Effect of arterial chemoreceptor stimulation: role of norepinephrine in hypoxic chemotransmission.
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Adrenergic alpha-2 Receptor Antagonists↗
Biomedical subjects
N R Prabhakar
Publications and source records attributed to N R Prabhakar.
Cardiorespiratory changes induced by vertebral artery injection of sodium cyanide in cats.
Brain stem hypoxia caused by vertebral artery injection of sodium cyanide (NaCN) (1-20 micrograms) in artificially ventilated cats depressed phrenic and stimulated sympathetic nerve activity with a simultaneous increase in arterial blood pressure. Larger doses of NaCN caused greater effects. Hypercapnia produced by inhalation of 7% CO2 in O2 tended to reduce NaCN-induced responses on phrenic activity but not on blood pressure or sympathetic activity. Infusion into the vertebral artery with hypoxic saline (3% CO2 in N2) altered blood pressure, also affecting phrenic and sympathetic nerves similarly to NaCN administration. However, washout of CO2 by infusion of 100% O2 bubbled saline at high flow rates (3.6 ml/min) depressed phrenic as well as sympathetic activity and blood pressure. Spinal transection at the first cervical level eliminated sympathetic excitatory response to intravertebral cyanide injection. However, a large dose of NaCN (600 micrograms) given intravenously in spinal animal excited sympathetic activity. We conclude that intravertebral injection of NaCN can be used to study the effects of local hypoxia of the brain stem on cardiorespiratory responses and that hypoxia acts at both these sites (brain stem and spinal cord) to stimulate sympathetic excitation.
Animals↗
Role of alpha 2-adrenergic receptors in the carotid body response to isocapnic hypoxia.
Alpha-2 adrenergic receptors have been identified in numerous tissues containing norepinephrine. Carotid bodies are sensory organs that detect changes in partial pressure of arterial oxygen and contain substantial amounts of norepinephrine. However, neither the presence nor the functional significance of alpha 2-receptors in the carotid body is known. The purpose of the present study was two-fold: (1) to determine the alpha 2-receptor density in the carotid body and (2) to assess their participation in the chemoreceptor responses to hypoxia. Experiments were performed on 27 anesthetized, paralyzed and artificially ventilated cats. Alpha-2 receptor binding determined by [125I]p-iodoclonidine averaged 10 +/- 2 fmol/mg of protein (n = 18 carotid bodies). Intracarotid infusion of an alpha 2-agonist (guanabenz; 0.5, 1, and 5 micrograms/min for 5 min) caused a dose-dependent depression of the baseline activity and 5 micrograms/min reduced the magnitude of the chemoreceptor response to isocapnic hypoxia by 61% (n = 8). Systemic administration of an alpha 2-antagonist (SKF-86466, 0.5-2 mg/kg) prevented the effects of guanabenz on the chemoreceptor activity. Furthermore, alpha 2-antagonist (0.5-2 mg/kg, i.v.) alone significantly increased baseline discharge by 68% and potentiated the chemoreceptor response to isocapnic hypoxia by 46% (n = 10). These results demonstrate that (1) alpha 2-adrenergic receptors are present in the carotid body and (2) they exert an inhibitory influence on chemoreceptor response to hypoxia. It is suggested that norepinephrine may tune the carotid body responses to hypoxia in part by its action on alpha 2-receptors.
Action Potentials↗
Chemoreceptor responses to substance P, physalaemin and eledoisin: evidence for neurokinin-1 receptors in the cat carotid body.
