Prenatal cigarette smoke exposure and postnatal respiratory responses to hypoxia and hypercapnia

Prenatal cigarette smoke (CS) exposure, in combination with hypoxia and/or hyperthermia can lead to gasping and attenuated recovery from hypoxia in 7 days old rat pups. We studied 95 unanesthetized spontaneously breathing 14 days old rat pups to investigate if the destabilizing effects of increased ambient temperature and prenatal CS exposure on respiratory control observed in 7 days old rats were still evident at day 14. This postnatal age was selected as it is beyond the analogous risk period for SIDS in human. Furthermore, we investigated if the breathing responses to hypercapnia are affected by prenatal CS exposure. Since high ambient (HA) temperature can lead to gasping and aberrant respiratory control, we recorded respiratory patterns at low (24-25°C) and high (29-30°C) ambient temperatures, and under hypoxic or hypercapnic states. No gasping was observed in 14 days old rat pups. During hypoxia, breathing frequency increased in the CS-exposed group under low and HA temperatures. Rectal temperature decreased only in the sham group in response to low ambient temperature hypoxia. At HA temperature, breathing frequency increased in both sham and CS-exposed groups during hypercapnia, however, it remained elevated during washout period only in the sham group. We demonstrate that prenatal CS exposure continues to have profound effects on respiratory and thermoregulatory responses to hypoxia and hypercapnia at day 14. The attenuated respiratory and thermoregulatory responses to acute hypoxia and hypercapnia on day 14 demonstrate a strong interaction between CS exposure, respiratory control, and thermoregulation during postnatal maturation.     

Changes in inspired gas composition and experimental bronchospasm in the rabbit.

In clinical practice, bronchospasm could be facilitated by hypoxia and by hypercapnia. In this study we assessed the influence of breathing a hypoxic (FIO2 = 0.10) or a hypercapnic (FICO2 = 0.08) gas mixture on the response to nebulized histamine (2% solution for 5 min) in anesthetized, tracheotomized, paralyzed and mechanically ventilated rabbits. Total respiratory resistance (Rrs) and elastance (Ers) were derived by least-square analysis from the relationship between tracheal pressure and flow. Control values of Rrs were larger during hypoxia and hypercapnia than in air while the values of Ers were similar. The absolute change in Rrs after histamine was similar in air and hypoxia, and larger in hypercapnia. The relative change, however, was smaller in hypoxia than in the two other conditions. Ers was also substantially increased by histamine and, contrary to Rrs, remained high 60 min after the aerosol. The results suggest: (1) that both hypoxia and hypercapnia increase airway resistance but do not change tissue properties; (2) that the response to histamine is depressed by hypoxia; (3) that a substantial part of the immediate response, and most, if not all, of the residual response after 60 min is due to changes in lung tissue viscoelastic properties.     

Upper airway resistance during progressive hypercapnia and progressive hypoxia in normal awake subjects

Ventilatory motor output is known to influence the upper airway. Although inspiratory upper airway resistance decreases during progressive hypoxia or hypercapnia, the effects of hypoxia and hypercapnia on expiratory upper airway resistance remain unknown. In the present study, we attempted to examine whether the expiratory and the inspiratory upper airway resistances were modified in the same way by progressive hyperoxic hypercapnia or by progressive normocapnic hypoxia. Nine healthy subjects (five males, four females, 33+/-9 years) participated in the study. Inspiratory upper airway (iUAR) and expiratory upper airway resistances (eUAR) were calculated at flow 300 ml x s(-1). Both resistances were obtained during a baseline period and during progressive hyperoxic hypercapnia or progressive normocapnic hypoxia. In all subjects, iUAR and eUAR decreased significantly during hypercapnic or hypoxic challenge (P<0.05). eUAR was always lower than iUAR during hypercapnic challenge (P<0.0001) and during hypoxic challenge (P<0.0001). The authors conclude that expiratory upper airway resistance, as with inspiratory resistance, decreases during progressive hypercapnia or during progressive hypoxia. Pharyngeal dilator or constrictor muscle activities may be implicated.     

