Effects of inspiratory impedance on the carotid–cardiac baroreflex response in humans

Abstract. We were interested in a therapeutic device designed to increase carotid–cardiac baroreflex sensitivity (BRS) since high BRS is associated with a lower risk for development of hypotension in humans with experimentally–induced central hypovolemia. We hypothesized that spontaneous breathing through an impedance threshold device (ITD) designed to increase negative intrathoracic pressure during inspiration and elevate arterial blood pressure would acutely increase BRS in humans.We tested this hypothesis by measuring heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures, and carotid-cardiac BRS in 10 female and 10 male subjects breathing through a face mask at three separate ITD conditions: (a) 6 cm H₂O; (b) 12 cm H₂O; and (c) a control (0 cm H₂O). HR was increased (P = 0. 013) from 64 ± 3 bpm during control to 68 ± 3 bpm at 6 cm H₂O ITD and 71 ± 4 bpm at 12 cm H₂O ITD breathing conditions. During ITD breathing, BRS was not altered but responses were shifted to higher arterial pressures. However, SBP and DBP were elevated for both the 6 and 12 cm H₂O conditions compared to the 0 cm H₂O condition, but returned to control (sham) levels by 30 minutes after cessation of ITD breathing. There were no gender effects for BRS or any hemodynamic responses to breathing through the ITD. We conclude that breathing with inspiratory impedance at relatively low pressures can increase baseline arterial blood pressure, i. e., reset the operational point for SBP on the baroreflex stimulus–response relationship, in healthy subjects. This resetting of the cardiac baroreflex may represent a mechanism that allows blood pressure to increase without a reflex–mediated reduction in HR.     

Systemic and regional (including superior mesenteric) haemodynamic responses during supine exercise while fasted and fed in normal man

The systemic and regional (including superior mesenteric artery, SMA) responses to exercise in the fasting and fed state were studied in ten normal subjects before, during and after 9 min of graded supine bicycle exercise on two separate occasions, when fasted and after a liquid meal. During exercise, blood pressure (BP) and cardiac index rose similarly in both states. Resting SMA blood flow was higher when fed (519 (282–619) versus 240 (133–255) ml/min,p<0.01). SMA blood flow fell during exercise in both states, to 98 (63–154) ml/min,p<0.01 when fasted and to 55 (42–149) ml/min,p<0.01 when fed. SMA vascular resistance rose during exercise in both states, but rose less when fasted by 36 (6–57)% versus 143 (36–240)% (NS). Resting forearm and leg blood flow (FBF and LBF) and vascular resistance (FVR and LVR) were similar fasted and fed. FBF and FVR did not change after exercise in either state. LBF rose and LVR fell similarly in both states. We conclude that in normal subjects, although splanchnic oxygen demand is likely to be greater after food, during light to moderate exercise splanchnic vasoconstriction contributes to maintenance of BP.     

Behaviorally-induced cardiovascular reactivity among sons of reported hypertensive and normotensive parents

The principal purpose of this investigation was to contrast the stress-related cardiovascular responses of sons of reported hypertensive and normotensive parents in a sample of 80 young adult volunteers. Each subject was scheduled for a single, one-hour experimental session. Measures of heart rate (HR) and systolic and diastolic blood pressure (SBP, DBP) were obtained during baseline periods and while subjects performed a difficult and frustrating cognitive task. Each subject also completed a standard family health inventory and, after exclusion of individuals indicating lack of information, uncertainty regarding parental health status, or otherwise providing unusable data (e.g. adopted sons), 20 of 69 remaining subjects reported a parental history of hypertension. Results indicated that relative to sons of normotensives, subjects reporting a hypertensive parent exhibited significantly higher mean SBP measurements during their performance of the experimental task, but not during a preceding (i.e. pre-task) baseline interval. Subsequent analyses also revealed that among subjects exhibiting the most appreciable HR acceleration in response to the experimental stressor, reported histories of parental hypertension were associated with elevated SBP measurements during both baseline and task periods. No similar relationships were observed with respect to DBP.     

