The stimulus modality of the hypoxic ventilatory response in rodents.
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Animals↗
Biomedical subjects
W K Milsom
Publications and source records attributed to W K Milsom.
Ventilatory responses to acute and chronic hypoxic hypercapnia in the ground squirrel.
Golden-mantled ground squirrels exhibited a strong hypoxic ventilatory response but a blunted hypercapnic ventilatory response and showed no interactive effects when both stimuli were presented together. They exhibited a resting hypoxic ventilatory drive which was eliminated by carotid body denervation. Carotid denervation also shifted the threshold of the hypoxic ventilatory response but had no effect on the slope of either the hypoxic or hypercapnic ventilatory responses. Chronic exposure (2-12 months) to hypoxic-hypercapnic conditions (16% O2, 4% CO2) resulted in a sustained increase in ventilation. Initial increases in both tidal volume (VT) and breathing frequency (fR) were followed by a subsequent further increase in VT and concomitant decrease in fR (acclimation) which had little overall effect on ventilation (VE) but further increased calculated alveolar ventilation (VA). Respiratory sensitivity to hypoxia and hypercapnia were unaltered under these conditions. On acute return to breathing room air, VE remained elevated (approximately 35%) compared to control animals suggesting that deacclimation takes time. Carotid body denervation in these animals had similar effects to those seen in control animals suggesting that acclimation did not involve changes in carotid body input.
Acute Disease↗
Chemoreceptors and control of episodic breathing in the bullfrog (Rana catesbeiana).
To test the hypothesis that the episodic breathing pattern of bullfrogs is necessarily caused by fluctuations of PaO2 and PaCO2/pH, the natural oscillations of blood gases associated with periods of ventilation and apnea were experimentally prevented by unidirectional ventilation (UDV) of lungs. UDV with air or a 50% O2 in N2 gas mixture eliminated breathing episodes; only sporadic single breaths were ever observed under these conditions. UDV with hypoxic or hypercarbic gas mixtures, however, produced episodic breathing despite the fact that UDV virtually eliminated fluctuations in pHa, PaCO2 and PaO2. Furthermore, the breathing patterns of animals with the same mean levels of blood gases and acid-base status, with (UDV) and without (non-UDV) phasic chemoreceptor input were identical. These data indicate that phasic chemoreceptor input plays little or no role in the control of the normal breathing pattern although some tonic level of chemoreceptor input is required for ventilation to occur. Animals on UDV were more sensitive to hypercarbic than hypoxic gases and hypoxemia and hypercapnia affected breathing pattern differently. This indicates that tonic chemoreceptor input also affects the length of the periods of apnea and ventilation but this must be through some mechanism other than an "on" or "off" threshold.
Animals↗
Effects of hibernation on blood oxygen transport in the golden-mantled ground squirrel.
Isocapnic O2 equilibrium curves (O2EC) were generated for winter hibernating and summer active ground squirrels (Spermophilus lateralis) at 7 degrees and 37 degrees C using thin blood film techniques. Half-saturation PO2 at 7 degrees C and pHa 7.46 were 5.8 +/- 0.1 and 6.9 +/- 0.2 Torr for hibernating and summer squirrels, respectively; P50 values at 37 degrees C and pHa 7.49 were 15.3 +/- 0.1 and 18.1 +/- 0.5 Torr, respectively. This increased blood O2 affinity in the winter animal results, in part, from reductions of RBC organic phosphates. The molar ratio ([ATP] + [DPG])/[Hb4] decreased from 1.55 in summer squirrels to 0.91 in winter hibernators. O2EC shape and CO2 Bohr effect were similar for the two animal groups, but varied with blood temperature. At 7 degrees C, Hill plots were nonlinear; Hill's n increased from values of 2.2-2.4 below 40% S to 2.7-2.9 above 60% S. At 37 degrees C, Hill plots were reasonably linear (n = 2.5). CO2 Bohr slopes (delta log P50/delta pH) for hibernating and euthermic squirrels were -0.37 +/- 0.02 and -0.40 +/- 0.03 at 7 degrees C, respectively, and -0.62 +/- 0.04 and -0.60 +/- 0.02 at 37 degrees C, respectively. Blood O2 capacity was significantly greater (P < 0.001) in the hibernator; hematocrit (55%) and [Hb] (19.1 g/dl) exceeded the summer squirrel values by 20% and 25%, respectively. Estimated PvO2 values for summer and winter animals at 7 degrees C and pH 7.46 were 7.25 and 6.94 Torr, respectively. This suggests that the effect of increased Hb-O2 affinity on PvO2 is offset by increased circulating [Hb]. We conclude that seasonal changes in the O2 transport properties of squirrel blood do not contribute to the depression of aerobic metabolism during winter hibernation.