Hypercapnic acidosis and compensated hypercapnia in control and pulmonary hypertensive piglets

Low tidal volume/inspiratory pressure ventilator strategies result in hypercapnia, which has been shown to increase pulmonary vasomotor tone. This may be particularly detrimental in infants and children with preexistent pulmonary hypertension. In this study, a piglet model of chronic hypoxia-induced pulmonary hypertension was used to test the hypotheses that: 1) the effects of hypercapnic acidosis are exaggerated by preexistent pulmonary hypertension; and 2) the pulmonary hemodynamic effects of hypercapnic acidosis are attenuated by normalizing pH. Pulmonary hypertension was induced by 2 weeks of hypoxia. Hemodynamic responses were measured in control and pulmonary hypertensive piglets during both normoxia and hypoxia under normocapnic, hypercapnic acidotic, and compensated hypercapnic conditions. We found that: 1) hypercapnic acidosis increased both normoxic and hypoxic pulmonary vascular resistance index (PVRI) in control piglets; 2) the pressor effects of hypercapnia were not attenuated by infusing bicarbonate to normalize the pH; and 3) piglets with chronic hypoxia-induced pulmonary hypertension had elevated baseline normoxic and hypoxic PVRI, but responded to hypercapnic acidosis and compensated hypercapnia in a similar way to control piglets. These data suggest that acute hypercapnic acidosis may have deleterious effects on the pulmonary hemodynamics of normal and pulmonary hypertensive subjects which may not be acutely reversed by buffering the pH.     

Slow breathing reduces chemoreflex response to hypoxia and hypercapnia, and increases baroreflex sensitivity.

OBJECTIVE: To investigate whether breathing more slowly modifies the sensitivity of the chemoreflex and baroreflex. DESIGN SETTING: University of Pavia, IRCCS Policlinico S. Matteo. PARTICIPANTS: Fifteen healthy individuals. INTERVENTIONS: Progressive isocapnic hypoxia and progressive hyperoxic hypercapnia were measured during spontaneous breathing and during a breathing rate fixed at 6 and 15 breaths per minute (b.p.m.). Main outcome measures: Variations in chemo- and baroreflex sensitivity (by monitoring ventilation, oxygen saturation, end-tidal carbon dioxide, R-R interval and blood pressure) induced by different breathing rates. RESULTS: Breathing at 6 b.p.m. depressed (P < 0.01) both hypoxic and hypercapnic chemoreflex responses, compared with spontaneous or 15 b.p.m. controlled breathing. Hypoxic and hypercapnic responses during spontaneous breathing correlated with baseline spontaneous breathing rate (r = -0.52 and r = +0.51, respectively; P = 0.05). Baroreflex sensitivity was greater (P < 0.05) during slow breathing at baseline and remained greater at end rebreathing. CONCLUSIONS: Slow breathing reduces the chemoreflex response to both hypoxia and hypercapnia. Enhanced baroreflex sensitivity might be one factor inhibiting the chemoreflex during slow breathing. A slowing breathing rate may be of benefit in conditions such as chronic heart failure that are associated with inappropriate chemoreflex activation.     

The effects of catecholamines on ventilation in rainbow trout during hypoxia or hypercapnia

This study assessed the effects of experimentally elevated plasma catecholamine levels on gill ventilation in rainbow trout (Oncorhyncus mykiss) exposed to various external ventilatory stimulants. Trout were exposed to hypoxia (water PO2 (PwO2) = 90 Torr) or hypercapnia (water PCO2 (PwCO2) = 4.5 Torr) for 30 min. These conditions caused gill ventilation volume (Vw) to increase by 2.3- and 1.5-fold, respectively, but did not stimulate release of catecholamines into the blood. While the stimulus (hypoxia or hypercapnia) was maintained, fish were given a bolus injection (0.3 ml), followed by intra-arterial infusion (0.6 ml.h-1), of a catecholamine mixture (2 x 10(-5) mol.l-1 adrenaline + 5 x 10(-6) mol.l-1 noradrenaline) to mimic the physiological concentrations and ratios of these catecholamines observed under more severe hypoxic or hypercapnic conditions. In hypoxic fish, this treatment caused a significant, but transient (5 min) depression of ventilation while during hypercapnia, the administration of exogenous catecholamines caused a more prolonged hypoventilatory response. These hypoventilatory responses occurred despite a catecholamine-induced blood acidosis (a potential ventilatory stimulant). To assess the importance of initial Vw and/or blood respiratory status on catecholamine-mediated hypoventilation, these experiments were repeated under hyperoxic (PwO2 = 640 Torr) hyperoxic hypercapnic (PwO2 = 510 Torr, PwCO2 = 4.8 Torr) or normoxic (PwO2 = 151 Torr) conditions in which Vw was either depressed (3.9-fold during hyperoxia) or unaffected. Intra-arterial infusion of catecholamines did not affect Vw under either of these experimental conditions. These results demonstrate that during a respiratory challenge, such as hypoxia or hypercapnia, physiologically relevant levels of circulating catecholamines can depress Vw and therefore do not support a stimulatory role for circulating catecholamines in the control of ventilation in fish.     

