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G E Bisgard

Publications and source records attributed to G E Bisgard.

At least 19 recordsLinked to original sources
PubMed2003

Level and duration of developmental hyperoxia influence impairment of hypoxic phrenic responses in rats.

Developmental hyperoxia (1-4 wk of 60% O2) causes long-lasting impairment of hypoxic phrenic responses in rats. We hypothesized that shorter or less severe hyperoxic exposures would produce similar changes. Hypoxic phrenic responses were measured in 3- to 5-mo-old, urethane-anesthetized rats exposed to 60% O2 for postnatal day 1 or week 1 or to 30% O2 for postnatal week 1. Whereas 1 day of 60% O2 had no lasting effects (P > 0.05 vs. control), both 1 wk of 60% O2 and 1 wk of 30% O2 decreased adult hypoxic phrenic responses (P < 0.05 vs. control), although the effects of 30% O2 were smaller. Hypoxic ventilatory responses (expressed as the ratio of minute ventilation to metabolic CO2 production) were also reduced in unanesthetized rats (5-10 mo old) exposed to 1 wk of 60% O2 during development (P < 0.05). An age-dependent increase toward normal hypoxic phrenic responses was observed in rats exposed to 1 wk of 60% O2 (P < 0.05), suggesting a degree of spontaneous recovery not observed after 1 mo of 60% O2. These data indicate that long-lasting effects of developmental hyperoxia depend on the level and duration of hyperoxic exposure.

Aging↗
PubMed2003

Adult carotid chemoafferent responses to hypoxia after 1, 2, and 4 wk of postnatal hyperoxia.

Exposing newborn rats to postnatal hyperoxia (60% O2) for 1-4 wk attenuates the ventilatory and phrenic nerve responses to acute hypoxia in adult rats. The goal of this research was to increase our understanding of the carotid chemoreceptor afferent neural input in this depressed response with different durations of postnatal hyperoxic exposure. Rats were exposed from a few days before birth to 1, 2, or 4 wk of 60% O2 and studied after 3-5 mo in normoxia. The rats were anesthetized with urethane. Whole carotid sinus nerve (CSN) responses to NaCN (40 microg/kg iv), 10 s of asphyxia and acute isocapnic hypoxia (arterial Po2 45 Torr) were determined. Mean CSN responses to stimuli after postnatal hyperoxia were reduced compared with controls. Responses in rats exposed to 1 wk of postnatal hyperoxia were less affected than those exposed to 2 and 4 wk of hyperoxia, which were equivalent to each other. These studies illustrate the importance of normoxia during the first 2 wk of life in development of carotid chemoreceptor afferent function.

Animals↗
PubMed2002

Life-long impairment of hypoxic phrenic responses in rats following 1 month of developmental hyperoxia.

Hypoxic ventilatory and phrenic responses are reduced in adult rats (3-5 months old) exposed to hyperoxia for the first month of life (hyperoxia treated). We previously reported that hypoxic phrenic responses were normal in a small sample of 14- to 15-month-old hyperoxia-treated rats, suggesting slow, spontaneous recovery. Subsequent attempts to identify the mechanism(s) underlying this spontaneous recovery of hypoxic phrenic responses led us to re-evaluate our earlier conclusion. Experiments were conducted in two groups of aged Sprague-Dawley rats (14-15 months old) which were anaesthetized, vagotomized, neuromuscularly blocked and ventilated: (1) a hyperoxia-treated group raised in 60 % O2 for the first 28 postnatal days; and (2) an age-matched control group raised in normoxia. Increases in minute phrenic activity and integrated phrenic nerve amplitude (integral Phr) during isocapnic hypoxia (arterial partial pressures of O2, 60, 50 and 40 +/- 1 mmHg) were greater in aged control (n = 15) than hyperoxia-treated rats (n = 11; P < or = 0.01). Phrenic burst frequency during hypoxia was not different between groups. To examine the central integration of carotid chemoafferent inputs, steady-state relationships between carotid sinus nerve (electrical) stimulation frequency and phrenic nerve activity were compared in aged control (n = 7) and hyperoxia-treated rats (n = 7). Minute phrenic activity, integral Phr and burst frequency were not different between groups at any stimulation frequency between 0.5 and 20 Hz. Carotid body chemoreceptor function was examined by recording whole carotid sinus nerve responses to cessation of ventilation or injection of cyanide in aged control and hyperoxia-treated rats. Electrical activity of the carotid sinus nerve did not change in five out of five hyperoxia-treated rats in response to stimuli that evoked robust increases in carotid sinus nerve activity in five out of five control rats. Estimates of carotid body volume were lower in aged hyperoxia-treated rats (4.4 (+/- 0.2) x 10(6) microm3) compared to controls (17.4 (+/- 1.6) x 10(6) microm3; P <0.01). We conclude that exposure to hyperoxia for the first month of life causes life-long impairment of carotid chemoreceptor function and, consequently, blunted phrenic responses to hypoxia.

