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Many studies have demonstrated that the ventrolateral medulla (VLM) plays an important role in the maintenance of systemic arterial pressure (SAP) and vascular tone. The VLM is divided into rostral (RVLM) and caudal (CVLM) portions which play opposing roles in regulating cardiovascular functions. The purposes of this study are to explore the relationship of fibers projecting between the RVLM and CVLM, and to investigate the effect of propofol (PPF, 2 mg/kg), an anesthetic agent, on modulating their neuronal firing rate (NFR). Forty-four adult cats were anaesthetized intraperitoneally with urethane (400 mg/kg) and alpha-chloralose (40 mg/kg). The femoral artery was cannulated to allow monitoring of SAP and heart rate (HR). The femoral vein was cannulated for intravenous drug administration. Microinjection of glutamate (Glu, 3.0 nmol/30 nl), kynurenic acid (Kyn, 3.0 nmol/30 nl), gamma-aminobutyric acid (GABA, 4.0 nmol/30 nl), or bicuculline (Bicu, 4.0 nmol/30 nl) into the RVLM produced SAP increases or decreases, but did not significantly change the NFR in the CVLM. This occurred even after intravenous administration of PPF. This shows that there are few fiber projections from the RVLM to the CVLM. Conversely, microinjection of Glu, Kyn, GABA or Bicu into the CVLM produced SAP changes, and the NFR in the RVLM was significantly changed. These changes were more significant after intravenous administration of PPF. These results show that there are more fibers projecting from the CVLM to the RVLM and fewer fibers projecting from the RVLM to the CVLM to affect the SAP and its NFR.

Dexamethasone is an effective antiemetic drug, but its mechanism of action is unclear. We designed this study to investigate the direct antiemetic action of dexamethasone in the medulla of cats. By using an oscillographic vomiting model, decerebrated cats received microinjections of dexamethasone 100 nL (1 microg, n = 7; 0.1 microg, n = 7) into the bilateral nuclei tractus solitarii, which led to a significant prolongation of the latency (1 microg, 6.4 +/- 1.1 min versus 28.2 +/- 4.9 min, P < 0.05; 0.1 microg, 6.7 +/- 1.1 min versus 27.1 +/- 5.0 min, P < 0.05) of the first emetic episode and significantly decreased the frequency of emetic episodes (1 microg, 2.7 +/- 0.8 versus 0.1 +/- 0.4, P < 0.05; 0.1 microg, 2.9 +/- 0.9 versus 0.3 +/- 0.5, P < 0.05) induced by xylazine. Pretreatment with mifepristone, a glucocorticoid receptor antagonist, blocked the antiemetic effect of dexamethasone in the bilateral nuclei tractus solitarii. However, microinjection of dexamethasone into the unilateral nucleus tractus solitarius alone did not alter the latency of the first emetic episode or the frequency of emetic episodes induced by xylazine. Local application of dexamethasone into the area postrema had no effect on the latency of the first emetic episode or the frequency of emetic episodes induced by xylazine. These results suggest that dexamethasone exerts its central antiemetic action through an activation of the glucocorticoid receptors in the bilateral nuclei tractus solitarii in the medulla.

Nitric oxide (NO) is synthesized from L-arginine by NO synthase (NOS). NO stimulates the soluble form of guanylyl cyclase (sGC) and induces accumulation of cyclic guanosine monophosphate (cGMP). The purpose of this study was to examine whether the cardiovascular responses induced by N-methyl-D-aspartate (NMDA) in the rostral ventrolateral medulla (RVLM) depend on the actions of NOS and sGC. In anesthetized cats, the extracellular NO level was measured by in vivo voltammetry using a nafion/porphyrine/o-phenylenediamine-coated carbon-fiber electrode. Microinjection of NMDA into the RVLM produced hypertension and bradycardia associated with NO formation. These NMDA-induced responses were attenuated by prior injections of 7-nitroindazole, a neuronal NO synthase (nNOS) inhibitor, and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a sGC inhibitor. These findings suggest that NO is involved in the NMDA-induced cardiovascular responses in the RVLM.

In 20 urethane-anaesthetised cats, microinjection of N -methyl- d -aspartate (NMDA) into the intermediate-lateral (IL-) or the dorsolateral (DL-) periaqueductal grey areas (PAG) of the midbrain elicited similar patterns of cardiovascular responses: increases in mean systemic arterial pressure (MSAP), heart rate (HR) and mean blood flows (F) of the common carotid and femoral arteries, accompanied with a ‘hissing–howling’ response. Similar increases in MSAP and Fs were induced by microinjections of S-nitroso- N -acetylpenicillamine (SNAP), a potent nitric oxide (NO) donor, on the IL-PAG (A2.5–A0.5). In contrast, microinjections of N G -nitro- l -arginine methyl ester ( l -NAME), a NO synthase inhibitor, in the same area elicited a decrease in MSAP and Fs. On the other hand, microinjections of either SNAP or l -NAME reversed the original IL-PAG responses when injected into the DL-PAG. Pretreatments with SNAP significantly inhibited NMDA-induced responses in the DL-PAG but potentiated such responses in the IL-PAG. In contrast, pretreatments with l -NAME potentiated the NMDA-induced responses in the DL-PAG but inhibited such responses in the IL-PAG. These data suggest that NO may be a neurotransmitter or neuromodulator that exerts differential function in different defense areas, namely the IL- and the DL-PAG.

