Minute Phrenic Activity Research Articles

Role of carbon dioxide oscillation in the control of respiration in the anesthetized dog.

In order to examine the role of respiratory oscillation of PaCO2 (CO2 oscillation) in the control of respiration, we performed veno-venous bypass using a membrane lung in 10 anesthetized paralyzed dogs, where the dog was put on fixed mechanical ventilation so that we could keep average PaCO2 and PaO2 constant by adjusting FICO2 and FIO2 during CO2 loading/unloading. By venous CO2 loading/unloading we could widely change the CO2 output from the lung (11-440% of the control) resulting in large changes in the arterial CO2 oscillations (50-280% of the control for the maximum rate of rise of PaCO2 and 40-350% of the control for the maximum rate of fall of PaCO2), which was measured by a rapidly responding intra-arterial pH electrode. Despite such wide variations in CO2 oscillations we did not find any consistent change in the respiratory center output (minute phrenic activity). This held true after compensating the changes in the minute phrenic activity for the CO2 sensitivity of each individual dog. Thus, the present results may suggest that the CO2 oscillation plays little role in the control of respiration in mild increase in VCO2.

CO2 sensitivity of cat phrenic neurogram during hypoxic respiratory depression

The CO2 response of the phrenic neurogram before and during CO-induced isocapnic brain hypoxia was studied in peripherally chemodenervated, vagotomized, paralyzed, ventilated cats with blood pressure held constant. During inhalation of 0.5% CO in 40% O2, arterial O2 content (CaO2) was reduced to 40% and minute phrenic activity to 38.4 +/- 9.4% (SE; n = 9) of prehypoxic levels, primarily due to depression of peak phrenic amplitude (PP). CO2 response, defined as the slope of the plot of PP vs. end-tidal PCO2 during CO2 rebreathing, was unaffected by phrenic depression even to the point of total suppression of phrenic activity in two cats. The effect of the tissue metabolic acidosis associated with hypoxia on phrenic CO2 sensitivity was assessed in a separate group of cats by blocking lactate formation during hypoxia with dichloroacetate (DCA). Preventing lactic acidosis during hypoxia did not affect the CO2 response of the phrenic activity during hypoxia. We conclude that 1) hypoxic depression does not limit the ability of central respiratory neurons to respond to CO2, and 2) the failure of DCA to affect the CO2 response of the phrenic neurogram suggests that brain intracellular lactic acidosis does not modify the phrenic response to hypercapnia.

Inhibitory and excitatory effects on respiration by phrenic nerve afferent stimulation in cats

Respiratory effects of electrical stimulation of phrenic nerve afferents were studied in anesthetized cats, either spontaneously breathing or paralyzed and ventilated. The type of phrenic afferent fibers activated was controlled by recording the evoked action potentials from dorsal root fibers. In both preparations, stimulation at a strength sufficient to activate small diameter myelinated phrenic nerve afferents induced a biphasic response. The first phase lasted a few respiratory cycles and was inhibitory and consisted of a decrease in tidal volume (V T) or phrenic activity (NA), inspiratory time (T I), respiratory duty cycle (T I/Ttot) and instantaneous ventilation (V̇ E) or minute phrenic activity (NMA). Expiratory time (T E) increased and breathing frequency (f) and mean inspiratory flow (V T/T I) or mean inspiratory neural activity (NA/T I) did not change. This short-term response was suppressed in animals pretreated with bicuculline. The second phase was a long-term excitation in which V T or NA, f, V̇ E or NMA and V T/T I or NA/T I increased whereas both T I and T I/Ttot decreased and T E did not change. Unlike published data, our results suggested that small-diameter myelinated phrenic nerve afferents are involved in these responses. These phrenic fibers, like afferents from other muscles, affect respiratory output and may play a role in the control of breathing.