Immunological analysis of the amino terminal and the C8 isomer of human myelin basic protein

The citrullination and N-terminus acylation of myelin basis protein (MBP) increases the heterogeneity among the MBP isoforms. The present study was undertaken to further characterize the immune response to the citrullinated from (C8) of MBP as well as to the variably acylated N-terminus of MBP. Six well-characterized murine monoclonal antibodies (mAbs) to human MBP-C8 or MBP peptides (four mAbs to MBP acetyl 1–9, one mAb to MBP 10–19 and one mAb to MBP 80–89), one murine T cell line (PL11) to human MBP peptide acetyl 1–9 and one Lewis rat T cell line (RT-1) to guinea pig (GP) MBP peptide 68–88 were used to assess reactivity with MBP-C1, MBP-C8, and MBP peptides including a series of MBP peptide 1–21 containing 0, 2, 4, 6, 8 or 10 carbon fatty acids. Enzyme-linked immunosorbent assay (ELISA) results revealed that all of the mAbs reacted with human MBP-C1 and MBP-C8 except anti-MBP 10–19 and anti-MBP-C8. The former reacted only with MBP-C1 and the latter only with MBP-C8. The presence and length of acylation of MBP peptide 1–21 modified reactivity. Three mAbs to MBP acetyl 1–9 reacted only with acetyl 1–21, and one mAb anti-MBP acetyl 1–9 reacted with all of MBP 1–21 preparations whether acylated or not. mAb anti-MBP-C8 generally reacted better with acylated MBP 1–21 having longer fatty acids. The PL11 T cell line strongly proliferated to human MBP-C1, MBP-C8 and MBP acetyl 1–9, responded, but less well, to MBP 1–21 with longer fatty acids and failed to respond to nonacylated MBP peptide 1–21. The RT-1 cell line responded strongly to GP MBP peptide 68–88, marginally to MBP-C8 and failed to respond to MBP-C1 or any of the other MBP peptides. Specific immune responses to different MBP charge isomers and different N-terminal acylating groups of MBP may play a role in immune-mediated demyelination.     

Exercise outcomes in prevalent users of stimulant medications

BackgroundTo compare users of stimulant medications with matched nonusers on exercise outcomes during a maximal treadmill exercise test.MethodsA cross-sectional study of a community-based cohort comparing propensity-score-matched stimulant medication users (n = 245) and nonusers (n = 735) who underwent a maximal treadmill exercise test in the Cooper Center Longitudinal Study cohort from January 1, 1995 to December 31, 2013. Main Outcomes were peak systolic blood pressure (SBP), average rise in SBP, peak heart rate (HR), and estimated VO₂max during exercise. A linear mixed model analysis was used to evaluate the effect of stimulant exposure on each of the exercise outcomes. In a sensitivity analysis, users were compared against nonusers for risk of chronotropic incompetence. Analyses were adjusted for relevant covariates and multiple testing.ResultsPeak HR during exercise was significantly lower in stimulant medication users (least square mean estimate 170.2 beats/minute) compared to nonusers (174.4 beats/minute; p < 0.0001). Moreover, stimulant medication users had an increased risk of chronotropic incompetence compared to nonusers (adjusted odds ratio 3.28, 95% confidence interval 1.70 to 6.34, p = 0.0008). No significant differences were observed in the outcomes of peak SBP, average SBP rise, and estimated VO₂max between matched groups.ConclusionsStimulant medication use was associated with a significant decrease in peak HR and an increased risk of chronotropic incompetence. Further investigation is required to understand the clinical significance of chronotropic incompetence in stimulant medication users. Concerns that stimulant medication use may increase peak SBP and average SBP during exercise were not supported by this study.     