We investigated the responses of systemic arterial pressure and vertebral sympathetic nerve activity to glutamate microinjections (0.1 M, 70 nl) in the dorsomedial (DM) and the rostral ventrolateral medulla (RVLM) before hypoxia and after reoxygenation (posthypoxia) after various degrees of hypoxia in anesthetized cats. Hypoxia was produced by ventilating 5% O2 and 95% N2 for different durations (hypoxia I-III). In intact cats, the glutamate-induced systemic arterial pressure and vertebral nerve activity responses of the DM were depressed after all degrees of hypoxia. Posthypoxic depression in the RVLM, however, was not observed until hypoxia II and III. Precollicular decerebration prevented depression in the RVLM, but, for the DM, it was effective only for hypoxia I. Baro- and chemoreceptor denervation abolished all posthypoxic depression in both the DM and the RVLM. Pressor responses to tyramine (100–400 μg/kg iv) remained unchanged after all degrees of hypoxia. These results suggest that the DM is more susceptible to hypoxia than the RVLM. The peripheral baro- and chemoreceptors and the suprapontine structures apparently play an important role in posthypoxic depression. Moreover, the depression is not due to the postganglionic norepinephrine depletion.

In 35 adult cats anesthetized with intraperitoneal chloralose and urethane, the ventrolateral medulla was explored by microinjection of kainic acid (KA, 24 mM, 200 nl) with metal electrode-tubing or glass micropipette to determine regions which elicit persistent apnea. Persistent apnea is defined as: (1) In spontaneously breathing cats, termination of respiration over 3 min with a decrease of the mean systemic arterial pressure (MSAP) to 25 mm Hg. (2) In animals under artificial ventilation and paralyzed by gallamine, cessation of bilateral phrenic nerve (PNA) activities over 25 min. The apnea producing area was located dorsal to the rostral pole of the lateral reticular nucleus, ventromedial to the ambiguous nucleus and immediately caudal to the retrofacial nucleus. Functionally, this region includes the rostral part of the ventral respiratory group (rVRG) encompassing the pre-BOtzinger area. We define this region as the VRG apnea producing area (VRG-Apa). Fatal apneusis was observed under following conditions: (1) Persistent apnea was produced after a single KA microinjection in one side of the VRG-Apa (5 animals). Microinjection of sodium glutamate (0.25 M, 70-200 nl) in the same area produced only brief apnea, while microinjection of kynurenic acid (0.1 M, 200 nl) showed little effect on the respiration but slightly increased the SAP. (2) Positioning an electrode nearby but not in the VRG-Apa with or without KA injection did not produce apnea. But when a second electrode insertion to the opposite VRG-Apa immediately produced persistent apnea even without KA injection (6 animals). (3) Midsagittal division of the medulla 0-5 mm rostral to the obex produced persistent silence of PNA on both sides in artificial ventilated animals (7 animals), while similar division 0-5 mm caudal to the obex (4 animals) produced a brief but reversible quiescence of PNA. In conclusion, findings of the present study support the existence of a restricted region of VRG-Apa. VRG-Apa on both sides are closely connected, and integrity of both VRG-Apa is essential for normal respiration.

Phrenic motoneurons (PMNs) receive intermittently glutaminergic inspiratory drives and GABAergic inhibition in adult mammals. Since gamma-amino-butyric acid (GABA) might act as an excitatory amino acid in early stages of development, we here investigated if GABA(A) receptors inhibit PMNs in neonates. Using in vitro neonatal rat brainstem-spinal cord preparation, local application of GABA and muscimol (a GABA(A) receptor agonist) to the vicinity of PMNs consistently reduced the inspiratory activity of C4 ventral roots. Under whole-cell patch-clamp conditions and in the presence of 0.5 microM TTX to block synaptic transmission, muscimol (10 microM) decreased whole-cell input resistance, and surprisingly, when PMNs were voltage-clamped at their resting membrane potential, muscimol induced depolarizing-inward, rather than hyperpolarizing-outward membrane current. Our findings indicate that GABA(A) receptors mediate a depolarizing blockade of the glutaminergic excitatory inputs to neonatal rat PMNs.

The functional correlation of the depressor caudal ventrolateral medulla (CVLM) with the two pressor regions, i.e. rostral ventrolateral medulla (RVLM) and dorsomedial medulla (DM), and with another inhibitory region, i.e. the paramedian reticular nucleus (PRN), were studied in cats anesthetized intraperitoneally with chloralose (40 mg/kg) and urethane (400 mg/kg). Systemic arterial pressure (SAP), heart rate (HR) and the sympathetic vertebral nerve activity (VNA) were recorded. The correct location of CVLM, RVLM or DM was determined by their specific responses, i.e. decreases of SAP, HR and VNA, for CVLM increases of these parameters for RVLM and DM, elicited first by electrical stimulation (80 Hz, 0.5 ms, 50-100 microA) then followed by microinjection of glutamate (Glu, 0.25 M, 70 nl). The depressor action of PRN was produced by electrical stimulation only. It was found that the depressor responses caused by the CVLM stimulation were greatly reduced 2 h after lesioning either the RVLM or DM by microinjection of kainic acid (KA, 24 mM, 200 nl) ipsilateral to the side of CVLM stimulation. The CVLM responses were further reduced after the remaining side of RVLM or DM was lesioned. The reduction of the CVLM-depressor responses was more apparent after the RVLM than DM lesioning. Data suggest that the CVLM-depressor responses are mediated through inhibition of the sympathetic-pressor neurons in both RVLM and DM with predominance of the former. Lesioning the PRN by KA and/or combination with DC electrolytic lesion reduced the CVLM-induced depressor responses. In turn, lesioning the CVLM by KA reduced the PRN-induced depressor responses. The reduction in the later manipulation was more apparent in the PRN-depressor responses than the CVLM-depressor responses. Data suggest that part of the PRN depressor action is mediated through activation of the CVLM.

