Biomedical subjects

J P Kiley

Publications and source records attributed to J P Kiley.

At least 37 records · Page 2Linked to original sources

PubMed1985

Excitatory and inhibitory effects of morphine on the intercostal-to-phrenic respiratory reflex.

The purpose of this study was to determine the effect of intravenously administered morphine on the intercostal-to-phrenic reflex in spinal (C1) cats. The carotid and vertebral arteries were ligated. In addition a metal clamp was placed around the neck and tightened in order to occlude all blood flow to the brain. The animals were vagotomized, paralyzed and ventilated artificially. End-tidal PCO2 and body temperature were kept constant by means of servocontrollers. The intercostal-to-phrenic reflex was activated by rhythmic tapping of the lower thorax anteriorly with a metal bar. Three different doses of morphine were used. The smallest dose (1 mg/kg) caused a marked stimulation of phrenic activity that lasted for more than 5 min. A larger dose (10 mg/kg) had only a mild excitatory effect. A much larger dose (50 mg/kg), on the other hand, caused inhibition of evoked phrenic activity. Possible mechanisms involved in mediating the dose dependent effects of morphine on the intercostal-to-phrenic reflex are discussed.

Animals↗

PubMed1985

Stimulation by central command of locomotion, respiration and circulation during exercise.

We studied the relationships between exercise (locomotion) and respiratory and circulatory responses in 19 cats that walked or ran normally on a treadmill, and in 16 paralyzed animals during fictive locomotion, i.e., locomotory activity in motor nerves to the legs. Preparations included anesthetized cats with intact brains and unanesthetized decorticate (hypothalamic) and decerebrate (mesencephalic) animals. Spontaneous actual locomotion and fictive locomotion occurred in all preparations except the mesencephalic cats. Electrical stimulation or injection of a GABA antagonist (picrotoxin) into the hypothalamic locomotor region caused locomotion to develop. In all cases when locomotion occurred, respiration and arterial pressure increased in proportion to the level of locomotor activity despite control or ablation of respiratory feedback mechanisms. Respiration and arterial pressure increased similarly during fictive locomotion despite the absence of muscular contraction or limb movement and the lack of change of metabolic rate. We conclude that the study provides experimental support for the feed-forward, or command signal, hypothesis for the genesis of proportional changes of respiration and circulation that occur during exercise. Feedback mechanisms are not required for its operation. We suggest that command signals emanating from the hypothalamus provide the primary drive for changes of respiration and circulation during exercise.

Animals↗

PubMed1985

Respiratory responses to medullary hydrogen ion changes in cats: different effects of respiratory and metabolic acidoses.

The steady-state responses of respiration, measured as integrated phrenic nerve activity, to hypercapnic acidosis of the medullary extracellular fluid (e.c.f.) and to metabolically generated acidosis were compared in paralysed, vagotomized and glomectomized cats. E.c.f. hydrogen ion concentration [( H+]) was measured directly by means of a small (2 mm diameter) pH electrode placed on the ventral medulla. The results in ten cats show that changes of medullary e.c.f. [H+] were linearly related to changes of end-tidal PCO2 both before (r = 0.999) and after (r = 0.996) development of metabolic acidosis. There was a curvilinear relation between hypercapnic e.c.f. [H+] changes and the respiratory response that reflects progressive saturation of a central neural pathway between the chemoreceptors and the respiratory controller. This relation was similar in form both before and after development of metabolic acidosis. When acidosis of metabolic origin was present, apnea occurred with only small decreases of CO2 despite a high [H+]. The respiratory responses to the same e.c.f. [H+] change were only about one-half as large when they were generated metabolically as when they were generated by raising PCO2. Both exogenously induced metabolic acidosis (HCl infusion) and endogenous acidosis yielded similar results. We conclude that the e.c.f. [H+] does not represent the unique stimulus to the central chemoreceptors. We discuss several alternate mechanisms for the action of CO2 and [H+] on central chemoreceptors but none can be considered definitive at the present time.

Animals↗

PubMed1985

Mechanisms of respiratory response to isoproterenol in glomectomized cats.