Electroacupuncture modulates the activity of the hippocampus-nucleus tractus solitarius-vagus nerve pathway to reduce myocardial ischemic injury

The hippocampus is involved in the regulation of the autonomic nervous system,together with the hypothalamus and brainstem nuclei,such as the paraventricular nucleus and nucleus tractus solitarius.The vagus nerve-nucleus tractus solitarius pathway has an important role in cardiovascular reflex regulation.Myocardial ischemia has been shown to cause changes in the autonomic nervous system,affecting the dynamic equilibrium of the sympathetic and vagal nerves.However,it remains poorly understood how the hippocampus communicates with brainstem nuclei to regulate the autonomic nervous system and alleviate myocardial ischemic tissue damage.A rat model of acute myocardial ischemia(AMI) was made by ligating the left anterior descending branch of the coronary artery.Three days before ischemia,the hippocampal CA1 region was damaged.Then,3 days after ischemia,electroacupuncture(EA) at Shenmen(HT7)-Tongli(HT5) was performed(continuous wave,1 m A,2 Hz,duration of 30 minutes).Cluster analysis of firing patterns showed that one type of neuron was found in rats in the sham and AMI groups.Three types of neurons were observed in the AMI + EA group.Six types of neurons were found in the AMI + EA + Lesion group.Correlation analysis showed that the frequency of vagus nerve discharge in each group was negatively correlated with heart rate(HR)(P 0.05,r =-0.424),and positively correlated with mean arterial pressure(MAP)(P 0.05,r = 0.40987) and the rate-pressure product(RPP)(P 0.05,r = 0.4252).The total frequency of the nucleus tractus solitarius discharge in each group was positively correlated with vagus nerve discharge(P 0.01,r = 0.7021),but not with hemodynamic index(HR: P 0.05,r =-0.03263; MAP: P 0.05,r =-0.08993; RPP: P 0.05,r =-0.03263).Some neurons(Neuron C) were negatively correlated with vagus nerve discharge,HR,MAP and RPP in the AMI + EA group(vagus nerve discharge: P 0.05,r =-0.87749; HR: P 0.01,r =-0.91902; MAP: P 0.05,r =-0.85691; RPP: P 0.01,r =-0.91902).Some neurons(Neurons C,D and E) were positively correlated with vagus nerve discharge,HR,MAP and RPP in the AMI + EA + Lesion group(vagus nerve discharge: P 0.01,r = 0.8905,P 0.01,r = 0.9725,P 0.01,r = 0.9054; HR: P 0.01,r = 0.9347,P 0.01,r = 0.9089,P 0.05,r = 0.8247; MAP: P 0.05,r = 0.8474,P 0.01,r = 0.9691,P 0.01,r = 0.9027; RPP: P 0.05,r = 0.8637,P 0.01,r = 0.9407,P 0.01,r = 0.9027).These findings show that the hippocampus-nucleus tractus solitarius-vagus nerve pathway is involved in the cardioprotective effect of EA at the heart meridian.Some interneurons in the nucleus tractus solitarius may play a particularly important role in the cardiomodulatory process.     

Prior exposure to superantigen can inhibit or exacerbate autoimmune encephalomyelitis: T-cell repertoire engaged by the autoantigen determines clinical outcome

Experimental allergic encephalomyelitis (EAE) is inducible in experimental animals immunized with myelin basic protein (MBP), proteolipid protein (PLP) or their peptides. We compared T-cell responses to encephalitogenic epitopes of PLP(43–64) and MBP(Ac1–11) in a single mouse strain, (PL/J × SJL)F1. MBP(1–11)-specific T-cell hybridomas expressed predominantly TCR Vβ8 or Vβ4, while PLP(43–64)-specific hybridomas expressed a diverse TCR repertoire. To analyze the biologic significance of the TCR repertoire (limited vs. diverse) to disease susceptibility, we pretreated mice with a superantigen (SEB), and then induced disease with these autoantigens. Mice injected with SEB and immunized with MBP(Ac1–11) showed significant inhibition of EAE, whereas SEB-pretreated mice immunized with PLP(43–64) had an increased severity of EAE and developed a chronic disease. These data demonstrate that prior exposure to microbial superantigens can significantly alter the autoimmune disease course depending upon the TCR repertoire used by the autoantigen.     