In vivo electrochemical detection was employed to examine iron-induced oxidative injury on dopamine dynamics in the nigrostriatal system of urethane-anesthetized rats. Seven days after an intranigral infusion of iron, oxidative stress was confirmed by an elevated lipid peroxidation in lesioned substantia nigra (SN). Local application of potassium (K+) evoked dopamine releases from the dopamine-containing nerve terminals in the striatum. Both amplitude and rate of clearance (Tc) of evoked dopamine releases were lower in striatum with lesioned SN; however, the time course parameters of dopamine release in the lesioned group were not different from those of the intact group, indicating a reduction in dopamine clearance. Indeed, iron-induced oxidative stress attenuated the effect of nomifensine, a high-affinity dopamine uptake blocker, on dopamine clearance. In striatum with intact SN, the amplitude and time course parameters of signals by exogenous dopamine were increased and Tc was decreased by nomifensine. In contrast, nomifensine did not significantly alter the dopamine signals of the lesioned group. Taken together, in addition to the increased lipid peroxidation in SN, our in vivo electrochemical data demonstrates that iron-induced oxidative injury attenuates K+-evoked dopamine release and dopamine uptake in the ipsilateral striatum. The diminished nomifensine effect implies a lack of high-affinity dopamine uptake sites.

1. Fifty-five intact and six baroreceptor denervated and vagotomized cats of either sex were anaesthetized intraperitoneally with urethane (400 mg/kg) and alpha-chloralose (40 mg/kg). Responses of the systemic arterial pressure (SAP), mean SAP (MSAP) and sympathetic vertebral nerve (VNA) and renal nerve activities (RNA) were recorded. 2. In intact animals, monosodium L-glutamate (Glu, 0.1 mol/L, 50 nL) was microinjected into pressor areas of the locus coeruleus (LC), gigantocellular tegmental field (GTF), rostral ventrolateral medulla (RVLM) and dorsomedial medulla (DM), and the depressor areas of caudal ventrolateral medulla (CVLM). The induced actions were compared before and after microinjection of either glutamate antagonists, glutamate diethylester (GDEE, 0.5 mol/L, 50-100 nL), a competitive AMPA receptor blocker, or 2-amino-5-phosphonovaleric acid (D-AP5, 0.025 mol/L, 50-100 nL), a competitive N-methyl-D-aspartate (NMDA) receptor blocker. GDEE completely blocked the increases of SAP and VNA elicited from all pressor areas. D-AP5 only partially blocked the pressor but slightly blocked VNA and RNA responses from LC, GTF and DM, particularly those from RVLM. Neither GDEE nor D-AP5 blocked the depressor responses of SAP and two nerve activities elicited from CVLM. 3. In baroreceptor denervated animals, NMDA (2 mmol/L, 50-100 nL) and AMPA (0.2 mmol/L, 50-100 nL) were micro-injected into the same pressor areas of GTF, RVLM and DM and the depressor area of CVLM responsive to Glu activation (0.1 mol/L, 30 nL). In RVLM, DM and CVLM, the results of either NMDA or AMPA were similar to those induced by Glu. However, in GTF, microinjection of either NMDA or AMPA did not induce similar responses to Glu. This suggests that the nature of GTF may differ from RVLM and DM. 4. The above results suggest that the Glu-induced pressor responses from LC, GTF, DM and especially RVLM, are primarily mediated through AMPA receptors. The Glu-induced depressor responses from CVLM may not be predominantly mediated by either AMPA or NMDA receptors. 5. In both baroreceptor-intact and -denervated cats stimulation of the pressor areas often produced an increase of VNA and a decrease of RNA, while in the depressor CVLM decreased both VNA and RNA. The VNA, but not RNA were positively correlated with the pressor responses, while both VNA and RNA were positively correlated with the depressor responses. This may suggest that neurons of the sympathetic vertebral and renal nerves are topographically organized in the brain.

Whether glutamate and serotonin would release and interact in the dorsal facial area (DFA) of cat medulla to regulate common carotid arterial (CCA) blood flow was explored by placing a microdialysis probe in DFA and employing high performance liquid chromatographic technique. Glutamate concentration was dose-dependently decreased by perfusion with serotonin, or alaproclate, a serotonin reuptake inhibitor. Serotonin and glutamate concentrations were increased by perfusion with KC1, a depolarizing agent. Furthermore, CCA blood flow was decreased when glutamate concentration was reduced by serotonin or alaproclate perfusion, and conversely increased when glutamate concentration was increased by KC1 perfusion. In conclusion, glutamate and serotonin releases in DFA that involve regulation of CCA blood flow are tonically mediated by nerve terminals. The glutamate release is depressed by the serotonin release.

SUMMARY 1. A small area in the dorsal part of the lateral tegmental field specifically responsible for the increase of blood flow in the common carotid artery (CCA) without accompanying change in the resting blood pressure was first identified in our laboratory. Since the area is located just dorsal to the facial nucleus, we named it the dorsal facial area (DFA; Kuo et al. 1987). 2. The purpose of this study was to clarify whether an increase of blood flow in intra- and/or extracranial tissues was responsible for the increase in CCA blood flow upon DFA stimulation, and to determine the role of cholinergic transmission in this response. 3. In 20 cats under chloralose and urethane anaesthesia, microsphere reference flow technique was used to measure the regional blood flow of intra- and extracranial tissues. 4. Electrical stimulation of the DFA appeared to increase the regional blood flow of both cerebral hemispheres (intra-cranial tissues) and to increase predominantly the regional blood flow of extracranial tissues on the side ipsilateral to stimulation. Increases in the regional blood flow of intracranial tissues were enhanced after i.v. administration of atropine but reduced with physostigmine. In contrast, increases in the regional blood flow of extracranial tissues were reduced after i.v. atropine but enhanced after physostigmine. 5. These findings suggest that DFA stimulation may promote the release of ACh in intra- and extracranial vessels. The muscarinic action may restrict the DFA-induced increase in blood flow of intracranial tissues, but enhance that of extracranial tissues.