The influence of NMDA receptor-mediated processes on breathing pattern in ground squirrels

The effects of blockade of N-methyl-D-aspartate (NMDA) type glutamate receptors by a non-competitive antagonist (MK-801) on cortical arousal, breathing pattern and ventilatory responses to hypoxia (10% O2 in N2) and hypercapnia (5% CO2 in air) were assessed in anesthetized (urethane) and unanesthetized golden-mantled ground squirrels (Spermophilus lateralis). Intra-cerebroventricular administration of MK-801 did not alter ventilation during wakefulness, although it did alter the pattern (breathing frequency and tidal volume components) of the hypercapnic ventilatory response, and suppressed the ventilatory response to hypoxia. Animals did not sleep following treatment with MK-801, and intravenous administration of MK-801 prevented expression of the sleep-like state normally observed in anesthetized animals. In anesthetized animals MK-801 elevated breathing frequency to levels observed without anesthesia, and suppressed the hypoxic ventilatory response. These data suggest that NMDA-type glutamatergic receptor-mediated processes influence cortical arousal and facilitate depression of breathing frequency during anesthesia and the hypoxic ventilatory response. Such processes are not essential for the hypercapnic ventilatory response.     

VENTILATORY RESPONSES TO HYPOXIA AND HYPERCAPNIA IN ASTHMATICS WITH PREVIOUS RESPIRATORY FAILURE

The ventilatory response to hypoxia and the ventilatory and mouth occlusion pressure response to hypercapnia was measured in 13 subjects who had previously developed respiratory failure or respiratory arrest during an acute asthma attack, In 11 of 12 subjects tested there was a normal response to hypercapnia. Six of the 13 subjects had an impaired response to hypoxia. Impaired hypoxic responsiveness may Contribute to the early onset of hypercapnic respiratory failure during acute severe asthma.     

The effect of aminophylline on function and intracellular pH of the rat diaphragm

We studied the effect of aminophylline on twitch tension (TT) and intracellular pH (pHi) in isolated rat diaphragm strips that were fatigued, hypercapnic, or hypoxic. Superfused muscles were directly stimulated at 0.5 Hz. The pHi was measured from distribution volumes of dimethyl-oxazolidinedione. Fatigue was induced by intermittent tetanic stimulation. Hypercapnia and hypoxia were produced by altering superfusate carbon dioxide tension (PCO2) or oxygen tension (PO2). Aminophylline (1.0 mmol.l-1) reversed the twitch decay seen during fatigue or hypercapnic acidosis, and caused partial recovery of twitch depression during hypoxia. Muscle fatigue was not due to an intracellular acidosis. Both hypercapnia and hypoxia lowered pHi. Aminophylline did not alter pHi in unstimulated muscles, but caused a significant fall in pHi in stimulated muscles that were fatigued or hypoxic. High dose aminophylline improved twitch tension in diaphragm strips that were fatigued, acidotic, or hypoxic. Twitch potentiation was not due to an intracellular alkalosis. Aminophylline lowered pHi in stimulated muscle, and thus, theoretically, could sometimes be harmful in the treatment of muscle fatigue.     