Substance P (SP) belongs to a group of peptides called tachykinins. Biological effects of SP are mediated by tachykinin receptors that have been classified as neurokinin-1 (NK-1), NK-2 and NK-3 subtypes. The aim of the present study is to elucidate the tachykinin receptor subtype(s) that mediate the excitatory effects of SP in the carotid body. For this purpose, we compared the carotid body responses elicited by SP with that of physalaemin and eledoisin. In other tissues, physalaemin exhibits equi or greater potency at NK-1 receptors and eledoisin exerts its effects more on NK-2 and NK-3 subtypes compared to SP. Experiments were performed on eight cats that were anaesthetized, paralyzed and artificially ventilated with room air. Close carotid body administration of SP and physalaemin produced dose-dependent augmentation of the chemoreceptor afferent activity. Chemoreceptor discharge, however, was unaffected by eledoisin. Compared to that by SP, the magnitude of excitation produced by physalaemin was the same at lower doses but significantly greater with the highest dose (100 nmol). The time course of the response induced by physalaemin, however, was the same as that by SP. The present results demonstrate that in the carotid body physalaemin is also either equi or relatively more potent than SP, whereas eledoisin has no effect on the chemoreceptor discharge. It is suggested that stimulation of the carotid body by SP is mediated by NK-1 but not NK-2 or NK-3 receptors.
Animals↗
Occurrence of neutral endopeptidase activity in the cat carotid body and its significance in chemoreception.
The carotid body contains both tachykinins and enkephalins. Neutral endopeptidase (NEP, E.C. 3.4.24.11), has been suggested to involve in the metabolism of these neuropeptides in several organs. In the present study we determined neutral endopeptidase activity of the cat carotid body and assessed its significance in chemoreception. The cytosolic and membrane fractions of the carotid body contained NEP-like activity whereas it occurred only in the membrane fractions of the superior cervical and the nodose ganglia. Phosphoramidon, thiorphan and metal ion chelators inhibited NEP-like activity of all the 3 tissues studied; other protease inhibitors, however, were ineffective. Close carotid body administration of phosphoramidon significantly potentiated the carotid body response to low PO2 but not to hypercapnia. The enhanced response to hypoxia following phosphoramidon was further augmented by naloxone, an enkephalin antagonist. These results demonstrate that the glomus tissue contains detectable amounts of NEP-like activity and its inhibition selectively affects the hypoxic response of the carotid body.
Animals↗
Effect of adenosine on isolated and superfused cat carotid body activity.
Adenosine is known to increase carotid chemoreceptor discharge in vivo. Since adenosine has powerful vascular effects it is possible that this chemoexcitation is indirectly caused by changes in carotid body blood flow. To evaluate this possibility the effect of adenosine (0.02-2.0 mumol) was assessed on the chemoreceptor activity of the cat carotid bodies in vitro. All three doses of adenosine produced an increase in chemoreceptor discharge which reached its maximum within 10-20 s and subsequently returned to preinjection controls within 1 min. The chemoreceptor excitation caused by adenosine was dose-dependent. These results suggest that adenosine induces chemoexcitation without changes in blood pressure and blood flow.
Action Potentials↗
Substance P and neurokinin A in the cat carotid body: localization, exogenous effects and changes in content in response to arterial pO2.
In the present work we studied the occurrence of substance P (SP) and neurokinin A (NKA) in the carotid bodies of cats by means of immunocytochemistry and radioimmunoassay (RIA). We also compared the exogenous effects of SP and NKA on carotid body sensory discharge. SP- and NKA-like immunoreactivities (SP-LI; NKA-LI) were seen in many glomus cells and in a sparse plexus of fine fibers. The SP-LI containing glomus cells and fibers also exhibited NKA-LI, suggesting that both these tachykinins coexist in the carotid body. Chemoreceptor discharge increased both by SP and NKA in a dose-dependent manner. The peak excitation produced by SP and NKA was the same when the effects were compared on an equimolar basis. The tachykinin content of the carotid bodies varied with changes in arterial pO2. During normoxia, SP and NKA levels were 57 +/- 8 and 85 +/- 14 fmol/mg, respectively. When the animals were exposed for 1 h to 100% O2, SP content was unchanged (51 +/- 4 fmol/mg), whereas NKA levels were significantly lower than during normoxia (29 +/- 3 fmol/mg, P less than 0.01). Following 1 h of hypoxia, SP content of the carotid body was 146 +/- 20 fmol/mg, a value higher than that obtained during normoxia and hyperoxia. NKA levels, on the other hand, were not significantly different from normoxic values. These results indicate that the cat carotid body (1) contains both SP and NKA, (2) both peptides augment neural discharge of the carotid body and (3) their levels in the carotid body are substantially altered by arterial oxygen, the natural stimulus to the chemoreceptors.
