Vestibulospinal and reticulospinal neuronal activity during locomotion in the intact cat. II. Walking on an inclined plane.
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The experiments described in this report were designed to determine the contribution of vestibulospinal neurons (VSNs) in Deiters' nucleus and of reticulospinal neurons (RSNs) in the medullary reticular formation to the modifications of the walking pattern that are associated with locomotion on an inclined plane. Neuronal discharge patterns were recorded from 44 VSNs and 63 RSNs in cats trained to walk on a treadmill whose orientation was varied from +20 degrees (uphill) to -10 degrees (downhill), referred to as pitch tilt, and from 20 degrees roll tilt left to 20 degrees roll tilt right. During uphill locomotion, a majority of VSNs (25/44) and rhythmically active RSNs (24/39) showed an increase in peak discharge frequency, above that observed during locomotion on a level surface. VSNs, unlike some of the RSNs, exhibited no major deviations from the overall pattern of the activity recorded during level walking. The relative increase in discharge frequency of the RSNs (on average, 31.8%) was slightly more than twice that observed in the VSNs (on average, 14.4%), although the average absolute change in discharge frequency was similar (18.2 Hz in VSNs and 21.6 Hz in RSNs). Changes in discharge frequency during roll tilt were generally more modest and were more variable, than those observed during uphill locomotion as were the relative changes in the different limb muscle electromyograms that we recorded. In general, discharge frequency in VSNs was more frequently increased when the treadmill was rolled to the right (ear down contralateral to the recording site) than when it was rolled to the left. Most VSNs that showed significant linear relationships with treadmill orientation in the roll plane increased their activity during right roll and decreased activity during left roll. Discharge activity in phasically modulated RSNs was also modified by roll tilt of the treadmill. Modulation of activity in RSNs that discharged twice in each step cycle was frequently reciprocal in that one burst of activity would increase during left roll and the other during right roll. The overall results indicate that each system contributes to the changes in postural tone that are required to adapt the gait for modification on an inclined surface. The characteristics of the discharge activity of the VSNs suggest a role primarily in the overall control of the level of electromyographic activity, while the characteristics of the RSNs suggest an additional role in determining the relative level of different muscles, particularly when the pattern is asymmetric. (+info)
Activation of pontine and medullary motor inhibitory regions reduces discharge in neurons located in the locus coeruleus and the anatomical equivalent of the midbrain locomotor region.
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Activation of the pontine inhibitory area (PIA) including the middle portion of the pontine reticular nucleus, oral part (PnO), or the gigantocellular reticular nucleus (Gi) suppresses muscle tone in decerebrate animals. The locus coeruleus (LC) and midbrain locomotor region (MLR) have been implicated in the facilitation of muscle tone. In the current study we investigated whether PIA and Gi stimulation causes changes in activity in these brainstem motor facilitatory systems. PIA stimulation evoked bilateral muscle tone suppression and inhibited 26 of 28 LC units and 33 of 36 tonically active units located in the anatomical equivalent of the MLR (caudal half of the cuneiform nucleus and the pedunculopontine tegmental nucleus). Gi stimulation evoked bilateral suppression of hindlimb muscle tone and inhibited 20 of 35 LC units and 24 of 24 neurons located in the MLR as well as facilitated 11 of 35 LC units. GABA and glycine release in the vicinity of LC was increased by 20-40% during ipsilateral PnO stimulation inducing hindlimb muscle tone suppression on the same side of the body. We conclude that activation of pontine and medullary inhibitory regions produces a coordinated reduction in the activity of the LC units and neurons located in the MLR related to muscle tone facilitation. The linkage between activation of brainstem motor inhibitory systems and inactivation of brainstem facilitatory systems may underlie the reduction in muscle tone in sleep as well as the modulation of muscle tone in the isolated brainstem. (+info)
The insertion/deletion polymorphism of the angiotensin-converting enzyme gene determines coronary vascular tone and nitric oxide activity.