Hypoxic and hypercapnic breathlessness in patients with type I diabetes mellitus

STUDY OBJECTIVES: The putative role of the performance of inspiratory muscles and breathing pattern in inducing dyspnea has been recently assessed during hypoxic stimulation in patients with type I diabetes (IDDM). Compared to a hypoxic stimulus, a hypercapnic stimulus, which may differently affect the pattern of breathing, could therefore modulate the coupling between respiratory effort and ventilatory output, which is involved in dyspnea sensation. SUBJECTS: Eight stable patients aged 19 to 48 years old, with IDDM (duration of disease, 36 to 240 months) and no smoking history, cardiopulmonary involvement, or autonomic neuropathy; and an age- and sex-matched control group. MEASUREMENTS: Pulmonary volumes, diffusing capacity of the lung for carbon monoxide, time and volume components (tidal volume [VT] and respiratory frequency), dynamic elastance (Eldyn), and swings in pleural pressure (Pessw) were measured. Maximal inspiratory pleural pressure (Pes) during a maximal sniff maneuver (Pessn), respiratory muscle effort or output (Pessw%Pessn), tension time index (TTI) = TI/total breathing cycle time x Pessw(%Pessn), and swing in Pes during VT as a percentage of Pessn were also evaluated. Dyspnea sensation was assessed by a modified Borg scale. Subjects were studied at baseline and during hypoxic and hypercapnic rebreathing tests. RESULTS: Compared to control subjects, patients exhibited normal routine spirometric function and Pessn, but a higher Eldyn, indicating peripheral airway involvement. In patients, but not in control subjects, Eldyn increased during both chemical stimuli and increased more during hypoxia than during hypercapnia. Also, changes in both VT and Pessw(%Pessn) on changes in PCO(2) were lower, while changes in Pessw(%Pessn)/VT, an index of neuroventilatory dissociation (NVD) of the ventilatory pump, on changes in PCO(2) were greater. Changes in VT and NVD for unit change in arterial oxygen saturation were lower and higher, respectively. Changes in Borg scale per changes in NVD were greater during both stimuli. Furthermore, compared to hypoxic conditions, a greater VT for any level of both minute volume and Pessw(%Pessn), and lower changes in Borg scale on changes in Pessw(%Pessn) and Pessw(%Pessn)/VT were found in hypercapnia. Changes in NVD and Borg scale related to changes in Eldyn with both chemical stimuli. CONCLUSIONS: In IDDM, the greater perception of dyspnea is associated with changes in inspiratory effort being out of proportion to changes in VT. The greater increase in Eldyn and the lower increase in VT may, in part, account for the greater perception of breathlessness during hypoxia.     

Aging effects on the interaction of hypercapnia and hypoxia as ventilatory stimuli

We measured ventilatory responses to progressive hypercapnia at two steady-state levels of oxygenation and to progressive hypoxia at two steady-state levels of CO2 in 10 elderly and 10 young individuals. Under hyperoxic conditions, the ventilatory response to progressive hypercapnia was not significantly different between age groups but, under hypoxic conditions, the response to hypercapnia was lower in the elderly group. The interaction of hypercapnic and hypoxic stimuli was greater among young persons as indicated by a higher ratio of the hypercapnic response slopes (hypoxic/hyperoxic); 1.48 +/- 0.19 versus 0.98 +/- 0.11, p less than .05. The ventilatory response to hypoxia at the lower CO2 level was significantly greater among elderly than among young adults but not significantly different between age groups at the higher CO2 level. The ratio of hypoxic response slopes (high PCO2/lower PCO2) was 1.56 +/- 0.17 among elderly participants and 3.14 +/- 0.63 among young participants (p less than .05). These results suggest that aging diminishes the multiplicative effect of hypercapnia and hypoxia as ventilatory stimuli.     

Depression of hypoxic and hypercapnic ventilatory drives in severe asthma.

Because of the previous finding of an attenuated hypoxic ventilatory drive in a teenager with severe asthma, the ventilatory responses to hypoxia and hypercapnia were examined during remission in 16 patients with the history of severe asthma. Spirometric and body plethysmographic pulmonary functions were normal or nearly normal just prior to ventilatory drive testing. The ventilatory responses to progressive isocapnic hypoxia and to hyperoxic hypercapnia were studied. Both hypoxic and hypercapnic drives were significantly depressed in the asthmatic patients. Factors known to blunt the ventilatory drives were not present in this group of patients. Hence, the etiology of these changes is unclear. In some patients, these depressed respiratory drives might contribute to hypoventilation, to severe hypoxemia, and to respiratory failure during severe asthma.     

Familial aspects of ventilatory control in patients with chronic obstructive pulmonary disease

To determine whether abnormal chemical drives to breathe in patients with chronic obstructive pulmonary disease (COPD) antedate the development of chronic CO2 retention, we measured ventilatory and P0.1 responses to hypercapnia and hypoxia in 14 such patients and 23 of their normal adult offspring. Hypoxic responses in the patients were positively correlated with the mean hypoxic responses of their offspring. Neither the hypercapnic responses nor the resting breathing patterns of the patients were related to those of their offspring. Hypoxic response was lower in offspring of hypercapnic patients than in offspring of normocapnic patients. Blunt hypoxic responses in patients with COPD are influenced by familial factors and may represent a premorbid "risk factor" in the development of CO2 retention in this disease. This does not appear to be true for hypercapnic response or breathing pattern.     

