ERK1/2 signaling pathway in mast cell activation-induced sensitization of esophageal nodose C-fiber neurons.

Sensitization of esophageal nociceptive afferents by inflammatory mediators plays an important role in esophageal inflammatory nociception. Our previous studies demonstrated that esophageal mast cell activation increases the excitability of esophageal nodose C-fibers. But the intracellular mechanism of this sensitization process is still less clear. We hypothesize that extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway plays an important role in mast cell activation-induced sensitization of esophageal nodose C-fiber neurons. Mast cell activation and in vivo esophageal distension-induced phosphorylations of ERK1/2 were studied by immuno-staining and Western blot in esophageal nodose neurons. Extracellular recordings were performed from nodose neurons using ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Nerve excitabilities were compared by action potentials evoked by esophageal distensions before and after mast cell activations with/without pretreatment of mitogen-activated protein kinases (MAPK)/ERK kinase inhibitor U0126. The expressions of phospho-ERK1/2 (p-ERK1/2) in the same nodose ganglia were then studied by Western blot. Mast cell activation enhances in vivo esophageal distension-induced phosphorylation of ERK1/2 in nodose neurons. This can be prevented by pretreatment with mast cell stabilizer cromolyn. In ex vivo esophageal-vagal preparations, both mast cell activation and proteinase-activated receptor 2 (PAR2)-activating peptide perfusion increases esophageal distension-induced mechano-excitability of esophageal nodose C-fibers and phosphorylation of ERK1/2 in nodose neurons. Pretreatment with MAPK/ERK kinase inhibitor U0126 prevents these potentiation effects. Collectively, our data demonstrated that mast cell activation enhances esophageal distension-induced mechano-excitability and phosphorylation of ERK1/2 in esophageal nodose C-fiber neurons. This reveals a new intracellular pathway of esophageal peripheral sensitization and inflammatory nociception.

Barosensory cells in the nucleus tractus solitarius receive convergent input from group III muscle afferents and central command.

Some neural mechanism must prevent the full expression of the baroreceptor reflex during static exercise because arterial blood pressure increases even though the baroreceptors are functioning. Two likely candidates are central command and input from the thin fiber muscle afferents evoking the exercise pressor reflex. Recently, activation of the mesencephalic locomotor region, an anatomical locus for central command, was found to inhibit the discharge of nucleus tractus solitarius cells that were stimulated by arterial baroreceptors in decerebrated cats. In contrast, the effect of thin fiber muscle afferent input on the discharge of nucleus tractus solitarius cells stimulated by baroreceptors is not known. Consequently in decerebrated unanesthetized cats, we examined the responses of barosensory nucleus tractus solitarius cells to stimulation of thin fiber muscle afferents and to stimulation of the mesencephalic locomotor region, a maneuver which evoked fictive locomotion. We found that electrical stimulation of either the mesencephalic locomotor region or the gastrocnemius nerve at current intensities that recruited group III afferents inhibited the discharge of nucleus tractus solitarius cells receiving baroreceptor input. We also found that the inhibitory effects of both gastrocnemius nerve stimulation and mesencephalic locomotor region stimulation converged onto the same barosensory nucleus tractus solitarius cells. We conclude that the nucleus tractus solitarius is probably the site whereby input from both central command and thin fiber muscle afferents function to reset the baroreceptor reflex during exercise.

Effects of static and rhythmic twitch contractions on the discharge of group III and IV muscle afferents.

Although both static and rhythmic twitch contractions of the hindlimb muscles of anaesthetised cats have been shown to reflexly evoke pressor responses, the increase in arterial pressure evoked by the former type of contraction has been shown to be substantially larger than that evoked by the latter. We have therefore recorded the impulse activity of single group III and IV muscle afferents, whose activation reflexly increases arterial pressure, while we both statically and rhythmically twitch-contracted the triceps surae muscles of anaesthetised cats. We found that group III afferents (n = 17) discharged significantly more impulses in response to static contraction than in response to rhythmic contraction. By contrast, group IV afferents (n = 18) fired approximately the same number of impulses in response to the two types of contraction. In addition, we found that many of the group III but only a few of the group IV afferents displayed discharge properties suggestive that these afferents were mechanoreceptors. We conclude that the discharge of group III afferents are likely to be responsible for the difference in the magnitudes of the reflex pressor responses evoked by static and rhythmic contraction.