Action Potentials↗
Integration of cardiorespiratory responses in the ventrolateral medulla.
Interventions confined to the region adjacent to the VMS can produce both respiratory and circulatory effects. Although it has been suggested that both breathing and vasomotor changes arise from the same neural elements near the VMS, our own investigations indicate that the neurons involved are closely linked but not identical. This belief is supported by recent studies which show that AII and angiotensin antagonists microinjected into the rostral portion of the VMS can significantly modify blood pressure and respiration but can produce effects of different sign. These observations, coupled with previous studies of the VMS, indicate the possibility that regions near the VMS may contribute to integration of circulatory and respiratory responses.
Animals↗
Involvement of ventral medullary surface in respiratory responses induced by 2,4-dinitrophenol.
We examined the contribution of the neural elements near the ventral medullary surface (VMS) to the respiratory response caused by 2,4-dinitrophenol (DNP). Two series of experiments were performed on 12 vagotomized and sinoaortic denervated cats. The first series examined the effect of focal cooling of the VMS on the respiratory response to DNP in four spontaneously breathing, anesthetized cats. When the VMS temperature was 37 degrees C, systemic administration of DNP increased minute ventilation under nearly isocapnic conditions, and focal cooling of the intermediate area of VMS to 20 degrees C attenuated the ventilatory augmentation caused by DNP. To eliminate the influence of anesthetics, a second group of experiments was performed on eight decerebrate, artificially ventilated cats while phrenic nerve activity was monitored as an index of respiration. AgNO3 (10%) was topically applied to the VMS until the respiratory response to inhaled CO2 was abolished. Apnea occurred in seven of eight cats after AgNO3, whereas in the remaining one animal, tidal phrenic activity decreased substantially. Systemic administration of DNP produced no respiratory excitation in any of the animals. On the other hand, rhythmic respiratory activity could be provoked by electrical stimulation of the mesencephalic locomotor area and carotid sinus nerve and by excitation of somatic afferents. Histological examination of the brain stem showed that the AgNO3 had penetrated no more than 350 microns from the ventral medullary surface. These results indicate superficial structures of the VMS are of potential importance in mediating the respiratory responses to hypermetabolism.
2,4-Dinitrophenol↗
Role of adenosine in hypoxic ventilatory depression.
The role of adenosine in the ventilatory depression induced by hypoxia was studied in 82 spontaneously breathing urethan-anesthetized 4-day-old rabbit pups. Respiration was monitored with a pneumotachograph. The animals were exposed to hypoxia (6% O2 in N2) for 30 min or until the occurrence of terminal apnea. In all animals hypoxia produced an initial increase in ventilation followed by a decrease. In the control group 52% of the animals became apneic after 7 min of hypoxic exposure. By contrast, pretreatment with dipyridamole (10 or 20 mg/kg), an adenosine uptake blocker, significantly shortened the time needed to reach apnea. Thus at 7 min of hypoxia 93% of the animals that received dipyridamole became apneic. On the other hand, administration of adenosine antagonists 8-p-sulfophenyltheophylline (5 or 8 mg/kg) and aminophylline (10 or 25 mg/kg) significantly prolonged the time required to produce apnea. Only 20% of the animals that received these antagonists became apneic at 7 min of hypoxia. These results suggest that adenosine is potentially involved in the ventilatory depression produced by hypoxia in neonatal rabbit pups.
Adenosine↗
Respiratory effects of N-methyl-D-aspartate on the ventrolateral medullary surface.