Objective: The aim was to evaluate the effects of an opiate agonist (U50,488H) and an opiate antagonist (naloxone) in myocardial ischaemia. Methods: A left thoracotomy was performed and the left coronary artery was ligated in adult Sprague-Dawley rats of either sex (350-400 g). Blood pressure, heart rate and electrocardiogram were measured before and after injections of U50,488H or naloxone and throughout the 30 min postligation period. Results: Following coronary artery occlusion, all rats in the control group developed arrhythmias, bradycardia, and hypotension. U50,488H potentiated and naloxone attenuated the ischaemia induced arrhythmias, bradycardia, and hypotension. Conclusions: The potentiating and blocking effects of U50,488H and naloxone, respectively, suggest that endogenous opioid peptides are involved in the pathophysiology of myocardial ischaemia and play an important role in ischaemic heart disease.

An isolated thoracic spinal cord of the neonatal rat in vitro spontaneously generates sympathetic nerve discharge (SND) at ~25 degrees C, but it fails in SND genesis ator = 10 degrees C. Basal levels of the c-Fos expression in the spinal cords incubated ator = 10 degrees C and ~25 degrees C were compared to determine the anatomical substrates that might participate in SND genesis. Cells that exhibited c-Fos immunoreactivity were virtually absent in the spinal cords incubated ator = 10 degrees C. However, in the spinal cords incubated at ~25 degrees C, c-Fos-positive cells were found in the dorsal laminae, the white matter, lamina X, and the intermediolateral cell column (IML). Cell identities were verified by double labeling of c-Fos with neuron-specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), or choline acetyltransferase (ChAT). The c-Fos-positive cells distributed in the white matter and lamina X were NeuN-negative or GFAP-positive and were glial cells. Endogenously active neurons showing c-Fos and NeuN double labeling were scattered in the dorsal laminae and concentrated in the IML. Double labeling of c-Fos and ChAT confirmed the presence of active sympathetic preganglionic neurons (SPNs) in the IML. Suppression of SND genesis by tetrodotoxin (TTX) or mecamylamine (MECA, nicotinic receptor blocker) almost abolished c-Fos expression in dorsal laminae, but only mildly affected c-Fos expression in the SPNs. Therefore, c-Fos expression in some SPNs does not require synaptic activation. Our results suggest that spinal SND genesis is initiated from some spontaneously active SPNs, which are capable of TTX- or MECA-resistant c-Fos expression.

The aim of this study was to investigate the effects of the cannabinoid receptor agonist, WIN55212-2, and the cannabinoid receptor antagonist, SR141716A, on dopamine (DA) release evoked by KC1 (120 mM) microinjected into the striatum. The cannabinoid agonist WIN55212-2 (1 and 5 mg/kg, i.p.) dose-dependently attenuated DA release in the striatum, whereas the cannabinoid receptor antagonist SR141716A (3 mg/kg, i.p.) produced the opposite effect. SR141716A (3 mg/kg, i.p.) blocked the effects on DA release by WIN55212-2 (5 mg/kg, i.p.). Vehicle alone did not change DA release. These results suggest that cannabinoids modulate DA release in the striatum.

The effect of propofol on neuronal activity in the rostral ventrolateral medulla (RVLM) is not well established. Therefore, we performed extracellular recording on neurons of the RVLM to investigate neuronal activity before and after administration of intravenous propofol. The mean systemic arterial pressure (MSAP), heart rate and integrated neuronal firing rate (INFR) in the RVLM were continuously recorded in anesthetized cats before and after intravenous injection of 2 mg/kg propofol or supplemental injections of 1, 2 and 4 mg/kg propofol that were given respectively. Additionally, we compared the MSAP, heart rate (HR), and INFR in the RVLM following intravenous injection of 2 mg/kg propofol or 12.5 microg/kg nitroprusside. Neuronal firing was dose-dependently and reversibly inhibited after the supplemental doses of 1, 2 and 4 mg/kg propofol. The control INFR was 14.2 +/- 9.9 Hz, and this decreased to 12.1 +/- 9.4 Hz after the first dose of propofol (P = 0.085 vs. control), and further decreased to 9.3 +/- 7.7 Hz (P = 0.001 vs. control) and 7.5 +/- 7.7 Hz (P0.001 vs. control) after the second and third doses of propofol, respectively. Besides, SAP and HR were dose-dependently decreased by propofol as well. However, the effects of propofol and nitroprusside on neuronal activity in the RVLM differed. Propofol inhibited neuronal firing, whereas nitroprusside activated neuronal firing. In conclusion, propofol may dose-dependently inhibit spontaneous neuronal activity and the baroreflex in the RVLM.

We examined the effects of serotonin (5-HT) on cardiovascular responses and blood flows in the right common carotid artery (RCCA), superior mesenteric artery (SMA) and right femoral artery (RFA), stimulated by glutamate (Glu) in the dorsomedial medulla (DM), rostral ventrolateral medulla (RVLM) and caudal ventrolateral medulla (CVLM). Microinjection of Glu into the DM produced increases in systemic arterial pressure (SAP) and flows in the RCCA and RFA, and decrease in flow in the SMA. Microinjection of Glu into the RVLM produced increases in SAP and decreases in flows in the RCCA, SMA and RFA. Prior microinjections of 5-HT into the same sites attenuated all the Glu-induced responses. Microinjection of Glu into the CVLM produced decreases in SAP and flows in the RCCA, SMA and RFA. These decreases were potentiated by prior injection of 5-HT. These findings suggest that 5-HT modulates the cardiovascular and blood flow responses induced by Glu in the medulla.

