Differential cardiorespiratory and sympathetic reflex responses to microinjection of neuromedin U in rat rostral ventrolateral medulla.

The rostral ventrolateral medulla (RVLM) regulates sympathetic vasomotor outflow and reflexes. Intracerebroventricular neuromedin U (NMU) increases sympathetic nerve activity (SNA), mean arterial pressure (MAP), and heart rate (HR), but the central nuclei that mediate these effects are unknown. In urethane-anesthetized, vagotomized, and artificially ventilated male Sprague-Dawley rats (n = 36) the effects of bilateral microinjection of NMU (50 nl, each side) into RVLM on cardiorespiratory variables, somatosympathetic reflex, arterial baroreflex, and chemoreflex were investigated. Microinjection of NMU into RVLM elicited a hypertension, tachycardia, and an increase in splanchnic SNA (SSNA) and lumbar SNA (LSNA) at lower doses (25 and 50 pmol). At higher dose (100 pmol), NMU caused a biphasic response, a brief hypertension and sympathoexcitation followed by prolonged hypotension and sympathoinhibition. The peak excitatory and inhibitory response was found at 100 pmol NMU with an increase in MAP, HR, SSNA, and LSNA of 36 mm Hg, 20 beats per minute, 34%, and 89%, respectively, and a decrease of 33 mm Hg, 25 beats per minute, 42%, and 52%, respectively, from baseline. NMU, in the RVLM, also increased phrenic nerve amplitude and the expiratory period and reduced the inspiratory period. NMU (100 pmol) attenuated the somatosympathetic reflex and the sympathoexcitatory and respiratory responses to hypoxia and hypercapnia. After NMU injection in RVLM, the maximum gain of the SSNA baroreflex function curve was increased, but that of the LSNA was reduced. The present study provides functional evidence for a complex differential modulatory activity of NMU on the cardiovascular and reflex responses that are integrated in the RVLM.

Neuromedin U causes biphasic cardiovascular effects and impairs baroreflex function in rostral ventrolateral medulla of spontaneously hypertensive rat.

Neuromedin U (NMU) causes biphasic cardiovascular and sympathetic responses and attenuates adaptive reflexes in the rostral ventrolateral medulla (RVLM) and spinal cord in normotensive animal. However, the role of NMU in the pathogenesis of hypertension is unknown. The effect of NMU on baseline cardiorespiratory variables in the RVLM and spinal cord were investigated in urethane-anaesthetized, vagotomized and artificially ventilated male spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Experiments were also conducted to determine the effects of NMU on somatosympathetic and baroreceptor reflexes in the RVLM of SHR and WKY. NMU injected into the RVLM and spinal cord elicited biphasic response, a brief pressor and sympathoexcitatory response followed by a prolonged depressor and sympathoinhibitory response in both hypertensive and normotensive rat models. The pressor, sympathoexcitatory and sympathoinhibitory responses evoked by NMU were exaggerated in SHR. Phrenic nerve amplitude was also increased following intrathecal or microinjection of NMU into the RVLM of both strains. NMU injection into the RVLM attenuated the somatosympathetic reflex in both SHR and WKY. Baroreflex sensitivity was impaired in SHR at baseline and further impaired following NMU injection into the RVLM. NMU did not affect baroreflex activity in WKY. The present study provides functional evidence that NMU can have an important effect on the cardiovascular and reflex responses that are integrated in the RVLM and spinal cord. A role for NMU in the development and maintenance of essential hypertension remains to be determined.

Orexin A in rat rostral ventrolateral medulla is pressor, sympatho-excitatory, increases barosensitivity and attenuates the somato-sympathetic reflex.

