Development of angiotensin II (Ang II)-dependent hypertension involves microglial activation and proinflammatory cytokine actions in the hypothalamic paraventricular nucleus (PVN). Cytokines activate receptor signaling pathways that can both acutely grade neuronal discharge and trigger long-term adaptive changes that modulate neuronal excitability through gene transcription. Here, we investigated contributions of PVN cytokines to maintenance of hypertension induced by infusion of Ang II (150 ng/kg/min, SC) for 14 days in rats consuming a 2% NaCl diet. Results indicate that bilateral PVN inhibition with the GABA-A receptor agonist muscimol (100 pmol/50 nL) caused significantly greater reductions of renal and splanchnic sympathetic nerve activity (SNA) and mean arterial pressure (MAP) in hypertensive than normotensive rats (P<0.01). Thus ongoing PVN neuronal activity appears required for support of hypertension. Next, the role of the prototypical cytokine tumor necrosis factor alpha (TNF-α) was investigated. Whereas PVN injection of TNF-α (0.3 pmol/50 nL) acutely increased lumbar and splanchnic SNA and MAP, interfering with endogenous TNF-α by injection of etanercept (10 µg/50 nL) was without effect in hypertensive and normotensive rats. We next determined that although microglial activation in PVN was increased in hypertensive rats, bilateral injections of minocycline (0.5 µg/50 nL), an inhibitor of microglial activation, failed to reduce lumbar or splanchnic SNA or MAP in hypertensive or normotensive rats. Collectively, these findings indicate that established Ang II-salt hypertension is supported by PVN neuronal activity, but short term maintenance of SNA and ABP does not depend on ongoing local actions of TNF-α.
Abstract-Microinjection of the inhibitory neurotransmitter ␥-aminobutyric acid B-subtype receptor agonist baclofen into the nucleus tractus solitarius increases arterial blood pressure and sympathetic nerve discharge. The baclofen-induced pressor response is enhanced in chronic hypertension. We hypothesized that a postsynaptic mechanism contributes to the enhanced responses to baclofen in hypertension. We investigated the postsynaptic effect of baclofen on second-order baroreceptor neurons, identified by 1,1Ј-dilinoleyl-3,3,3Ј,3Ј-tetra-methylindocarbocyanine, 4-chlorobenzenesulphonate labeling of the aortic nerve, in nucleus tractus solitarius slices from sham-operated normotensive and unilateral nephrectomized, renal-wrap hypertensive rats. Key Words: cardiovasular regulation Ⅲ baroreceptor Ⅲ baroreflex Ⅲ hypertension Ⅲ blood pressure T he nucleus tractus solitarius (NTS) is the first site of baroreceptor afferent integration within the central nervous system. 1,2 The synaptic transmission of baroreceptor afferents within the NTS is constantly modulated by both excitatory and inhibitory inputs mediated by many neurotransmitters, including the inhibitory neurotransmitter ␥-aminobutyric acid (GABA). Microinjection of baclofen, a selective GABA B-subtype (GABA B ) receptor agonist, into the NTS results in an increase in arterial pressure, heart rate, and renal sympathetic nerve discharge, 3-5 which are expected, because baclofen inhibits NTS neurons that integrate baroreceptor afferent inputs. 6 -8 This baclofen-induced pressor response is enhanced in several animal models of chronic hypertension, including the spontaneously hypertensive rat, 9,10 deoxycorticosterone salt-hypertensive rats, 11 and 1-kidney, renal wrap models of hypertension. 6 -8,12 Baclofen can presynaptically inhibit glutamate release from afferent terminals and postsynaptically induce outward current to reduce neuronal excitability in the NTS. 13 However, it is not known to what extent postsynaptic GABA B receptor-mediated inhibition contributes to the enhanced baclofen-induced pressor response in chronic hypertension.Previous studies from this laboratory have demonstrated that renal-wrap hypertension is associated with increased GABA B receptor-mediated inhibition of baroreceptor-evoked discharge in NTS neurons 8 and increased expression of GABA B receptor mRNA in the NTS. 7 To clarify GABA B receptor-mediated cellular mechanisms in the neuronal adaptations to chronic hypertension, the present study investigated the postsynaptic effect of baclofen on NTS neurons receiving monosynaptic afferent inputs from baroreceptors and the influence of chronic hypertension on the postsynaptic response to baclofen. We addressed these questions using an in vitro patch-clamp method to directly investigate the postsynaptic effect of baclofen on second-order baroreceptor neurons in the NTS. The results demonstrated that, after chronic hypertension, second-order neurons showed enhanced postsynaptic responses to baclofen. This enhanced postsynaptic baclofen ef...