Bicuculline and strychnine suppress the mesencephalic locomotor region-induced inhibition of group III muscle afferent input to the dorsal horn.

We examined the effect of iontophoretic application of bicuculline methiodide and strychnine hydrochloride on the mesencephalic locomotor region (MLR)-induced inhibition of dorsal horn cells in paralyzed cats. The activity of 60 dorsal horn cells was recorded extracellularly in laminae I, II, V-VII of spinal segments L7-S1. Each of the cells was shown to receive group III muscle afferent input as demonstrated by their responses to electrical stimulation of the tibial nerve (mean latency and threshold of activation: 20.1+/-6.4 ms and 15.2+/-1.4 times motor threshold, respectively). Electrical stimulation of the MLR suppressed transmission in group III muscle afferent pathways to dorsal horn cells. Specifically the average number of impulses generated by the dorsal horn neurons in response to a single pulse applied to the tibial nerve was decreased by 78+/-2.8% (n=60) during the MLR stimulation. Iontophoretic application (10-50 nA) of bicuculline and strychnine (5-10 mM) suppressed the MLR-induced inhibition of transmission of group III afferent input to laminae I and II cells by 69+/-5% (n=10) and 29+/-7% (n=7), respectively. Likewise, bicuculline and strychnine suppressed the MLR-induced inhibition of transmission of group III afferent input to lamina V cells by 59+/-13% (n=14) and 39+/-11% (n=10), respectively. Our findings raise the possibility that GABA and glycine release onto dorsal horn neurons in the spinal cord may play an important role in the suppression by central motor command of thin fiber muscle afferent-reflex pathways.

Pressor reflex response to static muscular contraction: its afferent arm and possible neurotransmitters.

Static muscular contraction has been shown to increase cardiovascular and ventilatory function in reflex manner. The sensory arm of this reflex arc is comprised of group III and IV muscle afferents. The discharge properties of these muscle afferents whose activation causes the pressor reflex response to contraction were investigated. Group III afferents were more responsive to mechanical stimuli, such as tendon stretch and probing their receptive fields than were group IV afferents. In contrast, group III afferents were less responsive to ischemic contraction than were group IV afferents. Equal percentages of group III and IV afferents were stimulated by potassium, lactic acid and arachidonic acid, each of which are metabolic products of contraction. Adenosine, phosphate and lactate, however, had no effect on the discharge of the afferents. Intrathecal injection of antagonists or antibodies to substance P and somatostatin attenuated the pressor response to contraction by about half, a finding that suggests a role for these 2 peptides in the spinal transmission of the reflex.

Estrogen attenuates the exercise pressor reflex in female cats.

In humans, the pressor and muscle sympathetic nerve responses to static exercise are less in women than in men. The difference has been attributed to the effect of estrogen on the exercise pressor reflex. Estrogen receptors are abundant in areas of the dorsal horn receiving input from group III and IV muscle afferents, which comprise the sensory limb of the exercise pressor reflex arc. These findings prompted us to investigate the effect of estrogen on the spinal pathway of the exercise pressor reflex arc. Previously, we found that the threshold concentration of 17beta-estradiol needed to attenuate the exercise pressor reflex in male decerebrate cats was 10 microg/ml (Schmitt PM and Kaufman MP. J Appl Physiol 94: 1431-1436, 2003). The threshold concentration for female cats, however, is not known. Consequently, we applied 17beta-estradiol to a well covering the L6-S1 spinal cord in decerebrate female cats. The exercise pressor reflex was evoked by electrical stimulation of the L7 or S1 ventral root, a maneuver that caused the hindlimb muscles to contract statically. We found that the pressor response to contraction averaged 38 +/- 7 mmHg before the application of 17beta-estradiol (0.01 microg/ml) to the spinal cord, whereas it averaged only 23 +/- 4 mmHg 30 min after application (P < 0.05). Recovery of the pressor response to contraction was not obtained for 2 h after application of 17beta-estradiol. Application of 17beta-estradiol in a dose of 0.001 microg/ml had no effect on the exercise pressor reflex (n = 5). We conclude that the concentration of 17beta-estradiol required to attenuate the exercise pressor reflex is 1,000 times more dilute in female cats than that needed to attenuate this reflex in male cats.

