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.

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.

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...

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.