Animals↗
The ventilatory response of rodents to changes in arterial oxygen content.
A strong correlation between the arterial oxygen partial pressure (PaO2) values for the threshold of the hypoxic ventilatory response (HVR) and the shoulder of the oxyhemoglobin equilibrium curve (OEC) is retained in heterothermic rodents as body temperature changes despite changes in hemoglobin-oxygen affinity. It has been suggested that this may reflect either temperature-induced changes in the response characteristics of arterial chemoreceptors or an ability to sense changes in arterial O2 content (CaO2). This study examined the extent to which changing CaO2 independent of PaO2 with carbon monoxide could contribute to the HVR in heterothermic (golden-mantled ground squirrels) and non-heterothermic rodents (rats). The HVR of isocapnic, anaesthetized rodents was assessed during both hypoxic hypoxia, which alters PaO2 and CaO2 simultaneously, and carbon monoxide hypoxia, which alters CaO2 independent of PaO2. While both species exhibited ventilatory responses to hypoxic hypoxia and carbon monoxide hypoxia, the HVR of the squirrel was consistently stronger than that of the rat. Reductions in CaO2 independent of PaO2 could still produce 60% of the full HVR seen with hypoxic hypoxia in both species. Simultaneous changes in PaO2, however, were necessary to produce the full response. While it seems likely that the results can be explained by the changes in tissue PO2 which would occur at receptor sites under the various conditions, such an explanation is not totally supported by other studies.
Animals↗
Patterns of respiration and heart rate during wakefulness and sleep in elephant seal pups.
Although breath holding during diving has been studied extensively in seals, the recent observation that these mammals also exhibit long-duration apnea while apparently sleeping has not been systematically examined. This project examined sleep apnea in northern elephant seal pups (Mirounga angustirostris). The animals exhibited a sequential sleep pattern of wakefulness-slow-wave sleep (SWS)-rapid eye movement (REM) sleep that resembled the normal pattern of mammalian sleep. The typical respiratory pattern during sleep in 4-mo-old pups consisted of short periods of continuous breathing separated by periods of apnea of up to 12 min. Several cycles of apnea and eupnea could occur during a single sleep episode. Breathing during a sleep cycle occurred only in SWS, never during REM sleep. The eupneic heart rate was characterized by significant sinus arrhythmia, and the apneic heart rate was similar to the minimum value during normal sinus arrhythmia. Patterns of change in breathing and heart rate associated with wakefulness and sleep were similar in seals sleeping underwater and on land. When sleeping underwater, the seals raised their heads to the surface to breathe without awakening. The changes in heart rate associated with normal sinus arrhythmia, sleep apnea, and diving apnea appear to be similar, suggesting regulation by a common homeostatic control mechanism.
Analysis of Variance↗
Vagal input enhances responsiveness of respiratory discharge to central changes in pH/CO2 in bullfrogs.