The rostral ventrolateral medulla (RVLM) plays an important role in the integration of cardiovascular functions. We examined the effect of asphyxia on cardiovascular responses, on sympathetic vertebral nerve activity (VNA) and nitric oxide (NO) formation in the RVLM, on hemodynamics, and on plasma concentrations of catecholamines, blood gas partial pressures and carbohydrate metabolites. Using 16 anesthetized cats we found that the systemic arterial pressure (SAP), VNA, NO formation and the release of plasma catecholamine components of norepinephrine and epinephrine were increased during asphyxia. The onset of NO production was significantly earlier than that of SAP and VNA. The venous partial pressure of O2 decreased, while the partial pressure of CO2 increased. Furthermore, metabolism of glucose and lactate increased, as did the blood concentrations of white and red blood cells, hemoglobin and platelets. Thus, asphyxia increased SAP, VNA and NO formation. It increased the plasma catecholamines, blood gases, carbohydrate metabolites and blood cells.

Using in vivo voltammetry to directly measure extracellular nitric oxide (NO) levels, our previous studies suggested that the neuronal NO synthase (nNOS) and cyclic guanosine monophosphate (cGMP) signal transducing systems are involved in the cardiovascular responses elicited by activation of N-methyl-D-aspartate (NMDA) receptors in the rostral ventrolateral medulla. In this study, we examined if the depressor responses elicited by activation of NMDA receptors in the caudal ventrolateral medulla (CVLM) also depend on the actions of nNOS and soluble guanylyl cyclase. In anesthetized cats, microinjection of NMDA into the CVLM produced hypotension and bradycardia associated with NO formation. These NMDA-induced responses were attenuated by prior injections of 2-amino-5-phosphonopentanoate (a NMDA receptor competitive antagonist), 7-nitroindazole (a nNOS inhibitor) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (an inhibitor of soluble guanylyl cyclase). These findings suggest that NO is also involved in the NMDA-induced depressor responses of the CVLM.

SUMMARY 1. The purpose of the present study was to investigate the effect of bilateral common carotid artery occlusion (BCCAO) on cardiovascular responses and nitric oxide (NO) formation in the nucleus tractus solitarius (NTS). 2. Twenty-three adult cats were anaesthetized intraperitoneally with urethane (400 mg/kg) and α-chloralose (40 mg/kg). The femoral artery was cannulated to allow monitoring of systemic arterial pressure (SAP) and heart rate (HR). The femoral vein was cannulated for intravenous drug administration. 3. Extracellular NO levels in the NTS were measured by in vivo voltammetry using an NO microsensor combined with a microcomputer-controlled apparatus. 4. Microinjection of l-arginine (30 nmol) into the NTS produced hypotension and NO release. This effect of l-arginine was not changed by 2 min of BCCAO. 5. Bilateral common carotid artery occlusion produced increases in SAP and NO levels. These effects were more apparent in vagotomized than in intact animals. 6. The onset latency of BCCAO-induced changes in SAP levels (8.4 ± 2.5 s) was longer than that for changes in NO (4.7 ± 1.7 s). 7. Bilateral common carotid artery occlusion induced hypertension and NO release in the NTS of intact and vagotomized animals. These cardiovascular and NO responses to BCCAO were significantly attenuated by NG-nitro-l-arginine methyl ester (10 mg/kg, i.v.) and MK-801 (2.5 mg/kg, i.v.). These data suggest that NO synthase and activation of N-methyl-d-aspartate receptors are involved in the cardiovascular and NO responses to BCCAO.

Propofol is a potent intravenous anesthetic. The action of propofol on the medullary depressor area, the caudal ventrolateral medulla (CVLM), has not been well established. We therefore performed extracellular recordings to study the neuronal activity of the CVLM in cats before and after intravenous propofol administration, to investigate its influence on neuronal firings.Experiments were performed on 31 cats anaesthetized with a mixture of alpha-chloralose and urethane administered intraperitoneally. Mean systemic arterial pressure, heart rate, and the neuronal firing (NF) rate were continuously recorded before and after intravenous injection of a single dose of 2 mg x kg(-1) propofol or separate supplemental doses of 1, 2, and 4 mg x kg(-1) propofol until those parameters had returned to the premedication level.Propofol dose-dependently and reversibly inhibited the NF rate after the supplemental doses of 1, 2, and 4 mg x kg(-1) propofol. The control NF rate of 17.9 +/- 8.6 Hz was depressed to 15.8 +/- 8.5 Hz after the first dose of propofol (p0.05 vs. the control), and was further depressed to 12.8 +/- 8.3 Hz (p0.05 vs. the control) and 10.0 +/- 7.9 Hz (p0.05 vs. the control) after the second and the third doses of propofol, respectively.The dose-dependent inhibition of the spontaneous neuronal firing rate is the main pharmacological action of propofol in the caudal ventrolateral medulla of cats.

Pressor and sympathoexcitatory responses induced by microinjection of glutamate (Glu) into the dorsomedial medulla (DM) were depressed after hypoxia in anesthetized cats. This study was undertaken to investigate which Glu receptor subtypes would be involved in the post-hypoxic depression. Hypoxia was induced by inhalation of a 5% O(2) and 95% N(2) gas mixture. The pressor and sympathoexcitatory responses to microinjections of N-methyl-D-aspartic acid (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) into the DM were significantly depressed after hypoxia, suggesting the involvement of both NMDA and AMPA receptors. However, pretreatment with kynurenic acid or DL-2-amino-5-phosphonopentanoic acid, but not 6-cyano-7-nitroquinoxaline-2,3-dione, 5 min before hypoxia could effectively prevent the post-hypoxic depression of Glu-induced responses. These results further suggest that post-hypoxic depression of Glu-induced responses in the DM was predominately mediated by NMDA receptors.

