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The fundamental role and corollary effects of neuropeptides that govern cardiorespiratory control in the brain stem are poorly understood. One such regulatory peptide, catestatin [Cts, human chromogranin A-(352-372)], noncompetitively inhibits nicotinic-cholinergic-stimulated catecholamine release. Previously, we demonstrated the presence of chromogranin A mRNA in brain stem neurons that are important for the maintenance of arterial pressure. In the present study, using immunofluorescence histochemistry, we show that Cts immunoreactivity is colocalized with tyrosine hydroxylase in C1 neurons of the rostral ventrolateral medulla (RVLM, n = 3). Furthermore, we investigated the effects of Cts on resting blood pressure, splanchnic sympathetic nerve activity, phrenic nerve activity, heart rate, and adaptive reflexes. Cts (1 mM in 50 nl or 100 [micro]M in 50-100 nl) was microinjected into the RVLM in urethane-anesthetized, vagotomized, ventilated Sprague-Dawley rats (n = 19). Cardiovascular responses to stimulation of carotid baroreceptors, peripheral chemoreceptors, and the sciatic nerve (somatosympathetic reflex) were analyzed. Cts (1 mM in 50 nl) increased resting arterial pressure (28 [+ or -] 3 mmHg at 2 min postinjection), sympathetic nerve activity (15 [+ or -] 3% at 2 min postinjection), and phrenic discharge amplitude (31 [+ or -] 4% at 10 min postinjection). Cts increased sympathetic barosensitivity 40% (slope increased from -0.05 [+ or -] 0.01 before Cts to -0.07 [+ or -] 0.01 after Cts) and attenuated the somatosympathetic reflex [1st peak: 36% (from 132 [+ or -] 32.1 to 84.0 [+ or -] 17.0 [micro]V); 2nd peak: 44% (from 65.1 [+ or -] 21.4 to 36.6 [+ or -] 14.1 [micro]V)] and chemoreflex (blood pressure response to anoxia decreased 55%, sympathetic response decreased 46%). The results suggest that Cts activates sympathoexcitatory bulbospinal neurons in the RVLM and plays an important regulatory role in adaptive reflexes. baroreflex; hypoxic chemoreflex; Sprague-Dawley rat; chromogranin doi: 10.1152/ajpregu.00335.2010.

Galanin is present in neurons in the brain that are important in the control of arterial pressure, and intracisternal administration of galanin evokes hypotension, but the site of action is unknown. In urethane-anesthetized, vagotomized mechanically ventilated Sprague-Dawley rats (n = 34), we investigated the effects of microinjecting galanin (1 mM, 50 nl, 50 pmol) into the rostral ventrolateral medulla on resting splanchnic sympathetic nerve activity, arterial pressure, heart rate, and phrenic nerve activity. Second, we determined the effect of microinjecting galanin into the rostral ventrolateral medulla on the cardiovascular response to stimulation of central and peripheral chemoreceptors, arterial baroreceptors, and the somatosympathetic reflex. Galanin caused a prolonged reduction in resting splanchnic sympathetic nerve activity (-37.0 [+ or -] 7.2% of baseline), mean arterial pressure (-17.0 [+ or -] 3.5 mmHg), and heart rate (-25.0 [+ or -] 9.1 beats/min). Galanin increased the sympathoinhibitory response to aortic depressor nerve stimulation by 51.8%, had no effect on the somatosympathetic reflex, and markedly attenuated the effect of hypercapnia and hypoxia on arterial pressure (by 65% and 92.4% of control, respectively). These results suggest a role for galanin neurotransmission in the integration of the cardiovascular responses to hypoxia, hypercapnia, and the sympathetic baroreflex in the rostral ventrolateral medulla. The data suggest that galanin may be an important peptide in the homeostatic regulation of chemosensory reflexes. baroreflex; somatosympathetic reflex; hypercapnia; hypoxia