This study investigated the interaction between vagal afferent input and central chemosensitivity in modulating the respiratory motor output of in vitro brain stem-spinal cord preparations from adult bullfrogs. With this preparation, the spatiotemporal distribution of respiratory-related motor output emulated that of intact bullfrogs; that is, the fictive breathing pattern was mostly episodic. Recordings from cranial motor nerves (V and X) showed that, without peripheral feedback, increasing the PCO2 of the mock cerebrospinal fluid (thereby reducing pH from 8.3 to 7.7) caused a modest increase in respiration-related burst frequency. When the pulmonary branch of a vagus nerve was stimulated phasically (2 V, 20 Hz, 0.2 ms) during each fictive breath to simulate afferent pulmonary stretch receptor feedback 1) the responsiveness of the preparation to the same changes in pH was augmented nearly threefold and 2) the breathing pattern remained episodic. It appears, therefore, that episodic breathing is an intrinsic property of the central nervous system in bullfrogs. It is concluded that there is a strong interaction between vagal feedback and central chemodetection in controlling the temporal relationships that characterize this episodic breathing pattern.
Animals↗
Ventilation is coupled to metabolic demands during progressive hypothermia in rodents.
We examined changes in ventilation and metabolic rate during hypothermia (36-27 degrees C) induced with exposure to helium-oxygen and cold in halothane anesthetized ground squirrels (Spermophilus lateralis) and rats. As a consequence of proportionate decreases in VCO2 and breathing frequency, the VE/VCO2 in both species remained constant. The changes which occurred in breathing pattern were also similar in the two species; an increase in TI and TE along with emergence of apneic periods between breaths at body temperatures below 31 degrees C. VT/TI and TI/TTOT decreased but VT remained constant with progressive hypothermia. The ventilatory responses to hypercapnia and hypoxia decreased to the same extent as the ventilatory and metabolic requirements in the ground squirrel but not the rat. The changes in VE and VCO2 during hypothermia in the ground squirrel predicted well the values observed in deep hibernation. We conclude that regulation of ventilation at reduced body temperatures is tightly coupled to metabolic demand.
Animals↗
Acidosis and metabolic rate in golden mantled ground squirrels (Spermophilus lateralis).
In this study, three series of experiments were conducted on euthermic, anesthetized, artificially ventilated golden mantled ground squirrels (Spermophilus lateralis), each of which altered pHa in a different fashion. In Series I, animals were randomly hypo- or hyper-ventilated. On average, pHa changed from 7.13 to 7.59, PaCO2 from 59.2 to 23.6 Torr, and PaO2 from 45.8 to 57.2 Torr between the two conditions, respectively. VO2 showed a significant positive correlation with pHa (r = +0.84) as well as PaO2 (r = + 0.60). In Series II, respiratory acidosis was produced by pump-ventilating animals with up to 10% inspired CO2 to reduce pHa to within the range 7.40 to 7.20. On average, pHa was reduced to 7.30, PaO2 to 50.1 Torr and PaCO2 was increased to 56.7 Torr. As in Series I, there was a significant positive correlation between VO2 and pHa (r = +0.78) and between VO2 and PaO2 (r = +0.71). In Series III, metabolic acidosis was produced by infusing lactic or acetic acid intravenously for 20 to 30 min. This reduced pHa from 7.56 to 7.32, PaO2 from 70.2 to 58.9 Torr, and elevated PaCO2 from 26.9 to 37.9 Torr (P < 0.05 in all cases). Contrary to Series I and II, VO2 increased with a decline in pHa (r = -0.65, P < 0.05) and PaO2 (r = -0.55, P < 0.05). Thus, despite a significant decline in pHa and PaO2 and an elevation of PaCO2 during all three series, VO2 changed in opposite directions during respiratory and metabolic acidosis. We conclude that whatever the mechanism involved, hypoventilation during the early stages of entrance into hibernation can contribute to the fall in metabolic rate.
Acidosis↗
Sensory receptors in the first gill arch of rainbow trout.