T and B cell responses to myelin basic protein and encephalitogenic epitopes

The major encephalitogenic epitope of myelin basic protein (MBP) for the Lewis rat includes residues 68–84, although a minor epitope has been localized to MBP residues 87–99. We synthesized MBP68–84 and MBP87–99, and immunized rats with these peptides or with MBP in complete Freund's adjuvant (CFA). MBP and MBP68–84 induced paralytic experimental autoimmune encephalomyelitis (EAE) at equimolar concentrations, whereas significantly higher dosages of MBP87–99 were required to elicit paralytic disease. Spleen cells (SpC) from MBP- or MBP68–84-immunized rats could be activated with either MBP or MBP68–84 to transfer EAE to recipients. Anti-MBP antibodies were detected by ELISA in rats immunized with MBP-CFA, and anti-MBP68–84 specific antibodies were present in serum obtained from MBP68–84-immunized animals. However, these antibodies were non-cross reactive. MBP87–99 elicited only a meager antibody response to the immunizing peptide, and cross reactivity with MBP was not observed. Thus, although MBP and each peptide exhibited encephalitogenic activity, and MBP and MBP68–84 were cross reactive at the T cell level, the absence of cross reactivity at the humoral level indicates that significant immunological differences exist between MBP and the synthetic determinants, which may reflect differences in epitope recognition by T and B lymphocytes.     

Enhanced carotid-cardiac baroreflex response and elimination of orthostatic hypotension 24 hours after acute exercise in paraplegics.

To test the hypothesis that an acute bout of maximal exercise can ameliorate orthostatic hypotension consequent to prolonged wheelchair confinement, we evaluated heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure responses during 15 minutes of 70 degrees head-up tilt (HUT) in 10 paraplegic subjects 24 hours after arm crank exercise designed to elicit maximal effort, and during a control (no exercise) conditions. Additionally, the carotid baroreceptor stimulus-cardiac response relationship was determined by measurement of R-R interval during external application of graded pressures to the carotid sinuses. One week separated the treatment conditions. The maximum slope of the carotid-cardiac baroreflex response was increased (p = 0.049) by exercise (6.2 +/- 1.7 msec/mmHg) compared to control (3.3 +/- 0.6). During control HUT, HR increased from 61 +/- 1 to 90 +/- 7 bpm (p = 0.001) while SBP decreased from 118 +/- 5 to 106 +/- 9 mmHg (p = 0.025). During HUT 24 hours after exercise, HR increased from 60 +/- 2 to 90 +/- 4 bpm (p = 0.001), but the reduction in SBP was essentially eliminated (116 +/- 5 to 113 +/- 5 mmHg). The reduction in SBP during control HUT (-12.0 +/- 4.6 mmHg) was four-fold larger (p = 0.017) than during HUT following exercise (-3.1 +/- 3.9 mmHg). DBP during HUT was not altered in either condition. A single bout of intense, dynamic arm crank exercise eliminated orthostatic hypotension in paraplegics. Equal HR response with smaller reduction in SBP during HUT after exercise was consistent with a measured increased sensitivity of the carotid-cardiac baroreflex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electroacupuncture pretreatment prevents cognitive impairment induced by limb ischemia–reperfusion via inhibition of microglial activation and attenuation of oxidative stress in rats

Limb ischemia–reperfusion (LI/R) is associated with high morbidity and mortality. Furthermore, critical trauma survivors can present cognitive impairment. Cognitive function, survival rate, oxidative stress and neuronal health were examined to elucidate (1) the magnitude of cognitive effects of prolonged reperfusion, (2) potential players in the mechanistic pathway mediating such effects, and (3) possible benefits of electroacupuncture (EA) pretreatment at Baihui (GV20), Yanglingquan (GB34), Taichong (LR3), Zusanli (ST36) and Xuehai (SP10) acupoints. LI/R was induced in rats by placing a rubber tourniquet on each hind limb for 3 h, and the animals were evaluated periodically for 7 d after LI/R. Rats subjected to LI/R had significantly lower survival rates, and displayed evidence of brain injury and cognitive dysfunction (as determined by the Morris water maze test) 1 d and 3 d after reperfusion compared to sham-operated controls. LI/R also resulted in higher levels of reactive oxygen species (ROS) and malondialdehyde (MDA), microglial activation, and decreased superoxide dismutase (SOD) activity within Cornu Ammonis area 1 (CA1) of the hippocampus. Depressed survival rates, microglial activation, oxidative damage, and histological changes, as well as cognitive dysfunction were partially or fully attenuated in rats that received 14 d of EA prior to LI/R. These findings indicate that LI/R can result in cognitive dysfunction related to activated microglia and elevated oxidative stress, and that EA has neuroprotective potential mediated, at least in part, by inhibition of microglial activation and attenuation of oxidative stress.     

