Increase In Total Ventilation Research Articles

Repeated Seizure Exposure in the SS Kcnj16‐/‐ Rat Causes Progressive Respiratory Suppression and Associated Brainstem Pathology

Kir5.1 is an inwardly rectifying potassium (Kir) channel subunit highly expressed in the kidney and brain and encoded by the Kcnj16 gene. Knockout of Kcnj16 in a Dahl salt-sensitive rat (SSKcnj16-/-) results in susceptibility to audiogenic, generalized tonic-clonic seizures (GTCSs), which when repeated lead to spontaneous mortality. Patients with uncontrolled epilepsy are at high risk for Sudden Unexplained Death in Epilepsy (SUDEP), hypothesized to be a result of severe cardiorespiratory suppression and/or failure. We hypothesized that repeated audiogenic seizures in SSKcnj16-/- rats lead to progressively worsening cardiorespiratory suppression and associated brainstem pathology. SSKcnj16-/- and wild-type (WT) rats (10-12 weeks of age) were exposed to the seizure-inducing acoustic stimulus 1/day (d) for 10d and breathing measurement were made before, during and after exposure. Solitary GTSCs acutely led to apnea and decreases in breathing frequency for ~5 min postictally, with no change or an increase in total ventilation due to an increase in tidal volume. We also found a significant reduction in breath-to-breath variability throughout the postictal period. After exposure to repeated seizures, postictal frequency suppression became more pronounced and compensatory increases in tidal volume were reduced, such that total ventilation was also significantly reduced. Repeated seizures also further attenuated the ventilatory response to hypercapnia (p=0.0073). To gain insights into the effects of repeated seizures on cardiorespiratory circuits in the brainstem, we used immunofluorescence staining/confocal imaging to label and quantify total serotonin (5-HT) immunoreactivity (ir), serotonergic neurons (tryptophan hydroxylase+, TPH), microglia (Iba1), astrocytes (GFAP), total neurons (NeuN), and total nuclei (DAPI) in respiratory brainstem nuclei of SSkcnj16-/- rats exposed to 0, 3, or 10 seizures (n=5/group). Repeated seizures resulted in reduced 5-HT-ir in multiple cardiorespiratory brainstem nuclei including the pre-Bötzinger Complex (pre-BötC), nucleus ambiguous (NA), and nucleus tractus solitarious (NTS) in addition to a decrease in 5-HT neurons. We also found increased Iba1-ir selectively within the pre-BötC and NA, whereas GFAP-ir was increased after 10 seizures in these same regions. This data suggests that inflammation and/or serotonergic dysregulation in cardiorespiratory brainstem nuclei may mediate progressive respiratory suppression following repeated seizures in this rat model.

Divergent cardio-ventilatory and locomotor effects of centrally and peripherally administered urotensin II and urotensin II-related peptides in trout.

The urotensin II (UII) gene family consists of four paralogous genes called UII, UII-related peptide (URP), URP1 and URP2. UII and URP peptides exhibit the same cyclic hexapeptide core sequence (CFWKYC) while the N- and C-terminal regions are variable. UII, URP1, and URP2 mRNAs are differentially expressed within the central nervous system of teleost fishes, suggesting that they may exert distinct functions. Although the cardiovascular, ventilatory and locomotor effects of UII have been described in teleosts, much less is known regarding the physiological actions of URPs. The goal of the present study was to compare the central and peripheral actions of picomolar doses (5–500 pmol) of trout UII, URP1, and URP2 on cardio-ventilatory variables and locomotor activity in the unanesthetized trout. Compared to vehicle, intracerebroventricular injection of UII, URP1 and URP2 evoked a gradual increase in total ventilation (VTOT) reaching statistical significance for doses of 50 and 500 pmol of UII and URP1 but for only 500 pmol of URP2. In addition, UII, URP1 and URP2 provoked an elevation of dorsal aortic blood pressure (PDA) accompanied with tachycardia. All peptides caused an increase in locomotor activity (ACT), at a threshold dose of 5 pmol for UII and URP1, and 50 pmol for URP2. After intra-arterial (IA) injection, and in contrast to their central effects, only the highest dose of UII and URP1 significantly elevated VTOT and ACT. UII produced a dose-dependent hypertensive effect with concomitant bradycardia while URP1 increased PDA and heart rate after injection of only the highest dose of peptide. URP2 did not evoke any cardio-ventilatory or locomotor effect after IA injection. Collectively, these findings support the hypothesis that endogenous UII, URP1 and URP2 in the trout brain may act as neurotransmitters and/or neuromodulators acting synergistically or differentially to control the cardio-respiratory and locomotor systems. In the periphery, the only physiological actions of these peptides might be those related to the well-known cardiovascular regulatory actions of UII. It remains to determine whether the observed divergent physiological effects of UII and URPs are due to differential interaction with the UT receptor or binding to distinct UT subtypes.