Effects of intravenous isoproterenol (2-3 micrograms) on arterial pressure, end-tidal CO2 partial pressure (PCO2), medullary extracellular fluid (ECF) pH, and phrenic activity were studied in 13 anesthetized paralyzed cats whose vagi and carotid sinus nerves were cut. The cats were servo-ventilated to keep PCO2 relatively constant. Injections of Ringer solution were without effect. Isoproterenol caused arterial pressure to fall, a transient small (1 Torr) increase of PCO2, increased venous CO2 return to the lungs, a medullary ECF acidosis, and a stimulation of respiration that continued to be elevated after arterial pressure, PCO2, and medullary ECF pH had returned to control. We show that the ECF acidosis is minimally due to the hypotension and to the small transient rise of PCO2. We also show that the respiratory response cannot be explained solely by the ECF acidosis. We conclude that, in addition to its known stimulation of peripheral chemoreceptors, isoproterenol causes medullary ECF to become acidic probably due to metabolic effects on neural tissue and has a separate direct stimulating effect on neurons in the brain.

Animals↗

PubMed1985

Respiration during hypothermia: effect of rewarming intermediate areas of ventral medulla.

We studied respiration (phrenic nerve activity) during progressive hypothermia to as low as 30.5 degrees C in five anesthetized, paralyzed, glomectomized, and vagotomized cats. PCO2 was maintained at a constant level throughout the experiments. We confirmed the results of a previous study (J. P. Kiley, F. L. Eldridge, and D. E. Millhorn, J. Appl. Physiol. 58: 295-312, 1985) in which respiratory minute output decreased progressively with cooling and respiratory frequency decreased markedly. In addition we show that focal rewarming to normal temperature (37.5 degrees C) of the structures in the intermediate areas on the ventral surface of the medulla resulted in a significant reversal of the depressed respiratory minute activity observed with hypothermia. Respiratory frequency, however, was unaffected by intermediate area rewarming. We conclude that the decreased respiratory activity during hypothermia is due to a generalized interference with neural function. A major portion of these effects is due to cooling of the intermediate areas, but the slowing of respiratory frequency appears to be an independent effect.

Animals↗

PubMed1985

Antagonism by theophylline of respiratory inhibition induced by adenosine.

The effects on respiration of an analogue of adenosine, L-2-N6-(phenylisopropyl)adenosine (PIA), and of the methylxanthine, theophylline, were determined in 19 vagotomized glomectomized cats whose end-tidal PCO2 was kept constant by means of a servo-controlled ventilator. Integrated phrenic nerve activity was used to represent respiratory output. Our results show that PIA, whether given systemically or into the third cerebral ventricle, depressed respiration. Systemically administered theophylline stimulated respiration. Theophylline given intravenously, or into the third ventricle not only reversed the depressive effects of previously administered PIA but caused further increases of respiration above the control level. Prior systemic administration of theophylline blocked both respiratory and hypotensive effects of subsequently administered PIA. Effects of either agent on medullary extracellular fluid pH did not explain the results. We conclude that the adenosine analogue PIA, acts to inhibit neurons in the brain that are involved in the control of respiration and that its effects are blocked by theophylline. We suggest that adenosine acts as a tonic modulator of respiration and that theophylline stimulates breathing by competitive antagonism of adenosine at neuronal receptor sites.

Adenosine↗

PubMed1984

Respiratory effects of a long-acting analog of adenosine.

The effect on respiration, measured as integrated phrenic nerve activity, of an analog of adenosine, N6(L-2-phenylisopropyl)adenosine (PIA), was determined in 26 paralyzed, vagotomized and glomectomized cats whose end-tidal pCO2 was kept constant by means of a servocontrolled ventilator. Whether given intravenously or into the third cerebral ventricle, PIA caused a dose-related depression of respiration, involving both tidal activity and respiratory frequency. In a group of 6 cats, the effects of intraventricular PIA or its vehicle alone on medullary extracellular fluid (ECF) pH were also determined. Vehicle alone had no effect on either ECF pH or respiratory activity. PIA was associated with the development over 10-20 min of a metabolic acidosis in the medulla, but still led to marked depression of respiration, thus ruling out an increase of medullary blood flow as cause of the decreased respiration. We conclude that the adenosine analog, PIA, acts to inhibit directly neurons in the brain that are involved in the control of respiration, and we suggest that adenosine may act as a tonic modulator of respiration.

Acid-Base Equilibrium↗

PubMed1984

Chemoreflex drive of ventilation during exercise in ducks.

