood pressure changes did not influence the release rate of arginine. In conclusion, experimental hypertension increases GABAergic activity in the LC by stimulating peripheral baroreceptors. In SAD rats, augmented blood pressure lability seems to be at least partly due to elevated glutamate outflow within the LC.
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PMID:Sinoaortic denervation abolishes blood pressure-induced GABA release in the locus coeruleus of conscious rats. 1623 53

Increased sympathetic outflow contributes to the pathogenesis of hypertension. However, the mechanisms of increased sympathetic drive in hypertension remain unclear. We examined the tonic GABAergic inhibition in control of the excitability of paraventricular (PVN) presympathetic neurons in spontaneously hypertensive rats (SHR) and normotensive controls, including Sprague-Dawley (SD) and Wistar-Kyoto (WKY) rats. Whole cell patch-clamp recordings were performed on retrogradely labeled PVN neurons projecting to the rostral ventrolateral medulla (RVLM) in brain slices. The basal firing rate of PVN neurons was significantly decreased in 13-wk-old SD and WKY rats but increased in 13-wk-old SHR, compared with their respective 6-wk-old controls. The GABA(A) antagonist bicuculline consistently increased the firing of PVN neurons in normotensive controls. Surprisingly, bicuculline either decreased the firing or had no effect in 59.3% of labeled cells in 13-wk-old SHR. In contrast, the GABA(B) antagonist CGP-55845 had no effect on the firing of PVN neurons in normotensive controls but significantly increased the firing of 75% of cells studied in 13-wk-old SHR. Furthermore, the evoked GABA(A) current decreased significantly in labeled PVN neurons of 13-wk-old SHR compared with that in normotensive controls. Both the frequency and amplitude of GABAergic spontaneously inhibitory postsynaptic currents were also reduced in 13-wk-old SHR. This study demonstrates an unexpected functional change in GABA(A) and GABA(B) receptors in regulation of the firing activity of PVN-RVLM neurons in SHR. This change in GABA(A) receptor function and GABAergic inputs to PVN output neurons may contribute to increased sympathetic outflow in hypertension.
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PMID:Plasticity of GABAergic control of hypothalamic presympathetic neurons in hypertension. 1624 12

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


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