Nitric oxide, synthesized from the semiessential amino acid L-arginine by nitric oxide synthase, is a remarkable regulatory molecule and plays an important role in physiological functions. However, the physiological role of nitric oxide in cardiovascular regulation by the central nervous system is not well understood. In this study we investigated the cardiovascular effects of nitric oxide in the lateral ventricle, nucleus tractus solitarii, area postrema, and rostral ventrolateral medulla in urethane-anesthetized male Sprague-Dawley rats. Microinjection of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, into the cerebral ventricle of rats elicited a dose-dependent increase in blood pressure and heart rate. This suggests that nitric oxide may be involved in central cardiovascular regulation. Unilateral microinjection (60 nL) of L-arginine (1 to 100 nmol) into the nucleus tractus solitarii and rostral ventrolateral medulla produced prominent dose-related depressor and bradycardic effects and reduced renal sympathetic nerve activity. However, L-arginine had no significant cardiovascular effects in the area postrema. In addition, 4 to 6 hours after intravenous injection of bacterial endotoxin-lipopolysaccharide (10 mg/kg), there was a time-related potentiation of the L-arginine-induced depressor and bradycardic effects in the nucleus tractus solitarii. These results indicate that nitric oxide is involved in central cardiovascular regulation. The depressor effect of nitric oxide in the nucleus tractus solitarii and rostral ventrolateral medulla may be through inhibition of renal sympathetic nerve activity.

The present study was performed to evaluate the effects of the tricyclic antidepressant amitriptyline on morphine tolerance in rats. Male Wistar rats were implanted with two intrathecal (i.t.) catheters with or without a microdialysis probe, then received a continuous i.t. infusion of saline (control) or morphine (15 microg/h) and/or amitriptyline (15 microg/h) for 5 days. The results showed that amitriptyline alone did not produce an antinociceptive effect, while morphine alone induced antinociceptive tolerance and down-regulation of spinal glutamate transporters (GLAST, GLT-1, and EAAC1) in the rat spinal cord dorsal horn. Co-administration of amitriptyline with morphine attenuated morphine tolerance and up-regulated GLAST and GLT-1 expression. On day 5, morphine challenge (10 microg/10 microl) resulted in a significant increase in levels of the excitatory amino acids (EAAs), aspartate and glutamate, in CSF dialysates in morphine-tolerant rats. Amitriptyline co-infusion not only markedly suppressed this morphine-evoked EAA release, but also preserved the antinociceptive effect of acute morphine challenge at the end of infusion. Glial cells activation and increased cytokine expression (TNFalpha, IL-1beta, and IL-6) in the rat spinal cord were induced by the 5-day morphine infusion and these neuroimmune responses were also prevented by amitriptyline co-infusion. These results show that amitriptyline not only attenuates morphine tolerance, but also preserves its antinociceptive effect. The mechanisms involved may include: (a) inhibition of pro-inflammatory cytokine expression, (b) prevention of glutamate transporter down-regulation, and even up-regulation of glial GTs GLAST and GLT-1 expression, with (c) attenuation of morphine-evoked EAA release following continuous long-term morphine infusion.

Background-Water ingestion raises blood pressure substantially in patients with perturbed autonomic control and more modestly in older subjects. It is unclear whether prophylactic water drinking improves orthostatic tolerance in normal healthy adults. Methods and Results-Twenty-two healthy subjects, 18 to 42 years of age, with no history of syncope underwent head-up tilt-