To determine if arterial chemoreceptors contribute to the ventilatory response during exercise, we measured minute ventilation (VI) in spontaneously breathing Pekin ducks (Anas platyrhynchos) during rest and running exercise when the inspired gas was switched from either 21% or 12% O2 to 100% O2 for 45 s (O2-test). In normoxia at rest (PaO2 = 99 Torr), inhaling 100% O2 reduced VI by 30%, while during resting hypoxic conditions (PaO2 = 56 Torr), 100% O2 inhalation reduced VI by 66%. During exercise, abruptly inhaling 100% O2 decreased VI by only 14% and 33% in normoxic and hypoxic conditions, respectively. Thus, only a small fraction of the ventilatory response during exercise under normoxic conditions is due to an arterial chemoreceptor input. However, during exercise in hypoxic conditions, arterial chemoreceptors provide a substantial portion of the total drive to ventilation.

Animals↗

PubMed1984

The effect of hypothermia on central neural control of respiration.

The effects of whole body hypothermia on metabolism, blood and medullary acid-base, and respiratory variables were determined in 29 paralyzed, vagotomized and glomectomized cats. Respiratory output was quantified from integrated phrenic nerve activity. Metabolic rate (VCO2) decreased progressively as temperature decreased. When end-tidal PCO2 was kept constant by decreasing artificial ventilation, cooling of the brain to 30.5 degrees C resulted in a large decrease of respiratory frequency (f) with prolongations of both inspiratory (TI) and expiratory (TE) times but an increase in neural tidal activity (VTN). Neural minute activity (MVN) and rate of rise of phrenic activity (RR) decreased moderately despite an acid shift of arterial and medullary extracellular fluid (ECF) pH and a decrease in the fractional dissociation of imidazole (alpha Im). Anesthesia, decerebration and spinal cord section at C7-T1 did not alter the responses. When ventilation was kept constant during cooling so that PCO2 decreased along with metabolic rate, all respiratory variables (VTN, f, MVN and RR) decreased significantly and reached near apneic levels at 30.5 degrees C. These changes were associated with an alkaline shift in ECF pH. Fractional dissociation of imidazole (alpha Im) remained constant at all temperatures. Our findings do not support the hypothesis of 'alphastat' regulation as a general explanation of central chemical control of breathing in homeotherms. We also present arguments that it may not apply to the control of breathing in ectotherms. We conclude that hypothermia affects both respiratory drive and timing mechanisms through its effect on neural synaptic function.

Acid-Base Equilibrium↗

PubMed1984

Oscillations of medullary extracellular fluid pH caused by breathing.

The purpose of this study was to determine if respiratory oscillations of arterial PCO2 are transmitted to the medullary ECF. Anesthetized, paralyzed cats whose vagi and carotid sinus nerves had been cut were studied. A flat surfaced pH electrode (2 mm in diameter) and a specially built differential amplifier were used to measure pH on the ventral surface of the medulla. Elimination of noise and high sensitivity were obtained by integrating the output from the pH amplifier with a digital voltmeter . We measured ECF pH oscillations that had the same period as the ventilator. The amplitude of the oscillations was about 0.006 unit when the ventilator was slow (less than 10/min). The amplitude decreased progressively as the rate was increased and oscillations were usually undetectable at rates above 25/min. Experiments were performed that ruled out mechanical artifact and ventilator-related fluctuations in arterial pressure as being causal. We conclude that oscillations of alveolar CO2 are transmitted to the brain by the circulation and result in oscillations of ECF pH.

Animals↗

PubMed1984

Effect of graded cooling of intermediate areas on respiratory response to vagal input.

The present study was undertaken to determine if the phrenic responses to vagally mediated inputs are also affected by focal cooling of the intermediate areas (IA) of the ventral medulla. Anesthetized, paralyzed cats whose vagi and carotid sinus nerves had been cut were studied. The IA were cooled focally with a thermostatically controlled thermode. When the IA were 40 degrees C, low intensity vagal stimulation caused inhibition of phrenic activity. The stimulus was also applied when IA were cooled to 30 and 20 degrees C. The magnitude of the inhibition was unaffected by the cooling. In another series of experiments, high intensity vagal stimulation was used. This led to an hyperpnea when IA were 40 degrees C. The magnitude of the response was much smaller when the test stimulus was given at lower IA temperatures. The effect of cooling IA on the phrenic response to mechanical stimulation of pulmonary stretch receptors and airway irritant receptors were also studied in cats with intact vagi. We found that the response to irritant receptor, but not to stretch receptor, stimulation was abolished by the cooling. We conclude that the intermediate areas are involved in the integration of afferent input from airway irritant receptors that reaches the respiratory controller via high threshold vagal afferents, but not involved in processing signals from pulmonary stretch receptors.

Animals↗

PubMed1984

Prolonged inhibition of respiration following acute hypoxia in glomectomized cats.