Attenuating effects of intrathecal clonidine on the exercise pressor reflex.

We tested the hypothesis that intrathecal injection of clonidine, an alpha 2-adrenergic agonist, attenuated the reflex cardiovascular and ventilatory responses to static muscular contraction in cats. Before clonidine (1 microgram in 0.2 ml), contraction-induced reflex increases (n = 10) in mean arterial pressure and ventilation averaged 25 +/- 3 mmHg and 359 +/- 105 ml/min, respectively, whereas after clonidine these increases averaged 8 +/- 4 mmHg and 200 +/- 114 ml/min, respectively (P less than 0.05). Clonidine had no effect on the heart rate response to contraction. Intrathecal injection of yohimbine (10 micrograms; n = 5), an alpha 2-adrenergic antagonist, but not prazosin (10 micrograms; n = 3), an alpha 1-adrenergic antagonist, prevented the attenuating effects of clonidine on the reflex pressor and ventilatory responses to contraction. Our findings were not due to the spread of clonidine to the medulla, because the reflex pressor and ventilatory responses to contraction were not attenuated by injection of clonidine (1 microgram) onto the medulla (n = 3). In addition, our findings were not due to a clonidine-induced withdrawal of sympathetic outflow, because intrathecal injection of clonidine (1 microgram) did not attenuate increases in arterial pressure and ventilation evoked by high-intensity electrical stimulation of the cut central end of the sciatic nerve (n = 5). Furthermore, our findings were not due to a local anesthetic action of clonidine, because application of this agent to the dorsal roots had no effect on the discharge of group IV muscle afferents. We conclude that stimulation of alpha 2-adrenergic receptors in the spinal cord attenuates the reflex pressor and ventilatory responses to static contraction.

Caudal ventrolateral medullary cells responsive to muscular contraction.

The pressor reflex evoked by muscular contraction (exercise pressor reflex) is held to be an important mechanism in producing the cardiovascular adjustments to static exercise. Recent experiments using lesioning and metabolic labeling methods have indicated that the caudal ventrolateral medulla may be a key integrative site for the reflex evoked by muscular contraction induced by ventral root stimulation. Therefore, we sought to determine whether cells in this region could be associated with the cardiovascular reflex accompanying muscular contraction through analysis of their discharge characteristics. Eighty cells were characterized as to their response to ventral root stimulus-induced static muscular contraction, intra-arterial capsaicin (selective groups III and IV stimulus), and mechanical probing. The cells' receptive fields were also determined by mechanical probing. The receptive fields were usually large, often including all four limbs and the trunk. Four response patterns were observed to static contractions: a brisk initial discharge followed by a gradual return toward control levels (slowly adapting), a brief onset and cessation response, a brief inhibition followed by a slowly adapting discharge, and inhibition alone. Virtually all cells tested were responsive to capsaicin. Histological analysis verified the position of the recorded cells. It is suggested that the cells most likely to participate in the pressor response to muscular contraction were those cells in the general region of the lateral reticular nucleus which responded with an initial and sustained discharge and the cells that were inhibited in the region of the nucleus ambiguus (possible inhibition of vagal outflow).

Effect of metabolic products of muscular contraction on discharge of group III and IV afferents.