Afferent neural activity was recorded from sensory receptors innervated by the glossopharyngeal nerve (cranial nerve IX) in isolated, perfused first gill arch preparations from rainbow trout. The present study demonstrates the presence of every major type of peripheral cardio-respiratory receptor described in fish in this preparation. Oxygen-sensitive chemoreceptors responsive to internal and/or external hypoxia and cyanide were present. Qualitatively these receptors behaved in an identical fashion which was also similar to that described for mammalian carotid body chemoreceptors. About 5% of the sensory receptors examined were O2-sensitive. proprioceptors were the most numerous receptor type identified and were sensitive to mechanical stimulation of the arch, rakers or filaments. Finally, baroreceptors, the least numerous class of receptor identified, were also present with activity that was altered in response to changes in perfusion pressure. While the reflex responses elicited by the stimulation of these receptors were not addressed in this study, it is likely that these receptors contribute to the reflex cardio-respiratory responses to changes in gill perfusion, gill deflection and hypoxia (environmental or internal) described in fishes. These data thus support suggestions concerning homologies between the first gill arch of teleosts and the carotid bodies of mammals and the importance of the first gill arch in trout in cardio-respiratory control.
Animals↗
Sleep and mammalian hibernation: homologous adaptations and homologous processes?
Evidence from electroencephalographic, thermoregulatory and cellular neurophysiological studies suggests that sleep and hibernation may be homologous adaptations for energy conservation. However, despite the similarities between non-rapid eye movement (NREM) sleep and hibernation, the restorative function normally associated with slow wave sleep appears not to occur during hibernation, perhaps because of the low body temperature (Tb). Cellular neurophysiological studies also suggest that a bout of hibernation is not exclusively NREM sleep but is punctuated by periods of wakefulness. The entrance to hibernation involves both an inhibition of cortical activity and activation of hypothalamic regions, whereas the arousal from hibernation is primarily a hypothalamic function. Multiple neurochemical systems are affected by the arousal state change that occurs in hibernation, and a serotonergic-opiatergic interaction, in particular, may be important in regulating these events. Among regulated physiological systems affected by arousal state changes, the episodic respiration evident in hibernation shows striking similarities to the apneas observed during sleep in both humans and other mammals. Although the slight down-regulation of Tb and metabolism that accompanies the transition from wakefulness to NREM sleep may have served as a preadaptation for the evolution of hibernation among the mammals, increasing consideration must be given to the possibility that hibernation represents an arousal state distinct from any known normothermic arousal state.
Animals↗
Differential effects of acetylcholine on coronary flow in isolated hypothermic hearts from rats and ground squirrels.
This study was designed to determine whether cholinergic receptors are operative in the coronary vessels of a hibernating species (golden mantled ground squirrel, Spermophilus lateralis) and a nonhibernating species (rat, Rattus norvegicus) under normothermic and hypothermic conditions. Coronary flow and left ventricular systolic pressure were measured in isolated perfused hearts from squirrels at 37, 20 or 7 degrees C and from rats at 37 and 20 degrees C. During cooling, rat hearts became arrhythmic and failed between 15 and 12 degrees C. Squirrel hearts remained functional at 7 degrees C. Bolus injections of acetylcholine (> 1.0 microgram) caused significant coronary vasoconstriction in rat hearts at 37 and 20 degrees C. Similar treatment caused mild coronary vasodilation in squirrel hearts at both temperatures. Squirrel hearts did not respond to acetylcholine at 7 degrees C. The responses in both species were blocked by atropine. Rat coronary vessels appear to contain muscarinic constrictor receptors similar to those described in humans, sheep, cattle and pigs. The coronary vessels of squirrels, by contrast, do not. In this latter species there appears to be a preponderance of muscarinic (possibly endothelial-relaxing-factor-linked) dilator receptors. Given that acetylcholine acts only as a mild vasodilator at higher temperatures in squirrels, parasympathetic regulation of coronary flow in the squirrel heart is unlikely, especially during hibernation.
Acetylcholine↗
Coordination of wingbeat and respiration in the Canada goose. I. Passive wing flapping.