Low cost of ventilation in the vagotomised alligator (Alligator mississippiensis)

Pulmonary ventilation requires energy, but the estimated costs of breathing in reptiles vary from 1 to 30% of resting metabolic rate. The low values have been estimated from changes in oxygen uptake during hypoxia or hypercapnia, but it remains possible that these treatments affected metabolism. We equipped alligators with masks for simultaneous measurements of ventilation and oxygen uptake during hypercapnia, hypoxia and bilateral vagotomy. Hypercapnia and hypoxia caused a marked increase in total ventilation, but oxygen uptake remained unchanged indicating a very low energetic cost of breathing. Upon vagotomy, breathing pattern changed to occasional and exceedingly deep breaths (76.1+/-11.1 ml kg(-1)) followed by buccal oscillations and shallower breaths (22.2+/-2.3 ml kg(-1)) interspersed between long non-ventilatory periods. This change in breathing pattern did not affect oxygen uptake. The duration of inspiration increased substantially upon vagotomy, so that inspiratory flow rate did not increase proportionally to tidal volume. These prolonged inspiratory times leads to less flow resistance and may explain that tidal volume could be increased substantially without a measurable energetic cost.

Cyclic phosphatidic acid stimulates respiration without producing vasopressor or tachycardiac effects in rats

The effects of a novel lipid mediator, cyclic phosphatidic acid (cPA), on respiratory and cardiovascular functions were examined in anesthetized rats. Intravenous (i.v.) administration of 3- O-carba-oleoyl-cPA at doses of 130 and 390 μg/kg produced dose-dependent increases in tidal volume and respiratory frequency, resulting in an increase in total ventilation. Heart rate was slightly decreased at a dose of 390 μg/kg, while systemic arterial pressure was not affected. Bilateral section of vagi and carotid sinus nerves designed to eliminate major regulatory inputs from the peripheral afferents to the respiratory center reduced these responses, but did not abolish them. These results indicate that cPA stimulates respiration, via central and peripheral mechanisms acting on the central respiratory rhythm generator in the brain stem. Administration of cPA may be of therapeutic value as a respiratory stimulant without producing vasopressor or tachycardiac effects, for treatment of respiratory disorders.

Regulation of ventilation in the caiman (Caiman latirostris): effects of inspired CO2 on pulmonary and upper airway chemoreceptors

In order to study the relative roles of receptors in the upper airways, lungs and systemic circulation in modulating the ventilatory response of caiman (Caiman latirostris) to inhaled CO2, gas mixtures of varying concentrations of CO2 were administered to animals breathing through an intact respiratory system, via a tracheal cannula by-passing the upper airways (before and after vagotomy), or via a cannula delivering gas to the upper airways alone. While increasing levels of hypercarbia led to a progressive increase in tidal volume in animals with intact respiratory systems (Series I), breathing frequency did not change until the CO2 level reached 7%, at which time it decreased. Despite this, at the higher levels of hypercarbia, the net effect was a large and progressive increase in total ventilation. There were no associated changes in heart rate or arterial blood pressure. On return to air, there was an immediate change in breathing pattern; breathing frequency increased above air-breathing values, roughly to the same maximum level regardless of the level of CO2 the animal had been previously breathing, and tidal volume returned rapidly toward resting (baseline) values. Total ventilation slowly returned to air breathing values. Administration of CO2 via different routes indicated that inhaled CO2 acted at both upper airway and pulmonary CO2-sensitive receptors to modify breathing pattern without inhibiting breathing overall. Our data suggest that in caiman, high levels of inspired CO2 promote slow, deep breathing. This will decrease dead-space ventilation and may reduce stratification in the saccular portions of the lung.