Phrenic nerve responses to hypoxia and CO 2 in decerebrate dogs

Phrenic responses to isocapnic hypoxia and hypercapnia were studied using paralyzed vagotomized dogs (either decerebrate or chloralose-anesthetized). The hypoxia-induced increase in phrenic minute activity (PMA) was significantly greater in anesthetized dogs when compared with the response observed in decerebrate dogs. Phrenic responses to hypercapnia were also significantly different in the two groups of dogs. Increases in phrenic amplitude (AMP) and frequency (FREQ) were observed in anesthetized dogs, whereas decerebrate dogs responded to CO 2 without a change in FREQ. Spontaneously breathing dogs (either decerebrate or anesthetized) were used for studying the effects of vagotomy on the integrated phrenic neurogram. Changes in phrenic pattern in response to vagotomy were qualitatively similar in anesthetized and decerebrate dogs. However, in decerebrate dogs, AMP was disproportionately increased relative to the decrease in FREQ such that PMA increased following vagal transection. Conversely, in anesthetized dogs, the increase in AMP and decrease in FREQ in response to vagotomy were proportional; PMA remained unchanged. These results suggest that mesencephalic decerebration disrupts neuronal circuits which participate in the chemical control of breathing. In addition, suprapontine structures may be involved in coupling FREQ and AMP (tidal volume) so that PMA (ventilation) is stabilized. Finally, these studies provide evidence for a vagally-independent frequency controller in dogs which is sensitive to hypoxia and hypercapnia, but appears to be highly dependent upon suprapontine structures.

Differential effects on phrenic output of two dopamine agonists, apomorphine and bromocriptine

Effects of dopamine agonists upon phrenic output were studied in decerebrate, vagotomized, paralyzed, carotid-body denervated dogs. Intravenous administration of dopamine was without effect in these dogs. Apomorphine (APO) increased phrenic minute activity while bromocriptine (BRO) decreased phrenic minute activity following intravenous injection at doses of 100 μg/kg for each drug. BRO-induced decreases in phrenic minute activity were associated with decreases in phrenic amplitude; burst frequency remained unchanged. Conversely, APO-induced increases in phrenic minute activity resulted from significant increases in both frequency and amplitude. Both APO and BRO significantly prolonged inspiratory duration and shortened expiratory duration. Responses to APO and BRO were abolished with haloperidol. These results confirm previous evidence for the existence of dopaminergic receptors within the central nervous system, which are inaccessible to exogenous dopamine, and which can alter timing as well as amplitude characteristics of the integrated phrenic neurogram. Both excitation and inhibition of phrenic activity following administration of APO and BRO are mediated by mechanisms within or below the caudal brainstem.

Dopaminergic modulation of respiratory timing mechanisms in carotid body-denervated dogs

The role of central dopaminergic mechanisms in ventilatory control was investigated by monitoring phrenic motorneuronal output of anesthetized dogs which were vagotomized, paralyzed and artificially ventilated and in which bilateral carotid body denervation had been performed. Intravenous administration of dopamine (DA) had no effect on phrenic output in these dogs. In contrast, apomorphine (APO), a potent dopaminergic agonist, which unlike dopamine, crosses the blood-brain barrier consistently and significantly prolonged inspiratory duration and shortened expiratory duration without altering phrenic amplitude. The dopaminergic antagonist haloperidol produced a frequency-dependent decrease in basal phrenic minute activity and reversed or abolished APO-induced changes in the phrenic profile. These data verify the specificity of APO for dopamine receptors and further suggest that DA receptors in the central nervous system exert a tonic effect on central respiratory control mechanisms. In contrast, domperidone, a dopaminergic antagonist which poorly penetrates the blood-brain barrier did not alter basal phrenic characteristics. Moreover, with the exception of inspiratory duration, domperidone did not antagonize APO-induced alterations in the phrenic profile. We conclude that dopaminergic mechanisms within the brain or spinal cord modulate timing relationships of central respiratory output.

Effects of hypercapnia and hypoxia on phrenic nerve activity and respiratory timing.