Depression of peripheral chemosensitivity by a dopaminergic mechanism in patients with obstructive sleep apnoea syndrome.

In the present study, respiratory drives to chemical stimuli and peripheral chemosensitivity were evaluated in patients with obstructive sleep apnoea (OSAS). The effects of oral administration of domperidone, a selective dopamine D2-receptor antagonist, were also examined, to study the respiratory effects of endogenous dopamine on peripheral chemoreceptors. Sixteen patients with OSAS and nine normal control subjects were studied. Respiratory responses to hypercapnia and hypoxia were measured using the rebreathing method and isocapnic progressive hypoxia method, respectively. The hypoxic withdrawal test, which measures the decrease in ventilation caused by two breaths of 100% O2 under mild hypercapnic hypoxic conditions (end-tidal oxygen and carbon dioxide tensions approximately 8.0 kPa and 5.3-6.7 kPa, respectively), was used to evaluate peripheral chemosensitivity. In the patients with OSAS, ventilatory responses to hypercapnia and hypoxia were significantly decreased compared with those of control subjects. Hypoxic withdrawal tests showed that peripheral chemosensitivity was significantly lower in patients with OSAS than in normal subjects. Hypercapnic ventilatory response and peripheral chemosensitivity were enhanced by administration of domperidone in the patients with OSAS, although no changes in either of these were observed in the control subjects. The hypoxic ventilatory response and peripheral chemosensitivity in the patients with OSAS were each significantly correlated with severity of hypoxia during sleep. These findings suggest that peripheral chemosensitivity in patients with obstructive sleep apnoea syndrome may be decreased as a result of abnormality in dopaminergic mechanisms and that the reduced chemosensitivity observed in patients with obstructive sleep apnoea syndrome may affect the severity of hypoxia during sleep.     

The effects of hypercapnia and hypoxia on single hypoglossal nerve fiber activity

The respiratory related modulation of hypoglossal nerve activity has been studied at the single fiber level in cats under hyperoxic hypercapnia and hypoxic conditions and their conduction velocities determined. Changes in fiber activity were compared to simultaneous changes occurring in phrenic activity. Three different kinds of discharge patterns were observed: (a) inspiratory, (b) phasic activity during both inspiration and expiration, and (c) continuous random activity with no respiratory modulation. These fibers could be grouped into three categories according to their pattern of discharge during CO2 breathing. Type I fibers, mean conduction velocity of 30.0 m/sec, exhibited only an inspiratory phasic discharge during 100% O2 breathing. Their discharge frequency increased rapidly with higher levels of CO2 and hypoxia. Type II fibers, mean conduction velocity of 36.7 m/sec, had three different kinds of inspiratory-expiratory discharge patterns during 100% O2 breathing. With increasing hypercapnia or hypoxia fibers of this group discharged phasically during inspiration and discharge at low frequency during expiration. Type III fibers had a non phasic discharge pattern at 100% O2 breathing and at all levels of CO2 tested (up to 10%). Discharge frequency rose during CO2 rebreathing and hypoxia, but the rate of increase was much less than Type I and Type II fibers. Their mean conduction velocity was 41.3 m/sec. The inspiratory activity of Type I and II fibers increased their activity more than the phrenic during hypercapnia and hypoxia. Type II and Type III fibers are responsible at least in part for the tonic activity of the nerve.     

Relation between dyspnea and personality in patients with pulmonary emphysema and healthy subjects]

To determine whether personality is related to dyspnea sensation, 19 healthy males and 17 male patients with pulmonary emphysema were tested for modified visual analog scale (VAS) during hypoxic and hypercapnic interventions. Personality was tested by both Yatabe-Guillford test and manifest anxiety scale. VAS score correlated positively with anxiety score during hypercapnia and inspiratory resistive loading under hypercapnia in healthy subjects. In patients, anxiety score correlated positively with VAS scores during hypoxia, hypercapnia, and resistive loading under hypercapnia. Scores for nervousness and cyclic tendency correlated with VAS scores during hypoxia and hypercapnia in patients. These results indicate close relation between anxiety and dyspnea in healthy as well as emphysematous subjects. In emphysema, nervousness and cyclic tendency are the additional determinants for dyspnea.     