Static muscular contraction has been firmly established to reflexly increase cardiovascular and ventilatory function. Although group III and IV fibers with endings in muscle have been shown to comprise the afferent arm of this reflex arc, little is known about the nature of the contraction-induced stimulus causing the activation of these fibers. This stimulus has often been suggested to be a metabolic product of muscular contraction. We have therefore recorded the impulse activity of group III and IV afferents with endings in the triceps surae muscles of barbiturate-anesthetized cats while we injected into the femoral artery substances believed to be metabolic products of muscular contraction. We found that lithium and sodium lactate (400 mM; 1 ml) had little or no effect on the discharge of group III and IV afferents. Likewise, monobasic sodium phosphate (20 and 400 mM; 1 ml) and 2-chloroadenosine (50-100 micrograms) had only trivial effects on the discharge of these afferents. By contrast, lactic acid (25 and 400 mM; 1 ml) and arachidonic acid (0.5-2.0 mg) caused significant increases in the activity of group III and IV afferents. Most of the excitatory effect of arachidonic acid on the discharge of the afferents was prevented by indomethacin, a cyclooxygenase inhibitor. We conclude that of the substances tested in our experiments, lactic acid and some cyclooxygenase products, such as prostaglandins and thromboxanes, are the most likely to be responsible for any metabolic stimulation of group III and IV afferents during muscular contraction.

Effect of arterial occlusion on responses of group III and IV afferents to dynamic exercise.

Our laboratory has shown previously that a low level of dynamic exercise induced by electrical stimulation of the mesencephalic locomotor region (MLR) stimulated group III and IV muscle afferents in decerebrate unanesthetized cats (C. M. Adreani, J. M. Hill, and M. P. Kaufman. J. Appl. Physiol. 83: 1811-1817, 1997). In the present study, we have extended these findings by examining the effect of occluding the arterial supply to the dynamically exercising muscles on the afferents' responses to MLR stimulation. In decerebrate cats, we found that arterial occlusion increased the responsiveness to a low level of dynamic exercise in 44% of the group III and 47% of the group IV afferents tested. Occlusion, compared with the freely perfused state, did not increase the concentrations of either hydrogen ion or lactate ion in the venous effluent from the exercising muscles. We conclude that arterial occlusion caused some unspecified substance to accumulate in the working muscles to increase the sensitivity of equal percentages of group III and IV afferents to dynamic exercise.

Pulmonary afferent control of breathing as end-expiratory lung volume decreases.

We studied reflex changes in breathing elicited by graded reductions in end-expiratory lung volume (EEVL) and the vagal nerves responsible. The chests of nine dogs anesthetized with alpha-chloralose were opened, and the lungs were ventilated by a phrenic nerve-driven servo-respirator. The immediate effects of a 50% reduction in end-expiratory transpulmonary pressure (EEPtp) from control (EEVL equivalent to functional residual capacity) were to significantly increase both tidal volume (VT) and breathing frequency (f) from 0.402 +/- 0.101 to 0.453 +/- 0.091 liter (mean +/- SD) and 11.8 +/- 5.4 to 15.7 +/- 6.4 breaths/min, respectively (P less than 0.05). Further reductions in EEPtp to 0 cmH2O did not change VT but augmented f to 19.6 +/- 6.6 breaths/min (P less than 0.05). The increase in f as EEVL decreased was due entirely to a reduction in expiratory time. Vagotomy abolished these reflexes. By 90 s after reduction in EEVL, arterial PCO2 fell significantly and VT returned to or below control values. We therefore repeated these experiments in five dogs whose blood gases were controlled by cardiopulmonary bypass. There were no secondary changes in VT and by 90 s breathing pattern could be characterized as rapid and deep. In another eight dogs submitted to the same collapse protocol, we recorded action potentials from all known categories of pulmonary vagal afferents. These studies demonstrated that the changes in breathing pattern induced by a 50% reduction in EEPtp were due to a withdrawal of slowly adapting stretch receptor activity; however, continued increases in f as EEVL was reduced further were due to increases in rapidly adapting stretch receptor activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Attenuation of reflex pressor and ventilatory responses to static muscular contraction by intrathecal opioids.