The present study examines the coexistence of neurons in the same cardiovascular point of the pontomedulla that integrates urinary bladder (UB) motility, and pelvic nerve activity (PNA). Microinjection of monosodium L-glutamate (Glu) into the locus coeruleus (LC), the gigantocellular tegmental field (FTG), the rostral ventrolateral medulla (RVLM), and the dorsomedial medulla (DM) produced pressor responses, whereas injection into the lateral tegmental field (FTL), the nucleus of tractus solitarii (NTS), and the caudal ventrolateral medulla (CVLM) produced depressor responses. However, microinjection of Glu into the dorsomotor nucleus of the vagus (DMV) and the ambiguus nucleus (AN), where the vagus nerve originates, produced marked bradycardia. Many of these cardiovascular responses were accompanied by increased, or decreased parasympathetic PNA. In six animals, sympathetic renal nerve activity (RNA) and PNA also increased simultaneously during the pressor response. The present study also examines the connection between the DMV-AN and the sacral intermediolateral column (IML), where parasympathetic preganglionic neurons (PGNs) of the pelvic nerve located. Biotinylated dextran amine (BDA), an anterograde tracer, was iontophoretically injected into the DMV or AN. No labelled terminal or neuron was detected in the sacral IML, but labelled terminals were observed in the bilateral LC, and also in the bilateral sides of the FTG, FTL, RVLM, DM, and CVLM. These results suggest that neurons of the DMV and/or AN may indirectly regulate the sacral parasympathetic PGNs through the LC for supraspinal control of the pelvic nerve. Furthermore, these results also suggest the coexistence of multiple autonomic integrating mechanisms of different kinds within various cardiovascular areas of the pontomedulla.

Increasing evidence has demonstrated that nitric oxide (NO) is involved in central cardiovascular regulation. In this study, we directly measured extracellular NO levels, in real-time, in the nucleus tractus solitarius (NTS) of anesthetized cats using Nafion/Porphyrine/o-Phenylenediamine-coated NO sensors. We found that local application of L-arginine (L-Arg) induced NO overflow in NTS and hypotension. These responses were potentiated in the vagotomized animals. Pretreatment with NO synthase (NOS)/guanylate cyclase inhibitor methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or NO scavenger hemoglobin attenuated L-Arg-induced hypotension, suggesting that exogenous supplement of NO suppressed cardiac functions through the NOS/cyclic guanosine monophosphate mechanism. The role of endogenous NO was examined after local application of N(G)-nitro-L-arginine methyl ester (L-NAME). We found that L-NAME suppressed endogenous NO levels in NTS and elicited hypertension and tachycardia. Taken together, our data suggest that NO is tonically released in the NTS to inhibit blood pressure.

Objective—To determine antiemetic efficacy of prophylactic administration of dexamethasone and its influence on sedation in cats sedated with xylazine hydrochloride. Animals—6 healthy adult cats (3 males and 3 females). Procedure—The prophylactic antiemetic effect of 4 doses of dexamethasone (1, 2, 4, and 8 mg/kg of body weight, IM) or saline (0.9% NaCl) solution (0.066 ml/kg, IM) administered 1 hour before administration of xylazine (0.66 mg/kg, IM) was evaluated. Cats initially were given saline treatment (day 0) and were given sequentially increasing doses of xylazine on days 7, 14, 21, and 28. After xylazine injection, all cats were observed for 30 minutes to allow assessment of frequency of emesis and time until onset of the first emetic episode. The influence of dexamethasone on xylazine-induced sedation in these cats also was evaluated. Results—Prior treatment with 4 or 8 mg/kg of dexamethasone significantly reduced the frequency of emetic episodes and also significantly prolonged the time until onset of the first emetic episode after xylazine injection. Time until onset of the first emetic episode also was significantly prolonged for dexamethasone at a dose of 2 mg/kg. Time until onset of sedation after administration of xylazine was not altered by administration of dexamethasone. Conclusions and Clinical Relevance—Dexamethasone (4 or 8 mg/kg, IM) significantly decreased the frequency of emetic episodes induced by xylazine without compromising sedative effects in cats. Dexamethasone may be used prophylactically as an antiemetic in cats treated with xylazine. (Am J Vet Res 2001;62:1218–1221)

SUMMARY 1. The role of nitric oxide (NO) in central cardiovascular regulation and the correlation between NO and glutamate-induced mechanisms is not clear. Microinjection of glutamate (3 nmol/ 30 nL) into dorsomedial medulla (DM) and rostral ventrolateral medulla (RVLM) increased arterial blood pressure (BP) and sympathetic vertebral nerve activity (VNA). Thus, in the present study, we examined the modulation by NO of glutamate-induced pressor responses in the DM and RVLM of cats. 2. Histochemical methods using nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) as a marker to stain neurons containing NO synthase (NOS), showed positive findings of NOS in both the DM and RVLM. 3. Microinjection of NG-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, into the DM or RVLM did not alter resting BP and VNA, but it did cause a dose-dependent attenuation of glutamate-induced pressor responses. Interestingly, the increase in NO levels that resulted from pretreatment with L-arginine (L-Arg) or sodium nitroprusside (SNP) did not alter resting BP and VNA, but still inhibited glutamate-induced pressor responses in the DM and RVLM in a dose-dependent manner. 4. We also examined whether NO modulated the pressor responses induced by activation of different excitatory amino acid receptors. N-Methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) were used. Consistent with the results from the initial glutamate studies, we observed that not only L-NAME, but also L-Arg and SNP attenuated pressor responses induced by NMDA and AMPA. No difference was found between the effects of NO on NMDA- and AMPA-induced pressor responses. 5. To investigate the possibility of a loss of agonist selectivity, the effects of D-2-amino-5-phosphonovalerate (D-AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) on AMPA and NMDA responses in the DM were examined. The results showed that CNQX did not alter NMDA-induced pressor responses, while D-AP5 failed to alter AMPA-induced responses. 6. Our results suggest that activation of the glutamate-induced pressor mechanism is regulated by changes in NO levels in the DM and RVLM. This implies that NO may play a permissive role to allow operation of the glutamate-activation mechanism.