Aging↗
PubMed2001

Induced recovery of hypoxic phrenic responses in adult rats exposed to hyperoxia for the first month of life.

1. Adult rats exposed to hyperoxia for the first month of life have permanently attenuated ventilatory and phrenic nerve responses to hypoxia. We tested the hypothesis that the blunted hypoxic phrenic response in hyperoxia-treated rats (inspired O(2) fraction, F(I,O2) = 0.6 for 28 post-natal days) could be actively restored to normal by intermittent (alternating 12 % O(2)/air at 5 min intervals; 12 h per night for 1 week) or sustained (12 % O(2) for 1 week) hypoxia. 2. Phrenic responses to isocapnic hypoxia (P(a,O2) = 60, 50 and 40 +/- 2 mmHg) were assessed in the following groups of anaesthetized, vagotomized adult Sprague-Dawley rats (age 4 months), treated with a neuromuscular blocking agent and ventilated: control, hyperoxia-treated and hyperoxia-treated exposed to either intermittent or sustained hypoxia as adults. Experiments on intermittent and sustained hypoxia-treated rats were performed on the morning following hypoxic exposures. 3. Both intermittent and sustained hypoxia enhanced hypoxic phrenic responses in hyperoxia-treated rats when expressed as minute phrenic activity (P < 0.05). Increases in phrenic burst amplitude during hypoxia were greater in hyperoxia-treated rats after intermittent hypoxia (P < 0.05), and a similar but non-significant trend was observed after sustained hypoxia. Hypoxia-induced changes in phrenic burst frequency were not significantly different among groups. 4. The estimated carotid body volume in control rats (11.5 (+/- 0.7) x 10(6) microm(3)) was greater than in the other treatment groups (P < 0.05). However, carotid body volume was significantly greater in hyperoxia-treated rats exposed to sustained hypoxia (6.3 (+/- 0.3) x 10(6) microm(3); P < 0.05) compared to hyperoxia-treated rats (3.3 (+/- 0.2) x 10(6) microm(3)) or hyperoxia-treated rats exposed to intermittent hypoxia (3.8 (+/- 0.3) x 10(6) microm(3)). 5. Hypoxic phrenic responses in hyperoxia-treated rats 1 week after intermittent hypoxia were similar to responses measured immediately after intermittent hypoxia, indicating persistent functional recovery. 6. The results indicate that diminished hypoxic phrenic responses in adult rats due to hyperoxia exposure for the first 28 post-natal days can be reversed by intermittent or sustained activation of the hypoxic ventilatory control system. Although the detailed mechanisms of functional recovery are unknown, we suggest that sustained hypoxia restores carotid chemoreceptor sensitivity, whereas intermittent hypoxia primarily augments central integration of synaptic inputs from chemoafferent neurons.

Animals↗
PubMed2001

Effect of 8-OH DPAT and ketanserin on the ventilatory acclimatization to hypoxia in awake goats.

We have previously reported that broad-spectrum serotonergic blockade increased the acute hypoxic ventilatory response in awake goats. The purpose of the present study was to examine the putative serotonin (5-HT) receptor subtype(s) that may have contributed to this response. Following the administration of the selective 5-HT(1A)-receptor agonist, 8-hydroxy-(2-di-n-propylamino) tetralin (8-OH DPAT, 0.1 mg x kg(-1)i.v.), there was an increase in normoxic expired minute ventilation (V(E)) that was due to an increased breathing frequency. V(E) increased during hypoxia but the change in V(E) (Delta V(E)) associated with hypoxic exposure was not different from the Delta V(E) of saline treated goats. The combination of 8-OH DPAT and a selective 5-HT(2A/2C) receptor antagonist, ketanserin (0.1 and 1.0 mg x kg(-1)i.v., respectively), also increased normoxic V(E) but did not alter the hypoxia induced Delta V(E). Both 8-OH DPAT alone and in combination with ketanserin attenuated the change in V(E) associated with sustained hypoxia but neither was able to attenuate the increased hypoxic ventilatory response that occurs following acclimatization. The augmented acute hypoxic ventilatory response that we previously reported does not appear to be mediated via the activation of the 5-HT(1A) receptor or through the combination of 5-HT(1A) activation and 5-HT(2A/2C) blockade. The results of this study further suggest that while 5-HT may modulate hypoxic ventilation it does not appear to be necessary for the development of ventilatory acclimatization to hypoxia.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Alpha2A-adrenoceptor mediated tachypnea in awake goats.