The effects of the noradrenaline precursor,l-threo-3,4-dihydroxy-phenylserine,in children with orthostatic intolerance

To evaluate the usefulness ofl-threo-3,4-dihydroxyphenylserine (l-DOPS), a precusor of noradrenaline, in the treatment of orthostatic intolearnce in children, we examined the circulatory responses to orthostatic stress and clinical symptoms before and after medication. Seven children with orthostatic intolerance, two boys and five girls, aged 11–15 years (mean age 13.3 years), were studied.l-DOPS (100–200 mg) was adminstered orally once or twice a day for 4 weeks. Blood pressure (BP) and heart rate (HR) were measured with a non-invasive beat-to-beat method (Finapres). All had a marked reduction in BP (SBP/DBP=–50±9/–27±6 mmHg) with prolonged recovery time in the initial phase during standing. Afterl-DOPS for 4 weeks, BP reduction in the initial phase was significantly attenuated (SBP/DBP=–37±9/–17±7 mmHg,p<0.05) and recovery time was normalized in all, although supine BP and HR were unchanged. Two reported relief of all symptoms, while in five symptoms were markedly improved. There were no adverse effects reported. These preliminary studies have indicated thatl-DOPS may be an effective drug for the treatment of orthostatic intolerance in children.     

Long–term exercise improves functional impairment but not quality of life in multiple sclerosis

Regular exercise is important for patients with multiple sclerosis (MS) to maintain their functional ability and general health. The aim of this study was to determine whether a long–term exercise program has any effect on functional impairment or healthrelated quality of life (HRQOL) in subjects with mild to moderate MS. In a randomised controlled trial, subjects in the intervention group (n = 47) exercised according to a progressive exercise program, mainly consisting of resistance training, for six months. Subjects in the control group (n = 48) received no intervention. The subjects were assessed at baseline and at six months using the Multiple Sclerosis Functional Composite (MSFC), the Expanded Disability Status Scale (EDSS), the Functional Independence Measure (FIM), the MS Quality of Life–54 (MSQOL–54) questionnaire and the Centre for Epidemiologic Studies Depression Scale (CES–D). The drop–out rate was low (4%) with 91 subjects completing the study. At six months, the exercising subjects showed improvement on the MSFC (mean score change 0.114, 95% confidence interval [CI] 0.010 to 0.218), whereas the control subjects showed deterioration (mean score change –0.128, 95 % CI –0.232 to –0.025). The change between groups was statistically significant (interaction, p = 0.001). Consistent with the physical nature of the intervention, the change predominantly occurred in leg function/ambulation. The effect seen in the EDSS, FIM, MSQOL–54 or CES–D was nil. These findings indicate that MSFC is more sensitive than EDSS in the detection of improvement in functional impairment as a result of regular exercise. The unfavourable results from HRQOL do not rule out the possibility that other types of exercise programs may improve it in MS.     

Inverse relationship between central serotonergic neurotransmission and blood pressure in alcohol-dependent male subjects

Summary. Data has accumulated indicating an inverse relation between central serotonergic (5-HT) neurotransmission and blood pressure in hypertensive rats and in healthy individuals. The present study aimed to elucidate whether an inverse relation exists between systolic (SBP) and diastolic (DBP) blood pressure levels and central 5-HT neurotransmission also in a group of alcohol-dependent individuals. Central 5-HT neurotransmission was assessed by using the maximum prolactin (PRL) responses to the 5-HT probe DL-fenfluramine (DL-FEN; 60 mg po) in 17 alcohol-dependent male subjects investigated during a period of on-going alcohol intake. BP was measured immediately before all time points for blood sampling, and readings before DL-FEN administration were used as the subjects resting BP. Results showed that there were inverse correlations between the maximum PRL responses to DL-FEN and the SBP levels (r = −0.57, p < 0.002) and with the DBP levels (r = −0.52, p < 0.05), respectively. The present study suggests the existence of an association between central 5-HT neurotransmission and blood pressure regulation also in alcohol-dependent individuals.     