We examined the involvement of caudal ventrolateral medulla (CVLM) in respiratory control. Microinjection of glutamate (Glu) into CVLM decreased systemic arterial blood pressure (SAP) and altered phrenic nerve activities (PNA). Among 143 depressor sites, 55% (78/143) increased respiratory frequency (Rf), while 72% altered PNA amplitude (36% increased and 36% decreased). A small but significant positive correlation was observed between the magnitudes of depressor responses and inhibition of PNA amplitude (r = 0.1718, n = 143), indicating a substantial cross-talk between depressor and PNA inhibitory neurons. Furthermore, microinjections of acetylcholine (ACh) mimicked the Glu-induced depressor responses. However, ACh did not alter Rf, but still reduced PNA amplitude. Our findings suggest that Rf-regulating and depressor neurons are two separate neuronal populations, coexisting in CVLM. The PNA inhibitory and depressor neurons, in contrast, could have stronger correlation.

An involvement of dopamine uptake in the N-methyl-D-aspartate (NMDA)-modulated dopaminergic transmission in rat striatum was studied using the technique of in vivo electrochemical detection. Microinjection of potassium (K+) evoked dopamine overflows from the dopamine-containing nerve terminals in the striatum. While application of NMDA did not evoke any dopamine overflow, co-application of NMDA and K+ induced larger dopamine overflows than those by K+ alone. Furthermore, dynamic analysis showed that the rate of clearance (Tc) was reduced by NMDA. Indeed, our uptake study demonstrated an NMDA-induced inhibition of dopamine clearance. The time course of electrochemical signals evoked by microinjection of exogenous dopamine was increased and Tc was reduced following NMDA application. In order to delineate the effects of NMDA on K(+)-evoked dopamine overflows and/or on dopamine uptake, nomifensine, a dopamine uptake inhibitor was used. Application of nomifensine potentiated K(+)-evoked dopamine overflows. Co-administration of NMDA further augmented dopamine overflows by the K+ and nomifensine mixture. Taken together, our data suggest that NMDA concomitantly potentiated dopamine overflows in response to depolarizing stimuli and attenuated dopamine uptake. The increment by NMDA of K(+)-evoked dopamine overflows may partially result from an attenuated dopamine uptake in rat striatum.

Propofol may cause hypotension and the mechanism is complex. The present study was designed to determine the direct actions of propofol in medulla of cats. Mean systemic arterial pressure (MSAP), heart rate (HR) and cardiac contractility (dp/dt) were compared before and after administration of propofol through the femoral vein (2, 3 or 4 mg · kg−1), vertebral artery (1 mg · kg−1) or the lateral cerebral ventnricle (0.5 mg · kg−1) in eight anaesthetized cats. To study the direct effect of propofol in medulla, pressor areas of the dorsomedial medulla (DM) and rostral ventrolateral medulla (RVLM), or the depressor area of the caudal ventrolateral medulla (CVLM) were first identified with electrical stimuli and then confirmed by pressure microinjection of glutamate (Glu, 0.25M, 30 nl) via a multibarrel-micropipette in 28 cats. One hour later, propofol (0.001%, 50 nl) was microinjected at the same site. Electrical stimulation and Glu were applied again to compare changes of SAR HR and dp/dt with that of the control. Propofol dose-dependently decreased SAR HR and cardiac contractility. The percent increase of MSAP induced by Glu were reduced by propofol in DM (59 ± 3 % vs 13 ± 2 %, n = 11.P 0.05). Our results show that propofol principally inhibits the vasomotor mechanism in the dorsomedial and ventrolateral medulla to effect its hypotensive actions. Nos resultats montrent que l’action hypotensive du propofol est causee par l’inhibition du mecanisme vasomoteur au niveau des zones bulbaires dorsomediane et ventrolaterale.

The penile erection ability (PEA) was assessed in 27 dogs with intact orchids (Group I), seven dogs with bilateral orchidectomy for one month (Group II) and four dogs with bilateral orchidectomy for three months (Group III). PEA was indicated by the increase of the intracorporeal pressure (ICP) upon electrical stimulation of the cavernous nerves. PEA was significantly decreased in both orchidectomized groups. However, when reduction in the blood pressure was considered, the difference in PEA between Group I and the orchidectomized group was no longer significant. Before the orchidectomy, plasma testosterone level of 22 adult male dogs varied widely from 105 to 6302 pg./ml. At one or three months after the orchidectomy in 11 dogs, it decreased to a level below 100 pg./ml. There was no significant change in the body weight in the post orchidectomy period. These findings indicate that the castration and/or the resulting low plasma testosterone level does not directly affect PEA through the peripheral neural and cavernosal mechanism.

Single unit activity was recorded by means of five-barrel micropipettes from temperature-sensitive neurons in the reticular formation of the medulla oblongata in urethanized cats. Acetylcholine (ACh), norepinephrine (NE) and 5-hydroxytryptamine (5-HT) were applied microiontophoretically to the immediate vicinity of the neurons. Both thermally sensitive and insensitive units responded to ACh (82.0%) and 5-HT (93.0%) by increasing discharge rate. Iontophoretically applied atropine, but not hexamethonium, antagonized the excitatory responses to ACh. NE was shown to have different effects on the medullary neurons. Most temperature-insensitive units were either nonresponsive (52.4%) or excited (28.6%) by NE, while a majority of warm-sensitive (61.8%) and cold-sensitive (55.6%) neurons were inhibited by NE. Iontophoretically application of the alpha-adrenergic blocking agent, phentolamine, or the beta-antagonists, propranolol, or sotalol, produced no effect on the inhibitory responses to NE. These results tend to support the current concept of the transmitter role of monoamines in thermoregulation.