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OBJECTIVES: We investigated whether the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene modulates vasomotor tone and endothelial function. BACKGROUND: The deletion allele of the ACE I/D polymorphism has been associated with increased incidence of cardiovascular pathology. The risk is synergistically increased in patients who also possess the C allele at position 1,166 of the angiotensin type I (AT1) receptor gene. METHODS: In 177 patients with coronary atherosclerosis or its risk factors, we investigated endothelial function with intracoronary acetylcholine (ACH), endothelium-independent smooth muscle function with sodium nitroprusside (SNP) and basal nitric oxide activity with L-NG monomethyl arginine. RESULTS: Compared with ACE II genotype, patients with the ACE DD genotype had lower coronary microvascular and epicardial responses with SNP (coronary blood flow increase 196 +/- 26% vs. 121 +/- 11%, p = 0.003, and diameter increase 21.9 +/- 2% vs. 17 +/- 1%, p = 0.03, ACE II vs. DD, respectively). L-NG monomethyl arginine induced greater constriction in patients with the ACE DD compared with ACE II genotype (coronary blood flow -10 +/- 4% vs. 11 +/- 5%, p = 0.003, ACE DD vs. II and diameter constriction -6.3 +/- 1.2% vs. -1.9 +/- 1.2%, p = 0.01, respectively, in patients with atherosclerosis). No difference in ACH-mediated vasomotion was detected between the three ACE genotypes. The AT1 receptor polymorphism did not influence responses to either SNP or ACH. CONCLUSIONS: Patients possessing the D allele of the ACE gene have increased vascular smooth muscle tone. The enhanced tone appears to be counterbalanced by an increase in basal nitric oxide activity in patients with atherosclerosis. (+info)
Contribution of endogenous nitric oxide to basal vasomotor tone of peripheral vessels and plasma B-type natriuretic peptide levels in patients with congestive heart failure.
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OBJECTIVES: We examined whether a relationship exists between the vasoconstrictive response to endogenous nitric oxide (NO) synthesis inhibition and the severity of heart failure in patients with congestive heart failure (CHF). BACKGROUND: Controversy exists as to whether the vasoconstrictive response to NO synthesis inhibition in patients with CHF is comparable to that in normal subjects or is enhanced. METHODS: Forearm blood flow (FBF) and calculated forearm vascular conductance (FVC) were obtained using plethysmography before and after administration of the NO synthesis inhibitor L-NMMA (NG-monomethyl-L-arginine) in 40 patients with CHF due to dilated cardiomyopathy and in 16 normal control subjects. Basal plasma B-type natriuretic peptide (BNP) and nitric oxide concentrations were measured in all subjects. RESULTS: Plasma BNP and nitrite/nitrate (NOx) levels in the patients group were significantly greater and baseline FBF was significantly less. Administration of L-NMMA significantly decreased FBF and FVC in both groups. The percent changes in FBF (%FBF) and FVC (%FVC) from the baseline after L-NMMA correlated significantly with plasma BNP level (%FBF: r = 0.72; %FVC: r = 0.76; both p < 0.001). Percent changes in both FBF and FVC were greater in patients with BNP > or = 100 pg/ml than in normal subjects; however, in patients with BNP < 100 pg/ml they were comparable to those in normal subjects. CONCLUSIONS: Vasoconstrictive response to L-NMMA in patients with CHF was preserved or enhanced in proportion to the basal plasma BNP level, indicating a close relationship between the contribution of endogenous NO to basal vasomotor tone and the severity of heart failure. (+info)
Effects of mibefradil and nifedipine on arteriolar myogenic responsiveness and intracellular Ca(2+).
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1. Ca(2+) entry mechanisms underlying spontaneous arteriolar tone and acute myogenic reactivity remain uncertain. These studies aimed to compare the effects of nifedipine and the putative T-channel blocker, mibefradil, on arteriolar myogenic responsiveness and intracellular Ca(2+) (Ca(2+)(i)). 2. First order cremaster muscle arterioles (1A) were isolated from rats, cannulated, pressurized to 70 mmHg in the absence of intraluminal flow, and mechanical responses studied by video microscopy. The Ca(2+)(i) was measured using fluorescence imaging of Fura 2 loaded arterioles. 3. Both nifedipine and mibefradil showed dose-dependent inhibition of spontaneous myogenic tone (at 70 mmHg; pEC(50) 7.04+/-0.17 vs 6.65+/-0.20 respectively, n=6 for both, n.s.) and KCl-induced vasoconstriction (at 70 mmHg; pEC(50) 6.93+/-0. 38 vs 6.45+/-0.27 respectively, n=6 for both, n.s.). 4. In arterioles maintained at 50 mmHg, nifedipine (10(-7) and 10(-5) M) caused a concentration dependent reduction in Ca(2+)(i), however, mibefradil (10(-7) and 10(-5) M) had no effect. Furthermore nifedipine significantly attenuated the increase in Ca(2+)(i) associated with an acute pressure step (50 - 120 mmHg) whereas mibefradil was considerably less effective. 5. Mibefradil (10(-7) M) significantly attenuated contractile responses to 60 mM KCl without altering the KCl-induced increase in Ca(2+)(i), in contrast to nifedipine (10(-7) M) which reduced both Ca(2+)(i) and contraction. 6. Membrane potential of arterioles with spontaneous myogenic tone (70 mmHg) was -41.5+/-1. 0 mV. Nifedipine (10(-7) or 10(-5) M) had no effect on membrane potential, however mibefradil (10(-5) M) caused significant depolarization. 7. In summary, both mibefradil and nifedipine inhibit arteriolar spontaneous tone and acute myogenic reactivity. While there may be overlap in the mechanisms by which these agents inhibit tone, differences in effects on membrane potential and intracellular Ca(2+) levels suggest mibefradil exhibits actions other than blockade of Ca(2+) entry in skeletal muscle arterioles. (+info)
Effects of membrane polarization and ischaemia on the excitability properties of human motor axons.