In the spontaneously breathing animal, respiratory responses to chemical stimuli are influenced by phasic proprioceptive inputs from the thorax. We have compared the effects of hypercapnia and hypoxia on the level and timing of phrenic nerve activity while these phasic afferent signals were absent. Progressive hyperoxic hypercapnia and isocapnic hypoxia were produced in anesthetized paralyzed dogs by allowing 3-5 min of apnea to follow mechanical ventilation with 100% O2 or 35% O2 in N2, respectively; during hypoxia, isocapnia was maintained by intravenous infusion of tris(hydroxymethyl)aminomethane buffer. The peak height (P) of nerve bursts, inspiratory time (TI), and expiratory time (TE) were measured from the phrenic neurogram. With the vagi intact or severed, hypoxia decreased TI, whereas hypercapnia did not; both stimuli decreased TE. At the same minute phrenic activity (P x frequency), P, TI, and TE were all less during hypoxia than during hypercapnia. The decreases in TI and TE with hypoxia were significantly less after carotid sinus denervation. The results indicate that the patterns of phrenic nerve activity in response to hypoxia and hypercapnia are different: hypoxia has a greater effect on respiratory timing, whereas hypercapnia has a greater effect on peak phrenic nerve activity. The effect of hypoxia on respiratory timing is largely mediated by the peripheral chemoreceptors.

Augmentation of carotid body chemoreceptor responses by isoproterenol in the cat

The effects of intravenous injections of isoproterenol (0.5–2 μg) on the response of carotid body chemoreceptor afferents and on integrated phrenic activity were investigated in twelse anesgthetized and three decerebrate, unanesthetized cats. All animals were paralyzed and artificially ventilated. Isoproterenol stimulated carotid chemoreceptor activity and this stimulation was augmented by both hypoxia and hypercapnia. Following an injection of isoproterenol, the ratio of the minute phrenic activity relative to mean carotid chemoreceptor activity was increased. Thus, the stimulation of inspiratory phrenic output exceeded the stimulation of the chemoreceptor afferent inout, and the peripheral chemoreflex activity does not account for the entire ventilatory response. To distinguish between a direct effect of isoproterenol and a possible secondary effect mediated via an increased venous return and an increased Pa CO 2 , the latencies of the response of carotid chemoreceptors to both isoproterenol and hypercapnia were compared before and after carbonic anhydrase inhibition by acetazolamide. After acetazolamide, the latency of the response to hypercapnia increased ferom 3.5 sec to 8 sec whereas the latency of response to isoproterenol increased less, from 4.7 sec to 6.3 sec. Thus, isoproterenol stimulation was not mediated by CO 2H +. Propanolol, which blocked the systemic vascular effect, only partially blocked the chemoreceptor stimulation caused by isoproterenol, indicting that the effect of isoproterenol on chemoreceptor activity was not due to systemic cardiovascular changes.

Stimulation of phrenic nerve activity by salicylate

To assess the possibility that salicylate stimulates VE by direct excitation of phrenic motoneurons, we compared two groups of anesthetized vagotomized dogs with respect to increases in phrenic nerve activity elicited by a large dose of sodium salicylate (225 mg/kg). The sole difference between the two groups of animals was the condition of the spinal cord (SC); SC remained intact in one group of animals (i.e., intact animals) whereas the other group of animals (i.e., T1 spinal-transected animals) underwent complete transection of the SC at the first thoracic level. Both groups of animals were ventilated by a respirator and arterial PCO2 was maintained constant throughout all experiments. Following salicylate infusion, intact animals exhibited two- to threefold increases in the frequency of phrenic nerve bursts and three- to fivefold increases in moving average minute phrenic activity (i.e., the summation of peak integrated burst activity per minute). In contrast, salicylate infusion into T1 spinal-transected animals elicited no statistically significant increase in the frequency of phrenic nerve bursts while increases in minute phrenic activity were limited to 32 +/- 8%. Since T1 spinal transection markedly diminishes increases in phrenic nerve activity elicited by salicylate, we conclude that salicylate stimulates VE by a reflex mechanism whose afferent pathways originate in metameres below T1.