BACKGROUND AND PURPOSE: The rostral ventrolateral medulla (RVLM) maintains sympathetic nerve activity (SNA), and integrates adaptive reflexes. Orexin A-immunoreactive neurones in the lateral hypothalamus project to the RVLM. Microinjection of orexin A into RVLM increases blood pressure and heart rate. However, the expression of orexin receptors, and effects of orexin A in the RVLM on splanchnic SNA (sSNA), respiration and adaptive reflexes are unknown. EXPERIMENTAL APPROACH: The effect of orexin A on baseline cardio-respiratory variables as well as the somato-sympathetic, baroreceptor and chemoreceptor reflexes in RVLM were investigated in urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats (n= 50). orexin A and its receptors were detected with fluorescence immunohistochemistry. KEY RESULTS: Tyrosine hydroxylase-immunoreactive neurones in the RVLM were frequently co-localized with orexin 1 (OX(1) ) and orexin 2 (OX(2) ) receptors and closely apposed to orexin A-immunoreactive terminals. Orexin A injected into the RVLM was pressor and sympatho-excitatory. Peak effects were observed at 50 pmol with increased mean arterial pressure (42 mmHg) and SNA (45%). Responses to orexin A (50 pmol) were attenuated by the OX(1) receptor antagonist, SB334867, and reproduced by the OX(2) receptor agonist, [Ala(11) , D-Leu(15) ]orexin B. Orexin A attenuated the somato-sympathetic reflex but increased baroreflex sensitivity. Orexin A increased or reduced sympatho-excitation following hypoxia or hypercapnia respectively. CONCLUSIONS AND IMPLICATIONS: Although central cardio-respiratory control mechanisms at rest do not rely on orexin, responses to adaptive stimuli are dramatically affected by the functional state of orexin receptors.

Orexin and central regulation of cardiorespiratory system.

The hypothalamic peptide orexin plays a role in many physiological systems including feeding behavior, sleep-wakefulness, reward system, stress, and nociception. In addition, it is now clear that orexin is involved in the central regulation of cardiorespiratory function. Here, we review the cardiorespiratory effects elicited by central orexin and consider the physiological role of this peptide in central cardiorespiratory control in normal and pathophysiological states. Orexin neurons are found exclusively in the hypothalamus but project to almost all brain regions including cardiorespiratory regulatory areas, where their receptors are also expressed. Administration of orexin into the nucleus tractus solitarius, rostral ventrolateral medulla, rostral ventromedial medulla, and spinal cord increases blood pressure, heart rate, and sympathetic nerve activity. Orexin neurons stimulate respiration and are sensitive to changes in pH. Orexin knockout mice have apnoeic episodes in sleep. Therefore, orexin may be a potentially important therapeutic target for the treatment of cardiorespiratory disorders.

Vasostatin I (CgA17-76) vasoconstricts rat splanchnic vascular bed but does not affect central cardiovascular function.

Vasostatin I (CgA(1-76)) is a naturally occurring biologically active peptide derived from chromogranin A (CgA), and is so named for its inhibitory effects on vascular tension. CgA mRNA is expressed abundantly in sympathoexcitatory catecholaminergic neurons of the rostral ventrolateral medulla (RVLM). CgA microinjection into the RVLM decreases blood pressure (BP), heart rate (HR) and sympathetic nerve activity (SNA). Proteolytic fragments of CgA are thought to be responsible for the cardiovascular effects observed. We hypothesised that vasostatin I is one of the fragments responsible for the central effects of CgA. We examined the role of a vasostatin I fragment, CgA(17-76) (VS-I((CgA17-76))), containing the portion important for biological effects. The effects of VS-I((CgA17-76)) delivered by intrathecal injection, or microinjection into the RVLM, on cardio-respiratory function in urethane anaesthetised, vagotomised, mechanically ventilated Sprague-Dawley rats (n=21) were evaluated. The effects of intrathecal VS-I((CgA17-76)) on the somato-sympathetic, baroreceptor and peripheral chemoreceptor reflexes were also examined. At the concentrations used (10, 100 or 200 µM, intrathecal; or 5 µM, RVLM microinjection) VS-I((CgA17-76)) produced no change in mean arterial pressure, HR, splanchnic SNA, phrenic nerve amplitude or phrenic nerve frequency. All reflexes examined were unchanged following intrathecal VS-I((CgA17-76)). In the periphery, VS-I((CgA17-76)) potentiated the contractile effects of noradrenaline on rat mesenteric arteries (n=6), with a significant left-shift in the dose response curve to noradrenaline (3.7×10(-7) vs 7.7×10(-7)). Our results indicate that VS-I((CgA17-76)) is active in the periphery but not centrally, and is not a central modulator of cardiorespiratory function and physiological reflexes.