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Multiple nerve excitability measurements have been proposed for clinical testing of nerve function, since excitability measures can provide evidence of altered axonal membrane properties and are complementary to conventional nerve conduction studies. An important determinant of excitability is membrane potential, and this study was undertaken to determine the changes in a range of excitability properties associated with alterations in membrane potential. Membrane potential was varied directly using DC polarizing currents and indirectly by ischaemia. The median nerve was stimulated at the wrist and the resultant compound muscle action potentials recorded from abductor pollicis brevis. Stimulus-response behaviour, strength-duration time constant (tau(SD)), threshold electrotonus to 100-ms polarizing currents, a current-threshold relationship and the recovery of excitability following supramaximal activation were each followed in four normal subjects during the two manoeuvres, using a recently described protocol. Membrane depolarization and ischaemia produced an increase in axonal excitability, an increase in the slope of the current-threshold relationship, a 'fanning in' of responses during threshold electrotonus, a decrease in super-excitability, and increases in both tau(SD) and the refractory period. Changes in the opposite direction occurred with membrane hyperpolarization and during the post-ischaemic period. One excitability parameter differentiated between the direct and indirect changes in membrane potential: late subexcitability was sensitive to polarizing currents but relatively insensitive to ischaemia, probably because of compensatory changes in extracellular potassium ions. These results should enable multiple excitability measurements to be used as a tool to identify changes in axonal membrane potential in neuropathy. (+info)
Peptide-induced Ca(2+) movements in a tonic insect muscle: effects of proctolin and periviscerokinin-2.
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Although most of the characterized insect neuropeptides have been detected by their actions on muscle contractions, not much is known about the mechanisms underlying excitation-contraction coupling. Thus we initiated a pharmacological study on the myotropic action of the peptides periviscerokinin-2 (PVK-2) and proctolin on the hyperneural muscle of the cockroach Periplaneta americana. Both peptides required extracellular Ca(2+) to induce muscle contraction, and a blockage of sarcolemmal Ca(2+) channels by Mn(2+) or La(3+) inhibited myotropic effects. The peptides were able to induce contractions in dependence on the extracellular Ca(2+) concentration in muscles depolarized with high K(+) saline. A reduction of extracellular Na(+), K(+), or Cl(-) did not effect peptide action. Nifedipine, an L-type Ca(2+)-channel blocker, partially blocked the response to both peptides but to a much lesser extent than contractions evoked by elevated K(+). Using calcium imaging with fluo-3, we show that proctolin induces an increase of the intracellular Ca(2+) concentration. In calcium-free saline, no increase of the intracellular Ca(2+) concentration could be detected. The inhibiting effect of ryanodine, thapsigargin, and TMB-8 on peptide-induced contractions suggests that Ca(2+) release from the sarcoplasmic reticulum plays a major role during peptide-induced contractions. Preliminary experiments suggest that the peptides do not employ cyclic nucleotides as second messengers, but may activate protein kinase C. Our results indicate that the peptides induce Ca(2+) influx by an activation or modulation of dihydropyridine-sensitive and voltage-independent sarcolemmal Ca(2+) channels. Ca(2+)-induced Ca(2+) release from intracellular stores, but not inositol trisphosphate-induced Ca(2+) release, seems to account for most of the observed increase in intracellular Ca(2+). Additionally, both peptides were able to potentiate glutamate-induced contractions at threshold concentrations. (+info)
Inducible and neuronal nitric oxide synthase involvement in lipopolysaccharide-induced sphincteric dysfunction.
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We examined the effect of endotoxin lipopolysaccharide (LPS) on the basal tone and on the effects of different stimuli and agonists and transcriptional and translational expression of nitric oxide (NO) synthase (NOS) isozymes in the lower esophageal sphincter (LES), pyloric sphincter (PS), and internal anal sphincter (IAS). NO release was also examined before and after LPS. LPS caused a dose-dependent fall in the basal tone and augmentation of the relaxation caused by nonadrenergic, noncholinergic (NANC) nerve stimulation in the LES and IAS. In the PS, LPS had no significant effect on the basal tone and caused an attenuation of the NANC relaxation and an augmentation of the contractile response of muscarinic agonist. Interestingly, the smooth muscle relaxation by atrial natriuretic factor was suppressed in the LES and IAS but not in the PS. These changes in the sphincteric function following LPS may be associated with increase in the inducible NOS (iNOS) expression since they were blocked by iNOS inhibitor L-canavanine. Augmentation of NANC relaxation in the LES and IAS smooth muscle by LPS may be due to the increased activity of neuronal NOS and NO production. (+info)