Despite its usefulness as a nongenetic model of hypertension, little information is available regarding baroreflex function in the Grollman, renal wrap model of hypertension in the rat. Baroreflex regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR) were studied in male, Sprague-Dawley rats hypertensive (HT) for 1 or 4-6 wk after unilateral nephrectomy and figure-8 ligature around the remaining kidney or normotensive (NT) after sham surgery. Rats were anesthetized with Inactin and RSNA, and HR was recorded during intravenous infusions of sodium nitroprusside or phenylephrine to lower or raise mean arterial pressure (MAP). Response curves were analyzed using a logistic sigmoid function. In 1- and 4-wk HT rats the midpoints of RSNA and HR reflex curves were shifted to the right (P < 0.05). Comparing NT to 1- or 4-wk HT rats, the gain of RSNA-MAP curves was no different; however, gain was reduced in the HR-MAP curves at both 1 and 4 wk in HT rats (P < 0.05). In anesthetized rats the HR range was small; therefore, MAP and HR were measured in conscious rats during intravenous injections of three doses of phenylephrine and three doses of sodium nitroprusside. Linear regressions revealed a reduced slope in both 1- and 4-wk HT rats compared with NT rats (P < 0.05). The results indicate that baroreflex curves are shifted to the right, to higher pressures, in hypertension. After 1-4 wk of hypertension the gain of baroreflex regulation of RSNA is not altered; however, the gain of HR regulation is reduced.
Originally, uptake-mediated termination of monoamine (e.g., serotonin and dopamine) signalling was believed to only occur via high-affinity, low-capacity transporters ("uptake ") such as the serotonin or dopamine transporters, respectively. Now, the important contribution of a second low-affinity, high-capacity class of biogenic amine transporters has been recognised, particularly in circumstances when uptake transporter function is reduced (e.g., antidepressant treatment). Pharmacologic or genetic reductions in uptake function can change locomotor, anxiety-like or stress-coping behaviours. Comparable behavioural investigations into reduced low-affinity, high-capacity transporter function are lacking, in part, due to a current dearth of drugs that selectively target particular low-affinity, high-capacity transporters, such as the plasma membrane monoamine transporter. Therefore, the most direct approach involves constitutive genetic knockout of these transporters. Other groups have reported that knockout of the low-affinity, high-capacity organic cation transporters 2 or 3 alters anxiety-like and stress-coping behaviours, but none have assessed behaviours in plasma membrane monoamine transporter knockout mice. Here, we evaluated adult male and female plasma membrane monoamine transporter wild-type, heterozygous and knockout mice in locomotor, anxiety-like and stress-coping behavioural tests. A mild enhancement of anxiety-related behaviour was noted in heterozygous mice. Active-coping behaviour was modestly and selectively increased in female knockout mice. These subtle behavioural changes support a supplemental role of plasma membrane monoamine transporter in serotonin and dopamine uptake, and suggest sex differences in transporter function should be examined more closely in future investigations.
Exposure to chronic intermittent hypoxia (CIH) is an animal model that mimics the repetitive bouts of hypoxemia experienced by humans with sleep apnea. Rats exposed to CIH develop hypertension that depends on the activation of sympathetic nerve activity (SNA). Since obesity and metabolic syndrome have been linked to neurogenic hypertension and sleep apnea, and because sleep apnea can adversely affect aerobic exercise capacity, we tested the hypothesis that rats bred for selection of low aerobic capacity running (LCR) would have a greater hypertensive response to CIH than rats bred for high aerobic capacity running (HCR). Blockade of ganglionic transmission was performed to compare the contribution of SNA to the maintenance of resting mean arterial pressure (MAP). Next, hypertensive responses to 7 days of CIH were compared across LCR and HCR rats (14-16 mo old). Finally, the contribution of the hypothalamic paraventricular nucleus (PVN) to the maintenance of SNA and hypertension after CIH was determined and compared across groups. Although LCR rats were less active and had greater body weights than HCR rats, resting MAP, the contribution of ongoing SNA to the maintenance of MAP, and hypertensive responses to CIH were similar between groups. Contrary to our hypothesis, chemical inhibition of the PVN with muscimol (1 mmol/100 nl) caused a larger fall of MAP in HCR rats than in LCR rats. We conclude that LCR rats do not have resting hypertension or an exaggerated hypertensive response to CIH. Interestingly, the maintenance of CIH hypertension in LCR rats compared with HCR rats appears less reliant on ongoing PVN neuronal activity.