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide present in the rat brain stem. The extent of its localization within catecholaminergic groups and bulbospinal sympathoexcitatory neurons is not established. Using immunohistochemistry and in situ hybridization, we determined the extent of any colocalization with catecholaminergic and/or bulbospinal projections from the brain stem was determined. PACAP mRNA was found in tyrosine hydroxylaseimmunoreactive (TH-ir) neurons in the C1-C3 cell groups. In the rostral ventrolateral medulla (RVLM), PACAP mRNA was found in 84% of the TH-ir neurons and 82% of bulbospinal TH-ir neurons. The functional significance of these PACAP mRNA positive bulbospinal neurons was tested by intrathecal administration of PACAP-38 in anaesthetized rats. Splanchnic sympathetic nerve activity doubled (110%) and heart rate rose significantly (19%), although blood pressure was unaffected. In addition, as previously reported, PACAP was found in the A1 cell group but not in the A5 cell group or in the locus coeruleus. The RVLM is the primary site responsible for the tonic and reflex control of blood pressure through the activity of bulbospinal presympathetic neurons, the majority of which contain TH. The results indicate 1) that pontomedullary neurons containing both TH and PACAP that project to the intermediolateral cell column originate from C1-C3 and not A5, and 2) intrathecal PACAP-38 causes a prolonged, sympathoexcitatory effect. intrathecal; barodenervation; cholera toxin B; Sprague-Dawley

Serotonin (5-HT) is crucial to normal reflex vagal modulation of heart rate (HR). Reduced baroreflex sensitivity [spontaneous baroreflex sensitivity (sBRS)] and HR variability (HRV) reflect impaired neural, particularly vagal, control of HR and are independently associated with depression. In conscious, telemetered Flinders-Sensitive Line (FSL) rats, a well-validated animal model of depression, we tested the hypothesis that cardiovascular regulatory abnormalities are present and associated with deficient serotonergic control of reflex cardiovagal function. In FSL rats and control Flinders-Resistant (FRL) and Sprague-Dawley (SD) rat strains, diurnal measurements of HR, arterial pressure (AP), activity, sBRS, and HRV were made. All strains had normal and similar diurnal variations in HR, AP, and activity. In FRL rats, HR was elevated, contributing to the reduced HRV and sBRS in this strain. In FSL rats, sBRS and high-frequency power HRV were reduced during the night, indicating reduced reflex cardiovagal activity. The ratio of low- to high-frequency bands of HRV was increased in FSL rats, suggesting a relative predominance of cardiac sympathetic and/or reflex activity compared with FRL and SD rats. These data show that conscious FSL rats have cardiovascular regulatory abnormalities similar to depressed humans. Acute changes in HR, AP, temperature, and sBRS in response to 8-hydroxy-2-(di-n-propylamino)tetralin, a 5-[HT.sub.1A], 5-[HT.sub.1B], and 5-[HT.sub.7] receptor agonist, were also determined. In FSL rats, despite inducing an exaggerated hypothermic effect, 8-hydroxy-2-(di-n-propylamino)teltralin did not decrease HR and AP or improve sBRS, suggesting impaired serotonergic neural control of cardiovagal activity. These data suggest that impaired serotonergic control of cardiac reflex function could be one mechanism linking reduced sBRS to increased cardiac risk in depression. serotonin- 1A receptors; 8-hydroxy-2-(di-n-propylamino)tetralin; Flinders Sensitive Line rat; vagus; telemetry

Acetylcholine receptors (AChR) are important in premotor and efferent control of autonomic function; however, the extent to which cardiovascular function is affected by genetic variations in AChR sensitivity is unknown. We assessed heart rate variability (HRV) and baroreflex sensitivity (BRS) in rats bred for resistance (FRL) or sensitivity (FSL) to cholinergic agents compared with Sprague-Dawley rats (SD), confirmed by using hypothermic responses evoked by the muscarinic agonist oxotremorine (0.2 mg/kg ip) (n [greater than or equal to] 9 rats/group). Arterial pressure, ECG, and splanchnic sympathetic (SNA) and phrenic (PNA) nerve activities were acquired under anesthesia (urethane 1.3 g/kg ip). HRV was assessed in time and frequency domains from short-term R-R interval data, and spontaneous heart rate BRS was obtained by using a sequence method at rest and after administration of atropine methylnitrate (mATR, 2 mg/kg iv). Heart rate and SNA baroreflex gains were assessed by using conventional pharmacological methods. FRL and FSL were normotensive but displayed elevated heart rates, reduced HRV and HF power, and spontaneous BRS compared with SD. mATR had no effect on these parameters in FRL or FSL, indicating reduced cardiovagal tone. FSL exhibited reduced PNA frequency, longer baroreflex latency, and reduced baroreflex gain of heart rate and SNA compared with FRL and SD, indicating in FSL dual impairment of cardiac and circulatory baroreflexes. These findings show that AChR resistance results in reduced cardiac muscarinic receptor function leading to cardiovagal insufficiency. In contrast, AChR sensitivity results in autonomic and respiratory abnormalities arising from alterations in central muscarinic and or other neurotransmitter receptors. heart rate variability; baroreflex sensitivity; Flinders Sensitive line; Flinders Resistant line

