Chronic intermittent hypoxia (CIH) in rats produces changes in the central regulation of cardiovascular and respiratory systems by unknown mechanisms. We hypothesized that CIH (6% O 2 for 40 s, every 9 min, 8 h day −1 ) for 10 days alters the central respiratory modulation of sympathetic activity. After CIH, awake rats (n = 14) exhibited higher levels of mean arterial pressure than controls (101 ± 3 versus 89 ± 3 mmHg, n = 15, P < 0.01). Recordings of phrenic, thoracic sympathetic, cervical vagus and abdominal nerves were performed in the in situ working heart-brainstem preparations of control and CIH juvenile rats. The data obtained in CIH rats revealed that: (i) abdominal (Abd) nerves exhibited an additional burst discharge in late expiration; (ii) thoracic sympathetic nerve activity (tSNA) was greater during late expiration than in controls (52 ± 5 versus 40 ± 3%; n = 11, P < 0.05; values expressed according to the maximal activity observed during inspiration and the noise level recorded at the end of each experiment), which was not dependent on peripheral chemoreceptors; (iii) the additional late expiratory activity in the Abd nerve correlated with the increased tSNA; (iv) the enhanced late expiratory activity in the Abd nerve unique to CIH rats was accompanied by reduced post-inspiratory activity in cervical vagus nerve compared to controls. The data indicate that CIH rats present an altered pattern of central sympathetic-respiratory coupling, with increased tSNA that correlates with enhanced late expiratory discharge in the Abd nerve. Thus, CIH alters the coupling between the central respiratory generator and sympathetic networks that may contribute to the induced hypertension in this experimental model.

Peripheral chemoreflex activation with potassium cyanide (KCN) in awake rats or in the working heart-brainstem preparation (WHBP) produces: (a) a sympathoexcitatory/pressor response; (b) bradycardia; and (c) an increase in the frequency of breathing. Our main aim was to evaluate neurotransmitters involved in mediating the sympathoexcitatory component of the chemoreflex within the nucleus tractus solitarii (NTS). In previous studies in conscious rats, the reflex bradycardia, but not the pressor response, was reduced by antagonism of either ionotropic glutamate or purinergic P2 receptors within the NTS. In the present study we evaluated a possible dual role of both P2 and NMDA receptors in the NTS for processing the sympathoexcitatory component (pressor response) of the chemoreflex in awake rats as well as in the WHBP. Simultaneous blockade of ionotropic glutamate receptors and P2 receptors by sequential microinjections of kynurenic acid (KYN, 2 nmol (50 nl) −1 ) and pyridoxalphosphate-6-azophenyl-2 ,4 -disulphonate (PPADS, 0.25 nmol (50 nl) −1 ) into the commissural NTS in awake rats produced a significant reduction in both the pressor (+38 ± 3 versus +8 ± 3 mmHg) and bradycardic responses (−172 ± 18 versus −16 ± 13 beats min −1 ; n = 13), but no significant changes in the tachypnoea measured using plethysmography (270 ± 30 versus 240 ± 21 cycles min −1 , n = 7) following chemoreflex activation in awake rats. Control microinjections of saline produced no significant changes in these reflex responses. In WHBP, microinjection of KYN (2 nmol (20 nl) −1 ) and PPADS (1.6 nmol (20 nl) −1 ) into the commissural NTS attenuated significantly both the increase in thoracic sympathetic activity (+52 ± 2% versus +17 ± 1%) and the bradycardic response (−151 ± 17 versus −21 ± 3 beats min −1 ) but produced no significant changes in the increase of the frequency of phrenic nerve discharge (+0.24 ± 0.02 versus +0.20 ± 0.02 Hz). The data indicate that combined microinjections of PPADS and KYN into the commissural NTS in both awake rats and the WHBP are required to produce a significant reduction in the sympathoexcitatory response (pressor response) to peripheral chemoreflex activation. We conclude that glutamatergic and purinergic mechanisms are part of the complex neurotransmission system of the sympathoexcitatory component of the chemoreflex at the level of the commissural NTS. There is both anatomical and functional evidence that the peripheral chemoreceptor afferents make their first synapses in the nucleus tractus solitarii (NTS) terminating mainly in the commissural NTS (Donoghue et al.

Neurogenic hypertension has been the subject of extensive research worldwide. This review is based on the premise that some forms of neurogenic hypertension are caused in part by the formation of angiotensin-II (Ang-II)-induced reactive oxygen species along the subfornical organ-paraventricular nucleus of the hypothalamus-rostral ventrolateral medulla pathway (SFO-PVN-RVLM pathway). We will discuss the recent contribution of our laboratory and others regarding the mechanisms by which neurons in the SFO (an important circumventricular organ) are activated by Ang-II, how the SFO communicates with two other important areas involved in sympathetic activity regulation (PVN and RVLM) and how Ang-II-induced reactive oxygen species participate along the SFO-PVN-RVLM pathway in the pathogenesis of neurogenic hypertension.

Abstract-Renovascular hypertension in mice is characterized by an elevation in hypothalamic angiotensin II levels. The paraventricular nucleus (PVN) is a major cardioregulatory site implicated in the neurogenic component of renovascular hypertension. Increased superoxide (O 2 Ϫ⅐ ) production in the PVN is involved in angiotensin II-dependent neurocardiovascular diseases such as hypertension and heart failure. Here, we tested the hypothesis that excessive O 2 Ϫ⅐ production and activation of the redox-regulated transcription factor activator protein-1 (AP-1) in PVN contributes to the development and maintenance of renovascular hypertension. Male C57BL/6 mice underwent implantation of radiotelemeters, bilateral PVN injections of an adenovirus (Ad) encoding superoxide dismutase (AdCuZnSOD) or a control gene (LacZ), and unilateral renal artery clipping (2-kidney, one-clip [2K1C]) or sham surgery. AP-1 activity was longitudinally monitored in vivo by bioluminescence imaging in 2K1C or sham mice that had undergone PVN-targeted microinjections of an Ad encoding the firefly luciferase (Luc) gene downstream of AP-1 response elements (AdAP-1Luc). 2K1C evoked chronic hypertension and an increase in O 2 Ϫ⅐ production in the PVN. Viral delivery of CuZnSOD to the PVN not only prevented the elevation in O 2 Ϫ⅐ but also abolished renovascular hypertension. 2K1C also caused a surge in AP-1 activity in the PVN, which paralleled the rise in O 2 Ϫ⅐ production in this brain region, and this was prevented by treatment with AdCuZnSOD. Finally, Ad-mediated expression of a dominant-negative inhibitor of AP-1 activity in the PVN prevented 2K1C-evoked hypertension. These results implicate oxidant signaling and AP-1 transcriptional activity in the PVN as key mediators in the pathogenesis of renovascular hypertension.

In the present study, we tested the hypothesis that chronic intermittent hypoxia (CIH) produces changes in the autonomic and respiratory responses to acute peripheral chemoreflex activation. To attain this goal, 3-week-old rats were exposed to 10 days of CIH (6% O 2 for 40 s at 9 min intervals; 8 h day −1 ). They were then used to obtain a working heart-brainstem preparation and, using this unanaesthetized experimental preparation, the chemoreflex was activated with potassium cyanide (0.05%, injected via the perfusion system), and the thoracic sympathetic nerve activity (tSNA), heart rate and phrenic nerve discharge (PND) were recorded. Rats subjected to CIH (n = 12), when compared with control animals (n = 12), presented the following significant changes in response to chemoreflex activation: (a) an increase in tSNA (78 ± 4 versus 48 ± 3%);