To further elucidate the role of alpha2-adrenoceptors (alpha2-ARs) in the control of respiratory rhythm we examined the ventilatory effects of guanfacine (a preferentially selective alpha2A-AR agonist) and clonidine (a non-selective alpha2-AR agonist) in awake adult goats. Systemic administration of guanfacine in cumulative doses (20 microg/kg; 140-180 microg/kg total cumulative dose) increased breathing in all animals in a dose-dependent manner. The excitatory effect was entirely mediated by increases in respiratory frequency. The magnitude of the guanfacine-induced tachypnea was similar to that produced by systemic administration of cumulative doses of clonidine (1-2 microg/kg; 4-10 microg/kg total cumulative dose) in the same animals studied on a separate day. Both guanfacine- and clonidine-induced tachypnea was reversed by the preferentially selective alpha2A-AR antagonist RX821002 (2-6 microg/kg IV). Unlike clonidine however, guanfacine administration did not produce slow arrhythmic breathing episodes (irregular TE intervals and central apneas) that are characteristic of alpha2-AR stimulation with alpha2-AR agonists in the awake goat. The results suggest that alpha2-AR agonist-induced ventilatory excitation (tachypnea) requires the activation of alpha2A-ARs whereas clonidine-induced ventilatory depression (arrhythmic breathing) requires the activation of an alternate alpha2-AR subtype (presumably alpha2C-ARs). The results further demonstrate that alpha2-AR pathways exert an important influence on respiratory rhythm in the awake goat.

Adrenergic alpha-Agonists↗
PubMed2001

Ventilatory effects of alpha2-adrenoceptor blockade in awake goats.

We sought to determine the extent to which alpha2-adrenoceptor (alpha2-AR) pathways exert a tonic influence on respiratory rhythm under normal physiological conditions. The ventilatory effects of alpha2-AR blockade with SKF-86466 were examined in awake adult goats. The antagonist effect of SKF-86466 at alpha(2)-ARs was evident both as a reversal of the ventilatory disturbances produced by the alpha2-AR agonist clonidine (5 microg/kg IV) and as a rightward shift in the potency of the agonist-evoked response after SKF-86466 pretreatment. Systemic administration of SKF-86466 in cumulative doses (25-250 microg/kg) or as a single bolus injection (500 microg/kg) produced dose-dependent increases in breathing in all animals. The excitatory effect was primarily mediated by increases in respiratory frequency that persisted for at least 120 min after injection (500 microg/kg). The time course and magnitude of the ventilatory response to SKF-86466 was similar in carotid body denervated animals. The ventilatory response to isocapnic hypoxia but not normoxic hypercapnia was significantly elevated after SKF-86466 administration (500 microg/kg). SKF-86466 (25-1000 microg/kg) produced dose-dependent increases in heart rate in all animals but did not significantly change mean arterial blood pressure at any dose. The results demonstrate that alpha2-AR pathways exert a tonic inhibitory influence on respiratory rhythm in the awake goat.

Adrenergic alpha-Agonists↗
PubMed2000

5-HT5a receptors in the carotid body chemoreception pathway of rat.

By using a specific antibody, 5-HT5a receptor-like immunoreactivity was revealed in the chemoreceptive, oxygen sensitive, carotid body (CB) type I cells, and neurons of the petrosal ganglion (PG) and the superior cervical ganglion (SCG) in rat. mRNA encoding for the 5-HTa receptor was also detected in these tissues by RT-PCR, and confirmed with DNA sequencing. The present study provides direct evidence that 5-HT5a receptors are expressed in the CB, PG and SCG, which all likely play fundamental roles in arterial chemoreception.

Afferent Pathways↗
PubMed2000

Carotid body mechanisms in acclimatization to hypoxia.

Most studies oriented toward examining mechanisms increasing carotid body (CB) sensitivity to hypoxia during ventilatory acclimatization (VAH) have focussed on the role of known neuromodulators of CB function. Two general categories of the neuromodulatory agents studied most extensively could be considered: those thought to be primarily inhibitory to CB function: dopamine, norepinephrine, nitric oxide and those thought to be primarily excitatory: substance P, endothelin. There is evidence that these putative inhibitory agents are up-regulated in the first weeks of chronic hypoxia and that substance P is down-regulated. All these changes would favor a decrease in CB sensitivity to hypoxia. There are data suggesting that CB endothelin activity is up-regulated in rats subjected to chronic hypoxia, a direction suggesting increased CB sensitivity to hypoxia. Dopamine may have an excitatory as well as an inhibitory role on the CB, but there is not yet evidence to indicate that an excitatory role for DA exists in chronic hypoxia. Ion channel studies of type I CB cells suggest increased excitability after prolonged hypoxia. The role of excitatory CB nicotinic receptors and putative serotonin type 3 receptors should be examined further for their potential role in VAH. It is suggested that a balance of excitatory and inhibitory modulation is responsible for increased CB sensitivity to hypoxia during VAH.