Differential recognition of sequences within the encephalitogenic region of myelin basic protein capable of eliciting cell-mediated immune responses in experimental autoimmune encephalomyelitis

The fine specificity of myelin basic protein (MBP) epitopes capable of eliciting in vivo delayed-type hypersensitivity responses in Lewis rats with experimental autoimmune encephalomyelitis (EAE) was compared to those eliciting in vitro antigen-specific T cell proliferation and augmentation of disease transfer. Utilizing a panel of synthetic peptides with sequences representing the 68–86 region of guinea pig (GP-) or bovine myelin basic protein (B-MBP), animals were primed with one species of peptide and subsequently challenged with either the same peptide or peptides with truncations or substitutions representative of the other species of MBP. In regard to minimal length sequences capable of eliciting delayed-type hypersensitivity (DTH), rats primed with GP-MBP and complete Freund's adjuvant (CFA) exhibited a hierarchical pattern of responsiveness to challenge with a series of truncated peptides, ranking as follows: GP-68–86 > GP-72–86 > GP-68–84 > > GP-75–86 = no activity. This response pattern corresponds to that previously reported for T cell proliferation and activation for disease transfer. Furthermore, a comparison of these T cell-mediated immune parameters, as elicited by the substituted peptides, revealed the response patterns of DTH reactivity to be similar to that previously described for in vitro T cell proliferation with significant DTH responses generated only by the peptide species for which the animal was primed. In contrast, a cross-reactive pattern of recognition was observed in cells mediating disease transfer, with all four 68–86 sequences capable of augmenting activation for adoptive transfer of disease, regardless of the peptide species for which the animal was primed. The differential antigen recognition patterns observed for these EAE-associated immune responses supports the hypothesis that multiple T_H cell subsets are involved in disease pathogenesis.     

Antibody to peptides of human myelin basic protein in post-rabies vaccine endophalomyelitis sera

Development of neurologic complications after Semple rabies vaccine is closely linked to deveopment of antibody to myelin basic protein (MBP). The portions of MBP against which the antibodies are directed were analyzed by enzyme immunoassays in sera and cerebrospinal fluid from 27 patients with vaccine complications. Most of the antibody was directed to regions of MBP peptides 45–89 ,and 90–170. There was no apparent correlation between antibody specificity for MBP peptides 1–44, 45–89 and 90–170 and the type of post-vaccinal neurologic comlication. We conclude that the immunoglobulin repertoire in human B lymphocytes for responding to human MBP favors the portion of the MBP molecule containing residues 42–170.     

Electro-acupuncture preconditioning abrogates the elevation of c-Fos and c-Jun expression in neonatal hypoxic-ischemic rat brains induced by glibenclamide, an ATP-sensitive potassium channel blocker

This study aimed to clarify the neuroprotective mechanism of electro-acupuncture (EA) preconditioning on hypoxic-ischemic brain injury (HIBI). Using Western blot, the expression of c-fos protein (c-Fos) and c-jun protein (c-Jun) induced by glibenclamide, an ATP-sensitive potassium (K_ATP) channel blocker was examined from cerebral cortical and hippocampal samples in neonatal hypoxic-ischemic rats, with or without EA preconditioning. EA was performed on Hegu (LI4), a well-known acupoint commonly used in Oriental medicine for the treatment of neuronal injury resulting from hypoxia–ischemia (HI). Preconditioned rats were treated with either diazoxide, a K_ATP channel opener, glibenclamide, or sterile saline injected into the left lateral ventricle (i.c.v.), with or without EA administration before HI insult. Interestingly, low c-Fos and c-Jun expressions were found both in diazoxide and EA groups, 24 h after HI. Furthermore, significant differences in relative optical density (ROD) were found between glibenclamide and HI control groups (P≤0.05), as well as between the group administered glibenclamide after EA and the HI control group (P≤0.05). However, the level of c-Fos and c-Jun expression in the group administered glibenclamide after EA was significantly lower than in the glibenclamide group (P≤0.05). The present findings indicate that the effectiveness of EA preconditioning against HIBI may be mediated via the opening of K_ATP channels.     