We have tested the hypothesis that intrathecal injections of opioid peptides attenuate the reflex pressor and ventilatory responses to static contraction of the triceps surae muscles of chloralose-anesthetized cats. We found that before intrathecal injections of [D-Ala2]Met-enkephalinamide (100 micrograms in 0.2 ml), static contraction increased mean arterial pressure and ventilation by 32 +/- 5 (SE) mmHg and 227 +/- 61 (SE) ml/min, whereas after injection of this opioid peptide, static contraction increased mean arterial pressure and ventilation by only 15 +/- 5 mmHg and 37 +/- 33 ml/min, respectively. The attenuation of both the pressor and ventilatory responses to static contraction by [D-Ala2]Met-enkephalinamide were statistically significant (P less than 0.05). Moreover, the attenuation was probably not caused by an opioid-induced withdrawal of sympathetic outflow because [D-Ala2]Met-enkephalinamide had no effect on the pressor and ventilatory responses evoked by high-intensity electrical stimulation of the central cut end of the sciatic nerve. In addition, intrathecal injection of peptides that were highly selective agonists for either the opioid mu- or delta-receptor attenuated the reflex responses to static contraction. Naloxone (1,000 micrograms), injected intrathecally, prevented the attenuation of the reflex responses to contraction by opioid peptides. We speculate that the opioid-induced attenuation of the reflex pressor and ventilatory responses to static contraction may have been due to suppression of substance P release from group III and IV muscle afferents.

Stimulation of vagal afferents inhibits locomotion in mesencephalic cats.

Using electrical stimulation of the mesencephalic locomotor region, we made decerebrate unanesthetized cats walk on a treadmill. The locomotion induced by stimulation of this midbrain area was assessed before and during activation of vagal afferents by either intravenous injection of phenylbiguanide or inflation of a balloon placed in the left atrium. Inflation of a balloon, which increased left atrial pressure by 7-25 mmHg, abolished locomotion in 9 of 10 cats tested. Bilateral cervical vagotomy prevented the abolition of locomotion by balloon inflation in each of two cats tested. Intravenous phenylbiguanide (50 or 100 micrograms/kg) or serotonin (40 micrograms/kg) injections abolished or attenuated walking induced by midbrain stimulation in 11 of 13 cats tested. In addition, intravenous phenylbiguanide injections abolished or attenuated locomotion with a shorter onset time than did systemic injections of this substance in five of six cats tested. Bilateral cervical vagotomy prevented the abolition of locomotion by phenylbiguanide injection in each of five cats tested. We conclude that locomotion can be prevented by a viscerosomatic reflex arising from the lungs and heart. The afferent arm of this reflex arc is the vagus nerve. Afferents such as slowly and rapidly adapting pulmonary stretch receptors, atrial receptors, and lung C-fibers may have had a role in preventing locomotion during the increase in left atrial pressure in our experiments. On the other hand, pulmonary C-fibers had a crucial role in preventing locomotion during intravenous injection of phenyl-biguanide. We speculate that this viscerosomatic reflex may help to explain in part the intolerance for exercise displayed by patients with congestive heart failure.

Stimulation of parabrachial nuclei dilates airways in cats.

Stimulation of the parabrachial nuclei has been shown to increase mean arterial pressure as well as to terminate inspiration. Nevertheless, the effect on airway caliber evoked by stimulation of the parabrachial nuclei is not known. Therefore, in chloralose-anesthetized cats, we microinjected DL-homocysteic acid (25 nl; 100 mM) into 44 sites in or near the lateral and medial parabrachial nuclei while calculating breath-by-breath total lung resistance and dynamic compliance. We found that, in 43 of these sites, microinjection of this excitatory amino acid consistently decreased total lung resistance but had no effect on dynamic compliance. The decrease in lung resistance was caused by a withdrawal of cholinergic tone to the airways. We could find no evidence that the decrease in total lung resistance evoked by stimulation of the parabrachial nuclei was caused by activation of either beta-adrenergic or nonadrenergic noncholinergic pathways. The decrease in total lung resistance evoked by stimulation of the parabrachial nuclei was not secondary to the baroreceptor reflex even though microinjection frequently increased mean arterial pressure. In addition, microinjection did not have consistent effects on phrenic nerve activity, although in individual circumstances the effect on this activity was quite large. We conclude that stimulation of cell bodies and dendrites in the parabrachial nuclei dilates the airways of anesthetized cats and that the effect is not secondary to the baroreceptor reflex.