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Rationale: Angiotensin (Ang) II exerts diverse physiological actions in both the peripheral and central neural systems. It was reported that the activity of Ang II is higher in the nucleus tractus solitarii (NTS) of spontaneously hypertensive rats (SHRs) and that angiotensin type-1 receptors are colocalized with NAD(P)H oxidase in the neurons of the NTS, resulting in the induction of local reactive oxygen species production by Ang II. However, the signaling mechanisms of Ang II that induce hypertension remain unclear. Objective: The aim of this study was to investigate the possible signaling pathways involved in Ang II-mediated blood pressure regulation in the NTS. Methods and Results: Male SHRs were treated with losartan or tempol for 2 weeks, after which systolic blood pressure was observed to decrease significantly. Dihydroethidium staining showed many cells with high reactive oxygen species in the NTS of SHRs. The addition of losartan or tempol decreased the numbers of reactive oxygen species-positive cells in the NTS. The systemic administration of losartan or tempol reduced the systolic blood pressure and increased NO production. Immunoblotting and immunohistochemical analysis further showed that inhibition of Ang II activity by losartan or tempol significantly increased the expression extracellular signal-regulated kinase (ERK)1/2, ribosomal protein S6 kinase (RSK), and also increased neuronal NO synthase (nNOS) phosphorylation. RSK was also found to bind directly to nNOS and induce phosphorylation at the Ser1416 position. Conclusions: Taken together, these results suggest that the ERK1/2-RSK-nNOS signaling pathway may play a significant role in Ang II-mediated central blood pressure regulation. (Circ Res. 2010;106:788-795.)Key Words: angiotensin II Ⅲ nucleus tractus solitarii Ⅲ neuronal nitric oxide synthase Ⅲ ribosomal protein S6 kinase Ⅲ reactive oxygen species T he nucleus tractus solitarii (NTS), which is located in the dorsal medulla of the brain stem, is the primary site of termination of the vagus and glossopharyngeal nerves. The NTS participates in cardiovascular, gastric, and gustatory control. Our previous studies demonstrated that several neuromodulators are involved in cardiovascular control of the NTS, including ATP, 1 adenosine, 2 neuropeptide Y, 3 angiotensin (Ang) II, 4 NO, 5 carbon monoxide, 6 and insulin. 7 Ang II is a powerful vasoconstrictor in the peripheral blood system that exerts effects on the central nervous system, regulating fluid balance and the secretion of aldosterone. Hyperactivity of Ang II has been shown to play a major role in hypertension. 8,9 Ang II is produced from enzymatic cleavage of angiotensinogen by renin and then by angiotensin converting enzyme. These pathological and physiological actions of Ang II are mediated through its type 1 receptor (AT 1 R). 10 Recent evidence suggests that hyperactivity of the brain renin-angiotensin system may play a critical role in mediating hypertension in spontaneously hypertensive rats (SHRs). 11 Significant differences in AT 1...

Nitric oxide (NO) is an endogenously synthesized effector molecule that acts as a neurotransmitter with novel properties in both the central and peripheral nervous systems. We previously reported that NO was involved in central cardiovascular regulation and modulated the baroreflex in the nucleus tractus solitarii (NTS) of rats. The aim of the present study was to determine whether NO and excitatory amino acids reciprocally release each other in the NTS. In normotensive Sprague-Dawley rats, intra-NTS microinjection of L-arginine (1 to 100 nmol/60 nL) produced a dose-dependent decrease in blood pressure and heart rate. Microinjection of excitatory amino acids L-glutamate and NMDA also produced depressor and bradycardic effects. These effects of L-glutamate or NMDA were blocked by prior administration of NO synthase inhibitor N(G)-methyl-L-arginine or N(G)-nitro-L-arginine methyl ester. Similarly, prior administration of N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione significantly attenuated the depressor and bradycardic effect of L-arginine. These results demonstrated a reciprocal attenuation of NO synthase inhibitor and NMDA receptor antagonist on NMDA and L-arginine responses, respectively, in the NTS and suggest that NO and NMDA receptors may interact in central cardiovascular regulation.

Several lines of evidence suggest that the N-methyl-D-aspartate receptor (NMDA) and nitric oxide (NO) systems are involved in morphine tolerance. Cyclooxygenase (COX) inhibitors may also play a role in morphine tolerance by interacting with both systems. In the present study, we examined the effects of the COX inhibitors N-(2-cyclohexyloxy-4-nitrophenyl) methanesulphonamide (NS-398, selective COX2 inhibitor) and indomethacin (non-selective COX inhibitor) on the development of antinociceptive tolerance of morphine in a rat spinal model. The antinociceptive effect was determined by the tail-flick test. Tolerance was induced by injection of morphine 50 micrograms intrathecally (i.t.) twice daily for 5 days. The effects of NS-398 and indomethacin on morphine antinociceptive tolerance were examined after administering these drugs i.t. 10 min before each morphine injection. Neither NS-398 nor indomethacin alone produced an antinociception effect at doses up to 40 micrograms. NS-398 and indomethacin did not enhance the antinociceptive effect of morphine in naïve and morphine-tolerant rats. However, they shifted the morphine antinociceptive dose-response curve to the left when coadministered with morphine during tolerance induction, and reduced the increase in the ED50 of morphine (dose producing 50% of the maximum response) three- to four-fold. Collectively, these findings and previous studies suggest that COX may be involved in the development of morphine tolerance without directly enhancing its antinociceptive effect.

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