Respiratory responses to several minutes exposure to hypoxia (PaO2 less than 30 torr) were determined in anesthetized, paralyzed, vagotomized and glomectomized cats whose end-tidal PCO2 and body temperature were kept constant. Respiratory activity was quantified from phrenic nerve activity. Animals breathed 100% O2 during the control period. The study reaffirmed that in glomectomized animals hypoxia causes depression of respiratory activity. The new finding was that phrenic activity remained significantly depressed below the original control level for more than one hr after return to the hyperoxic state. Medullary ECF pH was measured in 3 cats. There was an acid shift of pH during hypoxia that persisted for more than one hour after return to hyperoxic state. We pretreated another group (n = 5) of animals with theophylline, a specific antagonist of the inhibitory neurotransmitter adenosine. Hypoxia still caused depression of respiratory activity, but it was less severe than in untreated animals. Upon return to the hyperoxic state, respiratory activity returned to the original control level within 10 min. We conclude that the long-lasting depression of respiration following hypoxia is mediated by adenosine. Furthermore, adenosine appears to be partially responsible for the acute depression of respiration during the hypoxic exposure.

Acute Disease↗

PubMed1984

Brain, blood and rectal temperature during whole body cooling.

To determine if rectal temperature is an adequate index of brain temperature during changing thermal conditions, we measured rectal, cerebral cortical, and carotid arterial blood temperatures simultaneously during whole body cooling in adult cats. The mean steady state rectal, brain and carotid arterial temperatures at the onset of cooling were: 39.2 +/- 0.2, 38.5 +/- 0.2, and 38.3 +/- 0.3 degrees C, respectively. Rectal temperature decreased faster than both brain and arterial blood, while only a small temperature difference was observed between brain and arterial blood, brain always exceeding blood. Rectal temperature cannot be considered an adequate index of brain temperature. Carotid arterial temperature is a better estimate of brain temperature.

Animals↗

PubMed1984

Respiratory effects of carbon dioxide-induced changes of medullary extracellular fluid pH in cats.

Acute and steady-state responses to hypercapnia of respiratory output, measured as integrated phrenic nerve activity, and medullary extracellular fluid (e.c.f.) pH, measured directly, were determined in paralysed, vagotomized and glomectomized cats. Medullary e.c.f. pH responds within seconds to an acute change of alveolar and arterial PCO2. The respiratory response closely and inversely matches the e.c.f. pH change, but not the cerebrospinal fluid pH change. The medullary e.c.f. pH change following a rapid step-change in end-tidal PCO2 requires at least 5 min for a new steady state to be achieved. Steady-state studies in twenty-six cats show: (a) that the respiratory response to progressive hypercapnic stimulation of the central chemoreceptors is curvilinear (Eldridge, Gill-Kumar & Millhorn, 1981), (b) that the relationship between increasing end-tidal PCO2 and medullary hydrogen ion concentration [(H+]) or changes of pH is linear (r = 0.995); a doubling of PCO2 causes 0.260 units pH change, (c) there is a curvilinear relationship between e.c.f. [H+] and the respiratory response that is the same as that found with CO2. We conclude that medullary e.c.f. pH measured by means of a surface electrode accurately reflects the CO2-induced [H+] stimulus to respiration. The decreasing respiratory responses to identical changes of central chemoreceptor input are due to progressive neuronal saturation of a central pathway between the chemoreceptors and the respiratory controller.

Animals↗

PubMed1983

Mechanism of respiratory effects of methylxanthines.

Neural respiratory responses to theophylline, aminophylline and ethylenediamine were determined in paralyzed, vagotomized and glomectomized cats whose end-tidal PCO2 and brain temperature were kept constant. Intravenous theophylline and aminophylline similarly stimulated respiration, but ethylenediamine had no effect. The following did not cause the response: muscular and mechanical factors, carotid body and vagal reflexes, spinally mediated mechanisms arising below C7, changes of arterial PCO2 or medullary ECF pH, changes of whole body metabolic rate or release of substances from the adrenal glands. Absence of suprapontine brain did not prevent the response. Pretreatment with a serotonin antagonist did not affect the response but two different dopamine antagonists caused its attenuation. When administered into the third ventricle, theophylline did not stimulate respiration, but both aminophylline and ethylenediamine, due to the latter's ability to mimic the inhibitory effects on neurons of gamma-aminobutyric acid (GABA), caused significant depression of respiration. We conclude that the neural respiratory response to systemically administered theophylline is mediated at the level of the brainstem, and somehow involves the action of the neurochemical dopamine. The failure of cerebroventricularly administered theophylline to stimulate respiration must be related to its inability to reach the appropriate neurons from the cerebrospinal fluid.