The effects of passive wing flapping on respiratory pattern were examined in decerebrate Canada geese. The birds were suspended dorsally with two spine clamps while the extended wings were continuously moved up and down with a device designed to reproduce actual wing flapping. Passive wing motion entrained respiration over limited ranges by both increasing and decreasing the respiratory period relative to rest. All ratios of wingbeat frequency to respiratory frequency seen during free flight (Soc. Neurosci. Abstr. 15: 391, 1989) were produced during passive wing flapping. In addition, the phase relationship between wingbeat frequency and respiratory frequency, inspiration starting near the peak of wing upstroke, was similar to that seen during free flight and was unaffected by perturbations of the wing-flapping cycle. Removal of all afferent activity from the wings did not affect the ability of continuous passive wing movement to entrain respiration. However, feedback from the wings was required to produce rapid within-breath shifts in the respiratory period in response to single wing flaps. In conclusion, although feedback from the chest wall/lung may be more important in producing entrainment during the stable conditions of passive wing flapping, wing-related feedback may be critically involved in mediating the rapid adjustments in respiratory pattern required to maintain coordination between wing and respiratory movements during free flight.
Afferent Pathways↗
Coordination of wingbeat and respiration in birds. II. "Fictive" flight.
To determine whether an interaction between central respiratory and locomotor networks may be involved in the observed coordination of wingbeat and respiratory rhythms during free flight in birds, we examined the relationship between wingbeat and respiratory activity in decerebrate Canada geese and Pekin ducks before and after paralysis. Locomotor activity was induced through electrical stimulation of brain stem locomotor regions. Respiratory frequency (fv) was monitored via pneumotachography and intercostal electromyogram recordings before paralysis and via intercostal and cranial nerve IX electroneurogram recordings after paralysis. Wingbeat frequency (fW) was monitored using pectoralis major electromyogram recordings before, and electroneurogram recordings after, paralysis. Respiratory and cardiovascular responses of decerebrate birds during active (nonparalyzed) and "fictive" (paralyzed) wing activity were qualitatively similar to those of a variety of vertebrate species to exercise. As seen during free flight, wingbeat and respiratory rhythms were always coordinated during electrically induced wing activity. Before paralysis during active wing flapping, coupling ratios (fW/fv) of 1:1, 2:1, 3:1, and 4:1 (wingbeats per breath) were observed. After paralysis, fW and fv remained coupled; however, 1:1 coordination predominated. All animals tested (n = 9) showed 1:1 coordination. Two animals also showed brief periods of 2:1 coupling. It is clear that locomotor and respiratory networks interact on a central level to produce a synchronized output. The observation that the coordination between fW and fv differs in paralyzed and nonparalyzed birds suggests that peripheral feedback is involved in the modulation of a centrally derived coordination.
Animals↗
Morphometric and metabolic indices of disuse in muscles of hibernating ground squirrels.
1. Morphological, biochemical and metabolic characteristics of hindlimb muscles from summer-active (SA), winter-active (WA) and hibernating (H) golden-mantled ground squirrels (Spermophilus lateralis) were examined to identify alterations resulting from seasonal periods of inactivity. 2. Cross-sectional areas of fibers from the soleus were reduced in both WA and H, although only significantly (P less than 0.05) in WA. Fibers in the EDL exhibited significant reductions in cross-sectional areas in both H and WA groups. Muscle fiber and capillary densities were altered in quantitative agreement with changes in cross-sectional areas. 3. Protein content was reduced 20% (P less than 0.05) in EDL from H and WA groups, but reductions (10%) in the soleus were not statistically significant. RNA content in WA and H groups was significantly decreased in soleus (20%) and EDL (35%) compared with SA, but DNA content was unchanged. 4. In the plantaris, triglyceride content was unchanged, but citrate synthase activity in H (210 +/- 13 mumol min-1 g-1) was significantly greater than in SA (177 +/- 10). In contrast, LDH activity in H was reduced by 25% (P less than 0.05) compared with SA. 5. These results demonstrate atrophic effects associated with seasonal inactivity in hibernating ground squirrels, but suggest the existence of natural mechanisms which limit the response.
Adaptation, Physiological↗
Intermittent breathing in vertebrates.