The effects of activation and blockade of the neurokinin 1 (NK1) receptor in the rostral ventrolateral medulla (RVLM) on arterial blood pressure (ABP), splanchnic sympathetic nerve activity (sSNA), phrenic nerve activity, the somato-sympathetic reflex, baroreflex, and chemoreflex were studied in urethane-anesthetized and artificially ventilated Sprague-Dawley rats. Bilateral microinjection of either the stable substance P analog (pGlu5, MePheS, Sar9)SP(5-11) (DiMe-SP) or the highly selective NK1 agonist [Sar9, Met ([O.sub.2])11]SP into the RVLM resulted in an increase in ABP, sSNA, and heart rate and an abolition of phrenic nerve activity. The effects of [Sar9, Met ([O.sub.2])11]SP were blocked by the selective nonpeptide NK1 receptor antagonist WIN 51708. NK1 receptor activation also dramatically attenuated the somato-sympathetic reflex elicited by tibial nerve stimulation, while leaving the baroreflex and chemoreflex unaffected. This effect was again blocked by WIN 51708. NK1 receptor antagonism in the RVLM, with WIN 51708 significantly attenuated the sympathoexcitatory response to hypoxia but had no effect on baseline respiratory function. Our findings suggest that substance P and the NK1 receptor play a significant role in the cardiorespiratory reflexes integrated within the RVLM. substance P; rostral ventrolateral medulla; baroreflex; brainstem; sympathetic nerve activity; neurokinin 1

The aim of this study was to examine the cardiorespiratory effects of chemically stimulating neurons in the midline medulla oblongata (MM) of artificially ventilated and freely breathing anesthetized rats. Earlier studies reported that stimulation of the MM elicits increases or decreases in mean arterial pressure (MAP) and phrenic nerve activity, depending on the mode and site of stimulation, anesthetic, and species. In the first series of experiments, rats were anesthetized with urethane, artificially ventilated, paralyzed, and bilaterally vagotomized. The rostrocaudal extent of the MM was mapped by microinjections of DL-homocysteic acid or L-glutamate (both 100 mM, 100 nl), and, in line with previous studies, most injections produced only small responses in MAP, heart rate, and splanchnic sympathetic nerve activity. Increases in respiratory parameters were evoked in caudal regions. However, activation of a discrete region of the MM at the level of the caudal pole of the facial nucleus (CP7) consistently caused a dramatic reduction in phrenic nerve amplitude and/or frequency and, in six rats, produced a prolonged apnea. The second series of experiments was carried out on freely breathing pentobarbitone sodium-anesthetized rats, with a diaphragmatic electromyogram used to monitor respiratory activity. Respiratory activity could again be abolished at CP7 after microinjections of glutamate (100 mM, 50 nl); however, these responses were accompanied by large decreases in MAP and moderate reductions in heart rate. This depression of respiratory activity may be due to activation of propriobulbar inhibitory neurons that project to known respiratory centers in the brain stem. medullary raphe nuclei; apnea; chemosensitivity

The location and types of opioid receptors that contribute to hypotension after hemorrhage were investigated. It was found that intrathecal naloxone methiodide inhibited the drop in blood pressure after hemorrhage and that intracisternal naloxone methiodide was less effective than intrathecal naloxone methiodide. Moreover, intravenous naloxone methiodide had no effect on the blood pressure after hemorrhage. These results indicate that the spinal cord in the major site of action of opioids in hemorrhage-induced hypotension.