Abstract-To identify central neurons participating in cardiovascular regulation in hypertension, we studied Fos staining, a marker for synaptically activated neurons, in adult male normotensive and hypertensive (HT) rats. At 1 and 4 weeks after induction of unilateral nephrectomy, renal wrap hypertension mean arterial pressure was 138Ϯ4 mm Hg (nϭ6) in 1-week HT rats and 159Ϯ6 mm Hg (nϭ6) in 4-week HT rats. Mean arterial pressure was 103Ϯ2 mm Hg (nϭ6) in sham-operated, normotensive rats. Mean arterial pressure was greater in both HT groups compared with normotensive rats, and the mean arterial pressure in 4-week HT rats was greater than that in 1-week HT rats. Rats were anesthetized and perfused, brains sectioned and processed using a Fos antibody, and the number of Fos immunoreactive neurons counted in sections through various brain regions. Hypertension of 1 or 4 weeks did not alter the number of Fos immunoreactive neurons in the area postrema, the supraoptic nucleus, and the median preoptic nucleus. The number of Fos immunoreactive neurons was increased after 1 and 4 weeks in the nucleus of the solitary tract, both the caudal and ventral lateral medulla, and the organum vasculosum of the lamina terminalis. In addition, after 4 weeks of HT, the number of Fos immunoreactive neurons was increased in the parabrachial nucleus and the paraventricular nucleus of the hypothalamus. The results indicate central regions active in acute and chronic HT rats and suggest certain areas that may be differentially activated depending on the duration of the hypertension. Key Words: baroreceptor Ⅲ brain Ⅲ immunohistochemistry I mmunocytochemistry for the protein Fos has been widely used to map the activation of specific regions of the central nervous system associated with acute homeostatic challenges. [1][2][3][4] Fos is an immediate early gene transcription factor that has been shown to be present in synaptically activated cells. 5 A number of studies in the rat have examined areas in the central nervous system where neurons express Fos after brief increases in arterial blood pressure 6 -13 ; however, few studies have sought to identify which of these areas might be active in chronically hypertensive (HT) rats. 14 -17 At present, our current understanding of central nervous system function in hypertension is limited because of the lack of quantitative answers to fundamental questions. Many of these questions deal with the overall operating characteristics of the peripheral and central sites that regulate blood pressure. For example, is the number of neurons active in a particular brain region different in an HT compared with a normotensive (NT) individual? Is the number of neurons active in a particular brain region graded as a function of the magnitude or the duration of the change in blood pressure?Therefore, quantification of the number of neurons in key central sites active in renal wrap HT rats is important. Such information could provide insights into areas that are likely candidates to mediate the elevated sympathetic ...
Compared to WKY rats, sympathetic nerve activity (SNA) and elevated arterial pressure (AP) in spontaneous hypertensive rats (SHR) is supported by enhanced glutamatergic drive of group 1 mGluR (mGluR1 & mGluR5) in the PVN. Whether enhanced group 1 mGluR activity is a genetically determined feature of sympathetic control unique to SHR or is a mechanism of PVN activation common to other hypertensive states is undetermined. To investigate this, euhydrated (EU) and 48 h water deprived (WD) rats were studied, as dehydration also acutely increases AP by increasing glutamatergic drive of the PVN. In conscious EU rats, injection of the group 1 mGluR agonist DHPG (2 nmol in 200 nl) increased AP (n=3, p<0.05). This effect was attenuated by prior PVN injection of the mGluR1 antagonist LY‐367385 (4 nmol in 200 nl; n=3, p<0.05), but not the mGluR5 antagonist MPEP (4 nmol in 200 nl; n=2). Injections of LY and MPEP alone were each without affect in EU (n=2) and WD rats (n=3). Similar results were obtained in EU (n=3) and WD (n=2) rats under anesthesia in which renal SNA was also unaffected by blockade of PVN group 1 mGluR. Thus, whereas activation of PVN group 1 mGluR is sympathoexcitatory and contributes to sympathetic support of ongoing AP in SHR, the latter appears not to be a common mechanism of PVN driven support of SNA or elevated AP, as no tonic role for PVN group 1 mGluR activity was observed either in EU or 48 h WD rats. HL102310 and HL088052 (GMT)
Microinjection of the GABAB receptor agonist baclofen into the NTS increases arterial pressure, heart rate and sympathetic nerve discharge. This response is enhanced in hypertension and is associated with increased post‐synaptic GABAB receptor function. We tested whether a presynaptic mechanism also contributes to the enhanced baclofen effect in hypertension. Whole‐cell recordings of NTS second‐order neurons identified by DiA labeling of aortic nerve were obtained in a brain slice from normotensive control (NT) and renal‐wrap hypertensive (HT) rats. After 4 weeks, arterial blood pressure was 162±9 mmHg in HT rats (n=6) and 107±3 mmHg in NT rats (n=6/11) (p<0.001). Baclofen reduced amplitude of evoked EPSCs (eEPSCs) elicited by tractus stimulation and the EC50 of was significantly greater in NT rats (1.5±0.5 μM, n=6) than HT rats (0.6±0.1 μM, n=6, p<0.05). Baclofen (1 μM) elicited greater inhibition of eEPSCs in HT (58±6%, n=9) than NT cells (40±6%, n=8, p<0.05). HT cells (0.60±0.08, n=8) had greater paired‐pulse ratio (PPR) of eEPSCs than NT cells (0.48±0.06, n=5, p<0.05). After application of baclofen (1 μM) HT cells (0.92±0.07) had greater PPR than NT cells (0.67±0.05, p<0.05). The results suggest that in renal‐wrap HT rats baclofen evokes an enhanced presynaptic inhibition of glutamate release in 2nd‐order baroreceptor neurons. This enhanced inhibition could alter baroreflex function in hypertension.
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