We studied the central effects of N-methyl-D-aspartate (NMDA) on respiration in 18 artificially ventilated cats anesthetized with alpha-chloralose. Unilateral topical application of NMDA (1 x 10(-8) mol) to the intermediate region of the ventrolateral medulla exaggerates the phrenic response to CO2 at end-tidal PCO2 levels of less than 50.0 Torr. At higher end-tidal PCO2 levels, however, such differences disappear. Unilateral NMDA application increases the activity of the right and left phrenic nerves equally. Furthermore, the magnitude of the phrenic response after unilateral application of NMDA was not different from that after bilateral application. NMDA also had a vasopressor action when applied to the ventrolateral medullary surface. In contrast to respiratory responses, bilateral application of NMDA caused a significant increase in blood pressure compared with unilateral application of NMDA. Application of the NMDA antagonist 2-amino-5-phosphonovaleric acid abolished both the blood pressure and respiratory effects of NMDA. These results suggest that CO2 and NMDA may act on a common respiratory premotoneuron to produce stimulation of breathing. Because blood pressure responses, unlike respiratory responses, were greater after bilateral application than after unilateral application of NMDA, it is suggested that the neural substrates for the two effects of NMDA seem to be different.
2-Amino-5-phosphonovalerate↗
Naloxone enhances the response to hypercapnia of spinal and cranial respiratory nerves.
To assess the effects of endogenous opiates on respiratory muscle responses to CO2, naloxone was administered intravenously to paralyzed, vagotomized and artificially ventilated cats anesthetized with alpha-chloralose. Neural activity was recorded from the phrenic, hypoglossal (HG), glossopharyngeal (GP) and recurrent laryngeal (RL) nerves. Before naloxone, phasic activity began first in the phrenic at a PETCO2 of 30.0 +/- 1.8 Torr, followed by the RL at a PETCO2 of 33.5 +/- 1.7 Torr, the HG at a PETCO2 of 39.9 +/- 2.1 Torr and the GP at a PETCO2 of 42.5 +/- 2.2 Torr during CO2 rebreathing. Naloxone had no significant effect on the apneic threshold of any of the nerves studied. Naloxone did, however, increase respiratory frequency (P less than 0.01) mainly by causing a significant (P less than 0.01) shortening of TE as it had no significant effect on TI. Naloxone also significantly increased the rate at which peak nerve activity increased with CO2 in the HG (P less than 0.01) and the GP (P less than 0.01) nerves, but not in the phrenic and RL nerves. Instead, the maximum activity produced by hypercapnia and the PETCO2 level at which maximum activity occurred in the phrenic, but not the RL, increased after naloxone. The result of these effects was that naloxone extended the range over which the HG and GP behaved proportionally with the phrenic, but it did not change the curvilinear nature of these relationships.
Animals↗
Inhibition of expiratory muscle EMG and motor unit activity during augmented breaths in cats.
To test the hypothesis that expiratory muscle activity is reduced during augmented breaths, electromyographic activity (EMG) of the triangularis sterni (TS) was recorded from eight pentobarbital anesthetized cats. Augmented breaths significantly increased tidal volume and peak diaphragm EMG, and prolonged inspiratory time and the first phase of expiration. However, the duration of the second phase of expiration was unchanged. Peak TS EMG was reduced during sighs in all animals, from 25 +/- 5 to 12 +/- 2 arbitrary units (P less than 0.005). Furthermore, the onset of TS activity during expiration was significantly delayed during augmented breaths (P less than 0.002), whereas the duration of expiratory firing tended to decrease but not significantly. Electrical activity was recorded from eight motor units of the TS in five cats. During resting breathing the motor units had a mean relative expiratory onset time of 46 +/- 4% of expiration, and a mean firing frequency of 19 +/- 2 impulses/sec. Two motor units became quiescent during augmented breaths. Of the remaining six motor units, three minimally shortened their duration of activity (by less than 15%) while three substantially abbreviated their period of firing (by 50% or more). In addition, all TS motor units reduced their mean firing frequency (P less than 0.05) and number of impulses per breath (P less than 0.002) during sighs. We conclude that expiratory activity of the triangularis sterni muscle is reduced during augmented breaths, due to a combination of motor unit derecruitment and a slowing of motor unit firing frequency.
Animals↗
Respiratory and vasomotor responses to focal cooling of the ventral medullary surface (VMS) of the rat.