Prolonged inhibition of rostral ventral lateral medullary premotor sympathetic neurons by electroacupuncture in cats

We have shown that electroacupuncture (EA) at the Neiguan-Jianshi (N-J) acupoints over the median nerve reduces myocardial ischemia by modulating the pressor response induced by application of bradykinin on the gallbladder. The present study was designed to investigate the neural substrate underlying the prolonged modulatory effect of EA on visceral afferent input into the rostral ventral lateral medulla (rVLM). Experiments were performed on ventilated anesthetized cats. Neuronal activity was recorded while either stimulating the splanchnic nerve or applying EA at the N-J acupoints. Thirty-three cells responsive to splanchnic nerve and median nerve stimulation were antidromically driven from the intermediolateral columns, T(2)-T(4), indicating their function as premotor sympathetic neurons. These neurons also received baroreceptor input demonstrating that they were cardiovascular sympathoexcitatory cells. Arterial pulse-triggered averaging and coherence analysis demonstrated a correlation between cardiac-related discharge activity with 2.8+/-0.3 Hz rhythms and arterial blood pressure. Stimulation (2 Hz, 1-4 mA, 0.5 ms) of the splanchnic nerve for 30 s evoked excitatory responses. These neuronal responses were reduced during and after 30-min stimulation of EA at the Neiguan-Jianshi acupoints. These splanchnic nerve-induced excitatory responses in neurons subjected to 30 min of EA were reduced by 68%. Iontophoresis of naloxone promptly reversed the EA-induced inhibitory effect by 52%. Neuronal activity in the rVLM induced by splanchnic nerve stimulation was reduced for 50 (or more) min after termination of EA in 7 of 12 rVLM neurons.Our results indicate that rVLM premotor sympathetic cardiovascular neurons receive convergent input from the gallbladder through the splanchnic nerve and N-J acupoints through the median nerves. Through an opioid mechanism, EA inhibits splanchnic nerve-induced excitatory responses of these rVLM neurons. Many of these neurons receiving convergent visceral and somatic input exhibit long-lasting inhibition by EA.     

The effects of exposure to moderate altitude on cardiovascular autonomic function in normal subjects

Cardiovascular responses to altitude have been studied on well-trained young subjects, generally at high altitudes (>4000 m). Less known are the effects of exposure to lower altitudes, easily reached by the general population. The aim of the study was to evaluate the effects of exposure to a moderate altitude (2950 m) on heart rate (HR), blood pressure (BP) profile, and cardiovascular autonomic function, and their correlation with hemoglobin oxygen saturation (HbO2S), in untrained subjects of a wide age range. Twenty-seven healthy normotensive subjects (age range 6–83; 8 children, 9 adults, and 10 elderly subjects) underwent a battery of noninvasive cardiovascular reflex tests and 24-h ambulatory BP monitoring. Corrected QT interval was also calculated. HbO₂S was measured with a transcutaneous oxymeter. All measurements were performed at about 200 m (s.l.) and repeated at 2950 m. 24-h HR and systolic/diastolic BP mean values increased at 2950 m in children (% change respectively: 6.4±6.4, p<0.05; 6.5±4.0/13.5±6.9, p<0.05), adults (4.9±8.1, NS; 6.0±5.1/8.1±5.8, p<0.05), and elderly subjects (7.2±4.8, p<0.05; 5.1±2.3/2.8±4.1, p<0.05 for systolic BP only). Standard deviation of BP mean values increased during night-time in the adult group (p<0.05). All subjects scored normal cardiovascular test results and no differences were observed after exposure to 2950m, at both 1 hour and 24 hours from arrival. After exposure to altitude, HbO₂S decreased significantly in the three groups, both on arrival and after 24 hours. No correlation was found between changes in HbO₂S and BP/HR responses, and cardiovascular test results. In conclusion, exposure to moderate altitudes, easily and often reached by the general population, causes a small but significant increase in BP and HR in healthy untrained subjects of a wide age range (6–83 years). Some physiological factors (eg, lower environmental temperature and lifestyle modification) together with hypoxia, possibly more than altered cardiovascular reactivity, seem responsible for this cardiovascular change. In terms of end-organ damage, the clinical relevance of this increase in BP and BP variability for repeated exposure is not known.     