Propranolol blocks metabolic rate increase but not ventilatory acclimatization to 4300 m

Previously, we found resting metabolic rate increased at high altitude but the mechanism and consequences of this increase were unclear. We sought to test the role of beta-sympathetic activation for increasing metabolic rate and the contribution of an increase in metabolic rate to raising total ventilation at altitude. Following baseline studies at sea level, two groups of six healthy male subjects received either placebo or propranolol (80 mg/8 h) for 3 days prior to ascent to Pikes Peak (4300 m) where treatment was continued for 15 days. O 2 consumption increased in placebo-treated subjects with a rise of 20 ± 5% ( X ± SEM) on day 1 and no change 0 ± 7% in propranolol-treated subjects (difference between groups, P < 0.05). The increase in total ventilation upon ascent was 28 ± 2% in the placebo group vs 9 ± 7% in the propranolol group ( P < 0.05) and was correlated with metabolic rate in individual subjects. Decreasing end-tidal P CO 2 , taken as an index of ventilatory acclimization, was similar in both groups. Thus, beta-sympathetic activation appears to increase metabolic rate upon ascent to high altitude and lead to a proportionate elevation in total ventilation but does not alter ventilatory acclimization.

Propranolol blocks metabolic rate increase but not ventilatory acclimatization to 4300 m

Previously, we found resting metabolic rate increased at high altitude but the mechanism and consequences of this increase were unclear. We sought to test the role of beta-sympathetic activation for increasing metabolic rate and the contribution of an increase in metabolic rate to raising total ventilation at altitude. Following baseline studies at sea level, two groups of six healthy male subjects received either placebo or propranolol (80 mg/8 h) for 3 days prior to ascent to Pikes Peak (4300 m) where treatment was continued for 15 days. O 2 consumption increased in placebo-treated subjects with a rise of 20 ± 5% (X̄ ± SEM) on day 1 and no change 0 ± 7% in propranolol-treated subjects (difference between groups, P < 0.05). The increase in total ventilation upon ascent was 28 ± 2% in the placebo group vs 9 ± 7% in the propranolol group ( P < 0.05) and was correlated with metabolic rate in individual subjects. Decreasing end-tidal P co 2 , taken as an index of ventilatory acclimatization, was similar in both groups. Thus, beta-sympathetic activation appears to increase metabolic rate upon ascent to high altitude and lead to a proportionate elevation in total ventilation but does not alter ventilatory acclimatization.

Increased metabolism contributes to increased resting ventilation at high altitude

Ventilatory acclimation to high altitude results in an increase in total or minute ventilation, and is associated with a fall in alveolar P CO 2 , i.e. alveolar hyperventilation. However, the extent to which the increase in total ventilation is matched by a greater metabolic rate (V̇ O 2 , V̇ CO 2 ) vs alveolar hyperventilation is unclear. We sought to determine the contribution of changes in metabolic rate to the increase in minute ventilation observed during exposure to high altitude. In 12 healthy male subjects taken from Denver, Colorado (1600 m) to Pikes Peak, Colorado (4300 m) for 5 days, resting minute ventilation increased from low to high altitude (+ 26% for the 5 days) and arterialized P CO 2 fell. Resting metabolic rate increased 16% for the 5 days and could account for more than half of the increase in minute ventilation. Among subjects the increases in ventilation on days 1, 2 and 4 were positively correlated with increased CO 2 production; they were not correlated with arterial oxygen saturation on any day. During exercise at high altitude, P CO 2 values were not different from those at rest and minute ventilation rose above low altitude values (+ 58% by day 5), but the increase could not be accounted for by an increased CO 2 production. Thus at rest but not during exercise a substantial portion of the rise in minute ventilation could be attributed to increased metabolic rate.

Respiratory function in recurrent pulmonary embolism.

Pulmonary arterial and right atrial pressure, cardiac output, lung volumes, blood gases, VD/VT ratio and alveoloarterial oxygen tension gradient were measured in 21 subjects with pulmonary hypertension due to recurrent pulmonary emboli. The mean pressure in pulmonary artery ranged from 19.5 to 97.0 mm Hg. Respiratory examination revealed normal spirometry and slight hypoxemia associated with an increase in alveoloarterial oxygen tension gradient. Lung transfer factor for CO was measured in nine patients; it was either normal or slightly reduced. Hyperventilation was found in the majority of patients already at rest. Pulmonary hypertension was believed to be the most important cause of alveolar hyperventilation in these patients. Total ventilation and VD/VT ratio were measured in 22 normal subjects at rest and during exercise, both with and without unilateral pulmonary artery occlusion. At rest, pulmonary artery occlusion did not lead to any change in total ventilation; during exercise, a 30-percent increase in total ventilation was observed with pulmonary artery occlusion. Pulmonary artery occlusion led to an increase in functional dead space only in those subjects in whom the tidal volume exceeded 700 ml. Whether this increase in tidal volume was associated with exercise or not did not make any difference. In patients with recurrent pulmonary embolism, the value of functional dead space was also higher only in subjects breathing with higher tidal volumes. It seems, therefore, that in the patients the same principle of unmasking the alveolar dead space by the increase in tidal volume can be demonstrated as in the model experiments with pulmonary artery occlusion