Experiments were performed on anesthetized, paralyzed and artificially ventilated rats after denervation of the vagus and carotid sinus nerves. The electrical activity of the phrenic and cervical sympathetic nerves (CS) along with the arterial blood pressure (BP) were monitored. Graded unilateral cooling of the ventral lateral surface (VMS) from 37 degrees C to 10 degrees C between 6th and 12th nerve rootlets did not affect the phrenic activity. Whereas, a significant depression or apnea was seen with cooling of an area between 1st cervical and 12th nerve rootlets. Bilateral cooling also produced similar respiratory responses. Respiratory depression could also be obtained during higher respiratory drive (7% CO2 in O2). On the other hand, a significant fall in BP and reduction in CS activity were observed with unilateral cooling in any of these VMS areas. However, the magnitude of BP decrease was less with 7% CO2 in O2 compared to 100% O2 breathing.
Animals↗
Influence of adrenaline and hypoxia on rat muscle receptors in vitro.
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Animals↗
Respiratory and vasomotor influences of the ventrolateral medulla.
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Animals↗
Respiratory and vasomotor effects of excitatory amino acid on ventral medullary surface.
Three glutamic acid analogues, N-methyl-D-aspartic (NMDA), quisqualic (QQ), and kainic (KAI) acids were applied topically to the ventral surface of the medulla (VMS) in paralyzed, vagotomized and carotid sinus denervated cats hyperventilated to apnea. Respiratory and vasomotor effects were assessed by changes in phrenic nerve activity and systemic arterial blood pressure. All three agents to varying degrees raised systemic blood pressure, but only NMDA consistently initiated phrenic nerve activity at pCO2 levels below that observed in control trials. KAI and QQ raised blood pressure even in those animals in which they had little effect on initiating phrenic nerve activity. Furthermore, respiratory responses were obtained from localized areas on VMS, namely the intermedio-caudal zone (I-C areas); whereas blood pressure elevations could be obtained from wider VMS areas including the rostral zone (R areas). In addition, the effects of the three amino acids on blood pressure were quantitatively different with KAI causing much greater increases in blood pressure than QQ or NMDA. The respiratory and vasomotor effects of NMDA and QQ were blocked by the use of 2-amino-5-phosphonovaleric acid and L-glutamic acid diethylester, their respective antagonists. The results suggest that neurons in the VMS which cause respiratory and vasomotor responses are not identical. Cells containing receptors stimulated by NMDA predominantly increase respiration, whereas cells containing receptors excited by KAI are more effective in eliciting vasomotor responses.
2-Amino-5-phosphonovalerate↗
Role of the vagal afferents in substance P-induced respiratory responses in anaesthetized rabbits.
Since substance P (SP)-like immunoreactivity has been demonstrated in vagal sensory fibres of bronchopulmonary origin, it was considered of interest to (1) characterize the pattern of responses to SP injected into the pulmonary as well as the systemic arterial system, and (2) assess the types of vagal afferents that are affected by SP. Experiments were performed on 15 pentobarbital-anaesthetized, spontaneously breathing rabbits. Efferent phrenic nerve activity was monitored as an index of central respiratory neural output. Intra-atrial injections of SP into the pulmonary circulation (100 ng kg-1) increased the respiratory rate, and peak integrated phrenic amplitude by 47 +/- 8 and 40 +/- 4%, respectively, above the controls. In addition, SP elicited augmented breaths (ABs) within 2-3 s in 67% of the trials. In contrast to right atrial injections, no ABs and no significant changes in respiratory rate were observed in response to intra-aortic injections of SP (100 ng kg-1). Tidal phrenic activity rise after aortic injections of SP was significantly less as compared with right atrial administrations of SP. Since both routes of administration decreased the arterial blood pressure to the same extent, these respiratory responses were not likely secondary to cardiovascular changes. After administration of an SP antagonist (D-Arg-D-Trp7,9, Leu11, SP), respiratory responses to SP were significantly attenuated. Also, the rate of occurrence of ABs elicited by releasing the tracheal occlusions was reduced (control 95 vs. 14% SP antagonist). Bilateral vagotomy abolished the tachypnoeic response and reduced the magnitude of the phrenic nerve increments caused by right atrial injection of SP.(ABSTRACT TRUNCATED AT 250 WORDS)
Afferent Pathways↗