QX-314 inhibits ectopic nerve activity associated with neuropathic pain

In animal models of neuropathic pain, transection or constrictive injury to peripheral nerves produces ectopic discharges originating at both injury sites and related dorsal root ganglia (DRG). In addition, hyperexcitability is observed in associated dorsal horn (DH) neurons of the spinal cord. As ectopic discharges are inhibited by agents that block voltage-sensitive Na⁺ channels, it has been postulated that accumulation of Na⁺ channels in the membrane at nerve injury sites may contribute to the development of ectopic nerve activity (ENA). The goal of the present study was to compare the sensitivity of ENA to lidocaine and QX-314, a positively charged lidocaine derivative, which is frequently assumed to be membrane impermeant. Experiments were performed on adult male Sprague–Dawley rats in which the common sciatic nerve had been transected 4–10 days earlier. Extracellular microelectrode recordings were made from DRG and DH neurons, and neuromal activity was measured in fine bundles of microfilaments teased from sciatic nerves in anesthetized and paralyzed rats. Comparative effects on heart rate (HR) and mean blood pressure (MBP) were also studied. To confirm that externally applied QX-314 is able to inhibit high frequency activity in sensory nerves, QX-314 was superfused over isolated rat vagus nerves during stimulation of compound action potentials in C-fibers (C-spikes). As expected, intravenously administered lidocaine inhibited ENA at all three sites. Lidocaine ED₅₀ values (expressed as mg/kg, with 95% confidence limits) were: 10.2 (7.8–13.3), 1.4 (0.8–2.4) and 0.9 (0.4–2.0) for neuromas, DRG and DH neurons, respectively. QX-314 also induced dose-dependent inhibition of ENA at neuromas and DRG, but produced only a small inhibition of DH neuron ENA. QX-314 had the following ED₅₀ values (mg/kg) for neuromas, DRG and DH neurons, respectively: 2.3 (2.0–2.8), 6.9 (4.7–26.5) and 85.7. QX-314-mediated inhibition of DRG ENA had a slow onset and was long-lasting, relative to lidocaine. Lidocaine or QX-314 also significantly reduced HR and MBP in the same dose range as that which reduced ENA in DRG or neuromas. In isolated rat vagus nerve recordings, QX-314 induced marked use-dependent inhibition of C-spike amplitude, with IC₅₀ values (μM) of 9000 (4600–18 000) and 350 (290–420) for low- (0.03 Hz) and high-frequency (30 Hz) C-spikes, respectively. These data support the hypothesis that Na⁺ channel accumulation contributes to the generation of ectopic discharges in neuromas and DRG, and suggests that intravenous QX-314 can acutely block Na⁺ channels at these sites.     

Non-invasive continuous arterial pressure, heart rate and stroke volume measurements during graded head-up tilt in normal man

The haemodynamic effects of head-up tilt (HUT) at different tilt angles were investigated non-invasively in eight normal male subjects. Mean arterial pressure (MAP; by Ohmeda Finapres 2300), stroke volume (SV) and heart rate (HR; by BoMed NCCOM3-R7S) were continuously recorded whilst performing a series of HUTs (55°, 10°, 20°, 30° and 55°) lasting 3 min each. The response to HUT was proportional to the sine of the tilt angle. The magnitude of the response varied between subjects. HUT to 55° resulted in mean (95% confidence limits) increases in MAP by 16 (±16)% and HR by 11 (±24)% and a decrease in SV by –25 (±22)%. These results were repeatable after 30 min. At small tilt angles, i.e. 20°, MAP did not change and HR decreased by –3 (±4)%. A detailed analysis revealed immediate dynamic (0–30 s), late dynamic (30–90 s) and plateau (after 90 s) phases in the response to HUT. In conclusion, HUT produces reproducible haemodynamic effects, although differences exist among subjects. A detailed analysis of these effects can be successfully performed using non-invasive methods.