Role of caudal ventrolateral medulla in reflex and central control of airway caliber.

We investigated the role played by the caudal ventrolateral (CVL) medulla in the reflex and central neural control of airway caliber in chloralose-anesthetized dogs. Changes in total lung resistance were evoked by four different stimuli. These changes were compared before and after bilateral injection of either ibotenic acid (75 nl; 100 mM) or cobalt chloride (75 nl; 50 mM) into the CVL medulla. The four stimuli used to change lung resistance were static muscular contraction, electrical stimulation of thin fiber afferents in the sciatic nerve, electrical stimulation of the posterior diencephalon, and hypoxia. The first three stimuli have been shown to decrease total lung resistance, whereas the latter stimulus has been shown to increase resistance. We found that injection of both ibotenic acid, which destroys cell bodies but not fibers of passage, and cobalt, which prevents synaptic transmission, either abolished or greatly attenuated the decrease in total lung resistance evoked by static contraction, by sciatic nerve stimulation, and by posterior diencephalic stimulation. We also found that injection of ibotenic acid and cobalt attenuated the reflex increase in lung resistance evoked by hypoxia. In control experiments, we found that bilateral injection of ibotenic acid into the dorsal medulla had no effect on the changes in total lung resistance evoked by these four stimuli. We conclude that the CVL medulla plays an important role in the reflex and central control of airway caliber.

Inhibition of aortic chemoreceptor discharge by pressor response to muscular contraction.

We have examined the effect of static contraction of the hindlimb muscles on the discharge of aortic chemoreceptors in chloralose-anesthetized cats. The responses of the chemoreceptors to contraction were dependent on the arterial pressure response to this maneuver. When contraction reflexly evoked a pressor response of at least 20 mmHg, the discharge of 26 chemoreceptors was reduced from control levels by 53% (P less than 0.01). The contraction-induced inhibition of chemoreceptor discharge was prevented by phentolamine, an alpha-adrenergic antagonist that also attenuated the contraction-induced pressor response. In addition, the inhibition evoked by contraction was simulated by injection of phenylephrine and inflation of an aortic balloon, both of which evoked pressor responses. However, when contraction failed to significantly change arterial pressure, the discharge of 20 aortic chemoreceptors was not significantly changed from control levels. We conclude that the reflex pressor response to static contraction inhibits the discharge of aortic chemoreceptors. This inhibition of discharge needs to be considered when interpreting the effects of aortic barodenervation on the cardiovascular responses to exercise.

Stimulation of H fields of Forel decreases total lung resistance in dogs.

Although there is considerable evidence that the H fields of Forel of the posterior diencephalon play an important role in the regulation of cardiovascular function, little is known about the role these areas play in the control of airway caliber. In chloralose-anesthetized paralyzed dogs, we used both electrical and chemical means to stimulate the H fields of Forel, while we monitored breath-by-breath changes in total lung resistance (TLR), a functional index of airway caliber. Electrical stimulation (200-250 microA, 80 Hz, 0.75 ms) of 82 histologically confirmed sites significantly decreased TLR from 9.2 +/- 0.4 to 7.9 +/- 0.4 cmH2O.l-1.s (P less than 0.01). The bronchodilation evoked by electrical stimulation was unaffected by beta-adrenergic blockade with propranolol but was abolished by cholinergic blockade with atropine. The increases in airway caliber evoked by stimulation were often accompanied by increases in phrenic nerve activity. Chemical stimulation of 21 of 82 sites with microinjections of DL-homocysteic acid (83 nl, 0.2 and 0.5 M), which stimulates cell bodies but not fibers of passage, also decreased TLR from 8.3 +/- 0.5 to 7.3 +/- 0.5 cmH2O.l-1.s (P less than 0.03). We conclude that stimulation of cell bodies in the H fields of Forel produces bronchodilation by withdrawal of cholinergic tone to airway smooth muscle.

Stimulation of the caudal ventrolateral medulla decreases total lung resistance in dogs.