The respiratory control system of animals exhibiting intermittent breathing patterns allows significant fluctuations in all respiratory variables. The extent of these fluctuations can be quite large, particularly in those species with episodic breathing patterns. In these animals, blood gases and pH seem to be regulated within a homeostatic range. Pattern generation in these animals would seem, therefore, to be less dependent on a central rhythm generator and more closely dependent on inputs from peripheral receptor systems and higher brain stem centers. The evidence does suggest, however, that the medulla is the important region for central nervous system coordination of ventilation in these animals just as it is in rhythmic breathers. Peripheral input from mechanoreceptors associated with the lungs and chemoreceptors associated with the lungs and/or arterial blood appear important in regulating (a) the tidal volume of each breath, (b) the length of the ventilatory period, and (c) the length of the ventilatory pause. One of the more important conclusions that can be drawn from the data is that all three variables appear to be under separate control. The relative roles of the various receptor groups in the control of each respiratory variable remain unclear. Given the intermittent nature of the breathing, broad oscillations occur in the PO2, and to a lesser extent, PCO2 in lungs, blood, and presumably tissues, with accompanying pH fluctuations in body fluids. Although the functional significance of the two distinct ventilatory patterns seen in these animals remains unclear, the fact that the episodic breathing pattern can be converted to a single breath pattern experimentally, suggests that both patterns are manifestations of a common underlying control system. The data suggest that the episodic breathing pattern arises from a single breath pattern as a consequence of vagally modulated input from supramedullary centers in the brain. The similarities between the data collected from all vertebrates is striking. These similarities suggest that a common mechanism may underlie the various intermittent breathing patterns seen under physiologic conditions in all vertebrates. The conversion of continuous breathing to intermittent breathing in some fish in normoxic or hyperoxic water, as well as in squirrels entering hibernation, further suggests that both continuous and intermittent breathing are manifestations of a common control system. Although it is still too early to do more than speculate, the possibility exists that intermittent breathing may be the consequence of a reduced metabolic rate (the one factor ectotherms and hibernating and sleeping endotherms have in common) such that animals no longer need to breath continuously to meet metabolic demands.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Propranolol inhibits O2-sensitive chemoreceptor activity in trout gills.
The effects of propranolol on the activity of O2-sensitive chemoreceptors innervated by cranial nerve IX were studied using an isolated, perfused first gill arch preparation from rainbow trout (Onchyrhyncos mykiss). Perfusing the gill with hypoxic perfusate resulted in an increase in chemoreceptor activity. Propranolol (100-200 nmol) added to the perfusate inhibited O2-receptor discharge during both normoxia and hypoxia and attenuated the response to bolus injections of NaCN (25 micrograms). These results suggest that a beta-adrenergic mechanism is involved in O2 chemoreception. They further suggest that the inhibitory effects of propranolol on branchial, O2-sensitive chemoreceptors may contribute to the attenuated hypoxic ventilatory reflex observed in intact fish after propranolol injections.
Animals↗
Mechanoreceptor modulation of endogenous respiratory rhythms in vertebrates.
While pulmonary mechanoreceptors appear to play little or no role in determining the eupneic breathing pattern in some species of vertebrates, they do in others as well as in all species under conditions of elevated respiratory drive. Tonic and phasic inputs from this receptor group have independent roles in determining breathing pattern. Thus withholding lung inflation produces very different results from receptor denervation. There are at least five phases to the respiratory cycle that appear to be under separate control. Tonic receptor input is involved primarily in regulating the length of the respiratory pause, which can occur at the end of inspiration or expiration, depending on the species. Phasic receptor input has different effects during different phases of the cycle as well as different effects at different times during a single phase. This activity contributes to phase switching during the ventilation cycle and thus to the regulation of breathing frequency and tidal volume. The significance of the modulatory effects of phasic input on the duration of different phases of the ventilation cycle is not totally clear, but the evidence suggests that phasic input acts to stabilize the respiratory pattern and may be instrumental in optimizing the breathing pattern in terms of ergometric costs. This appears to be the case in all vertebrate classes, despite dramatic differences in the mechanical events associated with ventilation arising from different respiratory pumps. These receptors also appear to have significant roles other than those associated with modulation of respiratory rhythm, particularly in lower vertebrates. Many of these roles, such as maintaining the integrity of the gill curtain in fish or buoyancy control and regulation of blood flow distribution in reptiles, may be as important as their role in modulating the endogenous rhythm.
Air↗