Acclimatization↗
PubMed2000

Clonidine induces upper airway closure in awake goats.

We examined the effects of the alpha(2)-adrenoceptor (alpha(2)-AR) agonist clonidine on pressure-flow relationships in the upper airway. Inspired and expired airflows, subglottic tracheal pressure (PTR), mask pressure and middle pharyngeal constrictor (MPC) and diaphragm electromyogram (EMG) activities were recorded in awake standing goats. Clonidine-induced central apneas were always associated with continuous tonic activation of the MPC. Subglottic PTR during expiration increased progressively in a dose-dependent manner after clonidine administration. In all cases, positive subglottic PTR was maintained throughout the duration of clonidine-induced apneas and was sufficient to retard or prevent expiratory flow during early and mid-expiration indicating complete airway closure. The effects of clonidine were reversed by selective alpha(2)-AR blockade with SKF-86466. Central apneas after spontaneous augmented breaths (sighs) were associated with continuous tonic activation of the MPC throughout the duration of the prolonged TE intervals. However, subglottic PTR during expiration was not significantly different from control breaths and there was no evidence of increased expiratory airway resistance or delayed expiratory flow. We conclude that continuous tonic activation of pharyngeal adductor muscles appears to be a constant feature of central apnea in the awake goat independent of the initiating cause of the apnea. However, our data suggest that MPC activation alone may not be sufficient to cause complete closure of the upper airway during central apnea.

Adrenergic alpha-Agonists↗
PubMed1999

Nonvagal tachypnea following alpha2-adrenoceptor stimulation in awake goats.

To assess the influence of vagal afferent feedback in the development of respiratory instabilities induced by alpha2-adrenoceptor (alpha2-AR) stimulation in the goat, we examined the ventilatory effects of clonidine, an alpha2-AR agonist, in awake tracheostomized goats before and after bilateral mid-cervical vagotomy. Prior to vagal section, systemic administration of clonidine (0.5-3.0 microg kg(-1)) induced a highly dysrhythmic pattern of breathing in all animals that was characterized by alternating episodes of tachypnea and slow irregular breathing patterns including prolonged and variable expiratory time (TE) intervals. Periods of apnea were commonly observed. Bilateral vagotomy resulted in a slower deeper breathing pattern and abolished the tachypnea evoked by intravenous administration of phenylbiguanide (PBG; 20-50 microg kg(-1)), a selective serotonin type 3 (5-HT3) receptor agonist. However, respiratory disturbances associated with alpha2-AR stimulation (including tachypnea) persisted after vagal section and were qualitatively and quantitatively similar to pre-vagotomy data demonstrating that vagal afferent feedback is not necessary for the development of respiratory disturbances induced by clonidine. The results suggest that respiratory dysrhythmias caused by alpha2-AR agonists in the goat are mediated by alpha2-ARs in the CNS.

Adrenergic alpha-Agonists↗
PubMed1999

Methysergide augments the acute, but not the sustained, hypoxic ventilatory response in goats.

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation that occurs during sustained hypoxia. As serotonin (5-HT) has been reported to be an important modulator of respiratory output, 5-HT may also play a role in VAH. Methysergide (a broad-spectrum 5-HT antagonist), was given to awake goats (1 mg kg(-1) i.v.) 30 min prior to being exposed to 4 h of isocapnic hypoxia. Although methysergide slightly decreased arterial pH, presumably due to a non-significant increase in arterial P(CO2), it did not alter normoxic ventilation. Following methysergide, the expired minute ventilation (VE) was significantly elevated above the control (saline) response after 30 min of hypoxia, but methysergide did not otherwise alter VAH. We repeated the study in the same goats using ketanserin, a specific 5-HT2A/2C receptor antagonist (1.2 mg kg(-1) i.v.). Ketanserin had no effect on the acute hypoxic ventilatory response, or on VAH. We conclude that while 5-HT modulates the acute hypoxic ventilatory response in goats, it does not appear to act through the 5-HT2A/2C receptor subtypes.

Acclimatization↗