Repeated electrical stimulation of the brain stem including the hypothalamus, pons and medulla in monkeys produced an increase in arterial blood pressure, cardiac arrhythmias, various degrees of S-T segment or T wave changes and structural damage to the myocardium. The following ultrastructural changes in the myocardium occurred: distension of sarcoplasmic reticulum, swelling of mitochondria, disarrangement of filamentous arrays, formation of contraction bands, dissociation of intercalated discs and focal necrosis. These changes are similar to those found in ischemic myocardial tissue and myocardial necrosis induced by catecholamines. The myocardial lesions are probably related to activation of the sympathetic mechanism in the brain stem.

Single unit activity was recorded with glass microelectrodes in the reticular formation of the medulla oblongata of cats lightly anesthetized with urethan, while medullary temperature was changed by surface irrigation with warm or cold artificial cerebrospinal fluid. In addition, water-perfusion thermodes were implanted over the preoptic anterior hypothalamus (POAH) region, and the effects of heating and cooling of the POAH on firing rate of medullary units were studied. One hundred and twenty-five temperature-sensitive neurons were studied in the medullary reticular formation. Out of these 125 neurons, 80 were warm-sensitive and 45 were cold-sensitive. Sixteen warm-sensitive medullary neurons were examined in responses to changes of POAH temperature. Ten units (62.5%) responded, and the remaining 6 units were not responsive to changes of the POAH temperature. Of 13 cold-sensitive neurons examined, 10 units (77.0%) responded. On the other hand, only 1 out of 7 (14.3%) temperature-insensitive neurons tested did respond to changes in the POAH temperature. These results suggest that the temperature signals sent out from thermosensitive structures in the hypothalamus might be transmitted to a major portion of temperature-sensitive neurons in the medullary reticular formation.

In cats under light chloralose and sodium pentobarbital anesthesia the effects of electrical stimulation of various visceral afferent nerves on leg extension induced by sciatic afferent stimulation were studied. Stimulation of the central end of the cervical vagus and stellate ganglion produced inhibition of induced leg extension while stimulation of the distal end of the thoracic vagus, coeliac ganglion, and splanchnic nerves produced facilitation. Decortication slightly reduced the inhibitory effect and greatly reduced the facilitatory effect. Additional decerebration greatly reduced the inhibitory effect and almost abolished the facilitatory effect. Spinal transection at C1 completely abolished the inhibitory and facilitatory effects on induced leg extension. These results suggest that visceral afferents facilitate sciatic induced leg extension principally through the cortex while they inhibit extension through the midbrain and hypothalamus.

Intravenous picrotoxin injection has been established as a model of producing arrhythmias, mainly through enhanced central sympathetic outflow. The effects of calcium-channel blockers, and a beta-blocker on these arrhythmias were tested in chloralose-anesthetized cats. Picrotoxin (10 mg/kg, i.v.) produced mostly ventricular, sometimes supraventricular tachycardias and ectopic beats, as well as a marked elevation of arterial blood pressure. Nifedipine at the doses of 2 micrograms/kg (i.v. or i.c.) and 5 micrograms/kg (i.v.) transiently suppressed the arrhythmias in some of the cats tested. With the dose of 10 micrograms/kg (i.v.), it promptly and consistently abolished the arrhythmias without recurrence and significantly reduced the blood pressure (-62 +/- 8/-59 +/- 8 mmHg, delta systolic pressure/delta diastolic pressure, p less than 0.001, n = 9). A similar degree of blood pressure reduction (-69 +/- 8/-67 +/- 7 mmHg, n = 6) after sodium nitroprusside (4-5 mg/kg, i.v.) injection abolished the arrhythmias in 4 of 6 cats; however, there was marked ECG evidence of myocardial ischemia in 3 cats. Verapamil (50 micrograms/kg, i.v.) transiently abolished the arrhythmias and significantly decreased the blood pressure (7/7 cats), whereas a larger dose (150 micrograms/kg) had a persistent effect (2/4 cats). Propranolol at a dose of 240 micrograms/kg also consistently abolished the arrhythmias without recurrence in all 4 cats. We conclude that nifedipine, verapamil and propranolol are effective in the treatment of picrotoxin-induced arrhythmias. This result indicates that calcium-channel blockers or beta-blockers may be clinically effective in the treatment or prevention of arrhythmias caused by intracranial lesions with enhanced sympathetic outflow.

Cardiovascular parameters of spontaneously breathing pond turtles (Cyclemys flavomarginata) anaesthetized with chloralose (4 mg 100 g−1) and urethane (40 mg 100 g−1), were examined during exploratory electrical stimulation of the brain stem. Turtles exhibited a low mean systemic arterial blood pressure (MSAP, average 25 mmHg) and slow heart rate (average 24 beats min−1). Upon stimulation, pressor (sympathetic), depressor (sympathetic inhibition), bradycardia and hypotensive (vagal) responses were elicited from regions of the brain stem extending from the hypothalamus to the medulla, principally in the medial region. The pressor response appeared after a longer latency than did the bradycardia and hypotensive responses. It developed rather slowly, and rarely attained a magnitude double its resting value. In contrast, stimulation of many points in the brain stem produced marked slowing or even cessation of the heart beat, and thus resulted in an immediate fall of the blood pressure even to zero. This cardio-inhibitory response depended on the integrity of the vagus nerves and was particularly marked upon stimulation in the caudal medulla, the areas of the ambiguus, solitary and dorsomotor nuclei of the vagus and the midline structures. When such an area was stimulated continuously the heart stopped beating throughout the stimulation. The longest period of cardiac arrest before the appearance of escape was 35 min. With continuous stimulation of the peripheral end of the cut vagus, the earliest escape beat occurred even later (65min). Epinephrine given intravenously produced an increase of MSAP and force of cardiac contraction, although the slope of pressor rise was shallow. Reflex bradycardia, however, was not observed. These experiments show that a very prominent vagal bradycardia can be evoked from the turtle brain stem, which may contribute to its well-known capacity for tolerating anoxia.