Although the role played by the caudal ventrolateral medulla in the regulation of the cardiovascular system has been extensively investigated, little is known about the role played by this area in the regulation of airway caliber. Therefore, in alpha-chloralose-anesthetized dogs, we used both electrical and chemical means to stimulate the caudal ventrolateral medulla while we monitored changes in total lung resistance breath by breath. We found that electrical stimulation (25 microA) of 26 sites in this area significantly decreased total lung resistance from 7.1 +/- 0.4 to 5.7 +/- 0.3 cmH2O.1-1.s (P less than 0.001). The bronchodilation evoked by electrical stimulation was unaffected by beta-adrenergic blockade but was abolished by cholinergic blockade. In addition, chemical stimulation of seven sites in the caudal ventrolateral medulla with microinjections of DL-homocysteic acid (0.2 M; 66 nl), which stimulates cell bodies but not fibers of passage, also decreased total lung resistance from 8.3 +/- 1.1 to 6.5 +/- 0.8 cmH2O.l-1.s (P less than 0.01). In contrast, microinjections of DL-homocysteic acid into the nucleus ambiguus (n = 6) increased total lung resistance from 7.5 +/- 0.5 to 9.2 +/- 0.4 cmH2O.l-1.s (P less than 0.05). We conclude that the caudal ventrolateral medulla contains a pool of cell bodies whose excitation causes bronchodilation by withdrawing cholinergic input to airway smooth muscle.

Attenuation of reflex pressor and ventilatory responses to static contraction by an NK-1 receptor antagonist.

The chemical messengers released onto second-order dorsal horn neurons from the spinal terminals of contraction-activated group III and IV muscle afferents have not been identified. One candidate is the tachykinin substance P. Related to substance P are two other tachykinins, neurokinin A (NKA) and neurokinin B (NKB), which, like substance P, have been isolated in the dorsal horn of the spinal cord and have receptors there. Whether NKA or NKB plays a transmitter/modulator role in the spinal processing of the exercise pressor reflex is unknown. Therefore, we tested the following hypotheses. After the intrathecal injection of a highly selective NK-1 (substance P) receptor antagonist onto the lumbosacral spinal cord, the reflex pressor and ventilatory responses to static muscular contraction will be attenuated. Likewise, after the intrathecal injection either of an NK-2 (NKA) receptor antagonist or an NK-3 (NKB) receptor antagonist onto the lumbrosacral spinal cord, the reflex pressor and ventilatory responses to static contraction will be attenuated. We found that, 10 min after the intrathecal injection of 100 micrograms of the NK-1 receptor antagonist, the pressor and ventilatory responses to contraction were significantly (P < 0.05) attenuated. Mean arterial pressure was attenuated by 13 +/- 3 mmHg (48%) and minute volume of ventilation by 120 +/- 38 ml/min (34%). The cardiovascular and ventilatory responses to contraction before either 100 micrograms of the NK-2 receptor antagonist or 100 micrograms of the NK-3 receptor antagonist were not different (P > 0.05) from those after the NK-2 or the NK-3 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Responses of group III and IV muscle afferents to dynamic exercise.

Tetanic contraction of hindlimb skeletal muscle, induced by electrical stimulation of either ventral roots or peripheral nerves, is well known to activate group III and IV afferents. Nevertheless, the effect of dynamic exercise on the discharge of these thin fiber afferents is unknown. To shed some light on this question, we recorded in decerebrate cats the discharge of 24 group III and 10 group IV afferents while the mesencephalic locomotor region (MLR) was stimulated electrically. Each of the 34 afferents had their receptive fields in the triceps surae muscles. Stimulation of the MLR for 1 min caused the triceps surae muscles to contract rhythmically, an effect induced by an alpha-motoneuron discharge pattern and recruitment order almost identical to that occurring during dynamic exercise. Eighteen of the 24 group III and 8 of the 10 group IV muscle afferents were stimulated by MLR stimulation. The oxygen consumption of the dynamically exercising triceps surae muscles was increased by 2.5-fold over their resting levels. We conclude that low levels of dynamic exercise stimulate group III and IV muscle afferents.