Background-Previously, we have shown that nitric oxide (NO) plays a significant role in central cardiovascular regulation and modulates the baroreflex in the nucleus tractus solitarii (NTS) of rats. NO production is mediated by activation of NO synthase (NOS). Insulin signaling was involved in controlling peripheral blood pressure via the activation of endothelial NOS. Here, we investigated whether the insulin signal transduction pathway is involved in controlling central cardiovascular effects. Methods and Results-Insulin was injected into NTS of urethane-anesthetized male Wistar-Kyoto (WKY) rats.Unilateral microinjection (60 nL) of insulin (100 IU/mL) into the NTS produced prominent depressor and bradycardic effects in 8-and 16-week-old WKY rats. In addition, pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the NOS inhibitor L-NAME into the NTS caused attenuation of the cardiovascular response evoked by insulin in either 8-or 16-week-old WKY rats. Western blot analysis showed a significant increase (2.6Ϯ0.4-fold; PϽ0.05) in Akt phosphorylation after insulin injection, whereas LY294002 abolished the insulin-induced effects. In situ Akt phosphorylation was found in NTS by immunohistochemistry analysis after injection of insulin. This in situ Akt phosphorylation was abolished significantly after injection of LY294002. Conclusions-Take together, these results suggest that the insulin-PI3K-Akt-NOS signaling pathway may play a significant role in central cardiovascular regulation. Key Words: insulin Ⅲ enzymes Ⅲ nitric oxide synthase N itric oxide (NO) has been indicated to affect sympathetic nerve activity, and it modulates blood pressure and heart rate (HR) in the nucleus tractus solitarii (NTS). 1,2 However, the mechanisms for these actions have not been clarified. NO is produced by NO synthase (NOS). 3 Previously, adenovirusmediated gene delivery of endothelial NOS (eNOS) into NTS caused hypotension and bradycardia. 4 The results suggested that genes involved in the eNOS upstream signal transduction pathway might control central cardiovascular effects.Studies have shown that insulin receptors are present in the central nervous system, 5 which indicates the significant role of insulin in the central nervous system. Havrankova et al 6 have demonstrated that insulin has an effect on cardiovascular function. Other reports also showed the effects of insulin on arterial pressure and HR after peripheral injection and suggested a function of insulin in central cardiovascular control. 7,8 Recent evidence has demonstrated that the peripheral and central influence by insulin on cardiovascular regulation is due to an influence it exerts in the sympathetic nervous system. 7 Moreover, insulin receptors are shown to be immunochemically positive in the NTS. 8 These data suggested that insulin-mediated signaling in the NTS may play a significant role in the regulation of cardiovascular activity.It then becomes important to study insulin-mediated signaling in the NTS to understand how insulin regul...

Abstract-It has been shown that nitric oxide (NO) is synthesized in the central nervous system as well as in vascular endothelial cells. We recently reported that NO was involved in central cardiovascular regulation, modulated the baroreflex, and was involved in a reciprocal release with excitatory amino acids in the nucleus tractus solitarii (NTS) of rats. We also reported previously that adenosine increased the release of glutamate in the NTS. The purpose of the present study was to investigate the possible interaction of NO and adenosine in the NTS. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Unilateral microinjection of L-arginine (3.3 nmol/60 nL) into the NTS produced decreases in blood pressure and heart rate. Microinjection of adenosine (2.3 nmol/60 nL) also produced depressive and bradycardic effects. These cardiovascular effects were attenuated by prior administration of the specific adenosine receptor antagonist DPSPX (0.92 nmol). Similarly, prior administration of NO synthase inhibitor The nucleus tractus solitarii (NTS) processes information from a visceral afferent receptor, including the baroreceptor afferent nerves, and plays an important role in the integration of autonomic control of the cardiovascular system. 5 NO synthase exists in intrinsic neurons within the NTS 6 and in central and primary afferent terminals within this nucleus. 7Tagawa et al 8 demonstrated that NO increases the neuronal activity of adjacent neurons in the NTS through an increase in cGMP. We recently reported that microinjection of L-arginine unilaterally into the NTS of anesthetized rats produced a pronounced concentration-dependent decrease in mean blood pressure (MBP), heart rate (HR), and renal sympathetic nerve activity. 9 We also found that the microinjection of NO synthase inhibitors attenuated the hemodynamic effects produced by activation of the baroreceptor reflex.10 Furthermore, NO and excitatory amino acids reciprocally release each other in the NTS. 11 These findings suggest that NO is involved in neural transmission and central cardiovascular regulation.Adenosine has been known to be a potent vasodilator acting through purinergic receptors on both vascular smooth muscle and endothelial cells. This endogenous nucleoside has been studied for its potential role as a neuromodulator in a number of autonomic functions.12 Much evidence has indicated that adenosine can also affect cardiovascular function within the CNS. [13][14][15] The highest density of adenosine uptake sites in the CNS has been observed in the NTS. 16 In this nucleus, adenosine decreases blood pressure (BP), HR, and renal sympathetic nerve activity [13][14][15] and modulates baroreflex responses. 17,18 Furthermore, it has been reported that perfusion of adenosine through a microdialysis probe can increase the release of glutamate in the NTS. 15 These effects are compatible with activation (rather than inhibition) of neuronal cells in the NTS, in which either electric stimulation 19 o...

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