Dyspnea: Pathophysiology and differential diagnosis

There is no single universally accepted theory that explains the mechanism of dyspnea production under all circumstances, although different conditions with varying pathophysiologic alterations frequently appear to lead a common mechanism of inappropriate respiratory muscle length-tension relationship. Dyspnea occurring with cardiac failure appears dependent on the presence of pulmonary congestion, which both alters sensory input to the respiratory center and directly increases the work of breathing. Dyspnea in patients with pulmonary disease appears related either to an increase in total ventilation, an increase in airway obstruction, a decrease in lung compliance, or combinations of the above. The recognition that cardiac failure is responsible for the presence of dyspnea in a patient generally presents little diagnostic difficulty, Similarly, pulmonary disease is readily recognized in most cases when it has progressed to the point of producing dyspnea. Diagnostic difficulties are encountered in determining the relative individual contributions of heart disease and chronic pulmonary disease when the patient has both disorders. Recognition of the source of dyspnea may also be difficult when anxiety or other emotional disturbances are present in a patient with heart or lung disease. Under these circumstances, careful evaluation of the pathophysiologic consequences of the particular condition involved is necessary. This can generally be accomplished by careful history and physical examination together with cardiac catheterization and/or pulmonary function studies.

Circulatory and Respiratory Adaptation during Prolonged Exercise in the Supine Position

AbstractCirculatory and respiratory changes during prolonged, non‐steady state exercise in the supine position were studied by the heart catheterization technique in six healthy young men of average physical fitness. The work load was chosen so that they could perform supine exercise for one hour. This load gave a mean heart rate of about 128 beats/min after 10 min and 142 beats/min after 50 min of work. The circulatory changes during these experimental conditions were characterized by a constant cardiac output and a continuous increase in heart rate, indicating a continuously falling stroke volume. The systemic arterial blood pressure fell continuously, but the mean pulmonary arterial pressure fell markedly between 10 and 20 minutes' work and then remained unchanged. The acid base status was fairly stable during exercise. The respiratory response was characterized by a slight increase in total ventilation, an unchanged alveolar ventilation and a slight increase in dead‐space ventilation. The small increase in total ventilation was due to a small increase in respiratory rate and tidal volume. The overall ventilation‐perfusion relationship was unchanged. Both circulatory and respiratory changes may be explained by a decreased tonus in the capacity vessels with a shift in the distribution of the blood.

CIRCULATORY AND RESPIRATORY ADAPTATION, DURING LONG-TERM, NON-STEADY STATE EXERCISE, IN THE SITTING POSITION.

AbstractEkelund, L. G. and A. Holmgren.Circulatory and respiratory adaptation during lone‐term, non‐steady state exercise in the sitting position. Acta physiol. scand. 1964.62. 240–255. — Circulatory and respiratory changes during long‐term, non‐steady state exercise in the sitting position was studied with heart catheterization technique in six healthy young men with average training. The work load was chosen individually to increase the heart rate to about 140–150 beats per minute after 10 min work and to 170–180 beats per min after 60 min work.The circulatory changesduring these experimental conditions were characterized by continuously falling systemic arterial blood pressure, constant cardiac output, and increasing heart rate, indicating a continuously fallinn stroke volume. The blood volume was lower during exercise than at rest in the supine position but remained unchanged between 10 and 50 min work. Theacid‐basestatus was characterized as a compensated metabolic acidosis, which remained essentially constant throughout the test. Therespiratory responsewas characterized by a successively increasing total ventilation, a moderate increase in alveolar ventilation and a marked increase in dead‐space ventilation. The increase in total ventilation was effectuated by an increase of both the respiratory rate and the tidal volume. The overallventilation‐perfusion relationshipshowed a slight continuous increase. Both circulatory and respiratory changes may be explained in the light of a gravitational shift in the distribution of the blood volume.