Aminophylline↗

PubMed1983

Exercise hyperpnea in the duck without intrapulmonary chemoreceptor involvement.

To determine the involvement of intrapulmonary chemoreceptors (IPC) in the control of breathing during exercise, it is necessary to hold the PCO2 in the microenvironment of these receptors constant at the resting value. We accomplished this in unanesthetized Pekin ducks by ligating the left pulmonary artery and diverting all of the cardiac output to the right lung, which was denervated. The ducks were then unidirectionally ventilated with a constant gas stream (5% CO2, 19% O2, balance N2) at a flow rate of 12 L X min-1. This procedure provided a constant microenvironment for the receptors in the left lung despite any changes in the chemical composition or flow rate of the blood going to the right lung during exercise. Ventilatory effort increased during running exercise (1.44 km X h-1 at a 3 degrees incline) by an average of 145% over resting values because of an increase in both respiratory frequency and tidal volume. Because no altered stimuli were presented to the IPC using this procedure, the increased ventilation with exercise could not have resulted from changes in their discharge frequency. We conclude that ventilation can increase during exercise in the duck in the absence of IPC involvement and that other neural input, possibly from muscle, is responsible for the hyperpnea.

Animals↗

PubMed1983

Cardiopulmonary control during exercise in the duck.

To determine the importance of nonhumoral drives to exercise hyperpnea in birds, we exercised adult White Pekin ducks on a treadmill (3 degrees incline) at 1.44 km X h-1 for 15 min during unidirectional artificial ventilation. Intrapulmonary gas concentrations and arterial blood gases could be regulated with this ventilation procedure while allowing ventilatory effort to be measured during both rest and exercise. Ducks were ventilated with gases containing either 4.0 or 5.0% CO2 in 19% O2 (balance N2) at a flow rate of 12 l X min-1. At that flow rate, arterial CO2 partial pressure (PaCO2) could be maintained within +/- 2 Torr of resting values throughout exercise. Arterial O2 partial pressure did not change significantly with exercise. Heart rate, mean arterial blood pressure, and mean right ventricular pressure increased significantly during exercise. On the average, minute ventilation (used as an indicator of the output from the central nervous system) increased approximately 400% over resting levels because of an increase in both tidal volume and respiratory frequency. CO2-sensitivity curves were obtained for each bird during rest. If the CO2 sensitivity remained unchanged during exercise, then the observed 1.5 Torr increase in PaCO2 during exercise would account for only about 6% of the total increase in ventilation over resting levels. During exercise, arterial [H+] increased approximately 4 nmol X l-1; this increase could account for about 18% of the total rise in ventilation. We conclude that only a minor component of the exercise hyperpnea in birds can be accounted for by a humoral mechanism; other factors, possibly from muscle afferents, appear responsible for most of the hyperpnea observed in the running duck.

Animals↗

PubMed1982

Intrapulmonary CO2 receptors and control of breathing in ducks: effects of prolonged circulation time to carotid bodies and brain.

The role of intrapulmonary chemoreceptors in the breath-to-breath control of spontaneous breathing was studied in anesthetized ducks by stimulating these receptors with changes in mixed venous CO2 loads during prolonged circulation time to the carotid bodies and brain by vascular loops placed in both brachiocephalic arteries. Blood equilibrated with gas mixtures of high (85% CO2-15% O2) or low CO2 (air) was infused into the right ventricle at 100 ml . min-1, while simultaneously withdrawing blood from the entrance of the right atrium at the same rate. A variety of cardiopulmonary and blood gas variables were measured. Infusing blood of high PCO2 increased both respiratory frequency and tidal volume long before the altered blood could have reached the carotid bodies or brain. The increase in ventilation was not enough to prevent a rise in PaCO2. Infusing blood of low PCO2 decreased both respiratory frequency and tidal volume. Again, the changes in respiration occurred before the infused blood had reached the carotid bodies or the brain. Infusion of blood similar in PCO2 to mixed venous blood did not significantly alter ventilation or arterial blood gases. The rapidity of the ventilation response to a change in mixed venous CO2 load led us to conclude that the intrapulmonary chemoreceptors can detect changes in mixed venous CO2 loads and that they initiate a ventilatory change appropriate to minimize alterations in PaCO2. These receptors, thus, can control breathing on a breath-to-breath basis in birds.

Animals↗