Peripheral chemosensitivity assessed by the modified transient O2 test in female twins

To evaluate genetic influence on the control of breathing in adult women, we measured, in healthy female twins, ventilatory responses to isocapnic progressive hypoxia and hyperoxic progressive hypercapnia, and the withdrawal response (the modified transient O2 test) which is considered to selectively reflect peripheral chemoreceptor activity. The withdrawal response was obtained as the magnitude of initial depression in ventilation induced by two breaths of O2 from steady-state hypercapnic hypoxia. Nine monozygotic twin pairs, aged 44 +/- SD17 years, and 7 dizygotic twin pairs, aged 39 +/- 8 years, were studied. Mean values for ventilatory responses to hypoxia and hypercapnia, and the withdrawal response were not different between MZ and DZ. The within-pair variance ratio (VDZ/VMZ) for the withdrawal response was significantly greater than one (p less than 0.05), although neither VDZ/VMZ for the hypoxic response nor that for the hypercapnic response was greater than one. These observations suggest that the peripheral chemosensitivity is influenced by genetic factors even in adult women, including aged subjects, when genetic influence is not apparent in the ventilatory responses to progressive hypoxia and hypercapnia.     

Modulation of respiratory reflexes by an excitatory amino acid mechanism in the ventrolateral medulla.

Results from several studies suggest that the ventrolateral medulla (VLM) is involved in modulating the respiratory response to central and/or peripheral chemoreceptor stimulation. Furthermore, the excitatory amino acid (EAA) glutamate has been shown to have marked effects on respiration when administered to VLM sites. The purpose of this study was to determine if an excitatory amino acid mechanism in the VLM modulates the respiratory responses to hypoxia or hypercapnia in anesthetized rats. Exposure to hypoxic or hypercapnic gas under control conditions elicited increases in respiratory activity (diaphragmatic EMG activity and breathing frequency). Bilateral injection of kynurenic acid (KYN), an EAA antagonist, into rostral VLM sites evoked significant increases in breathing frequency; injections more caudal in the VLM typically caused apnea. Significantly larger increases in respiratory output were elicited by both hypoxia and hypercapnia after rostral VLM microinjections of KYN. The accentuated responses returned to control levels after a recovery of approximately 100 min. Microinjection of xanthurenic acid (XAN), an inactive analog of kynurenic acid, into the VLM prior to KYN had only slight effects on resting respiratory activity and no effects on the responses to hypoxia or hypercapnia. These results suggest two separate VLM sites which modulate respiration by EAA mechanisms. A more rostral site tonically inhibits respiratory activity and the respiratory responses to chemoreceptor stimulation and more caudal VLM sites may be required for the maintenance of respiratory activity.     

Abnormal breathing during sleep and chemical control of breathing during wakefulness in patients with sleep apnea syndrome

The possible role of ventilatory control in relation to sleep apnea has not yet been clarified. We investigated the relationship between awake ventilatory drives to hypoxia and hypercapnia and sleep-disordered breathing in 21 subjects with sleep apnea syndrome. The awake hypoxic ventilatory drive, which was evaluated by occlusion pressure responses, was inversely correlated with the magnitude of maximal oxygen desaturation during sleep as well as the ratio of duration with more than 4 and 10% oxygen desaturation to total sleep time. On the other hand, the awake hypercapnic ventilatory drive was not correlated with these parameters of sleep desaturation. Apnea index and duration were not correlated with the degree of hypoxic or hypercapnic ventilatory drive, respectively. Our study concluded that sleep desaturation is better correlated with hypoxic ventilatory drive than with hypercapnic ventilatory drive in patients with sleep apnea syndrome. These results are different from the results obtained in the patients with COPD in our previous study.     

Hypoxic, hypercapnic acidosis decreases tension and increases fatigue in hamster diaphragm muscle in vitro

Hypoxia and hypercapnic acidosis have been shown to have a negative inotropic effect on diaphragmatic contractility. The effect of combined hypercapnia and hypoxia was studied in vitro using hamster diaphragm strips. A 12% CO2, 21% O2, and 67% N2 gas mixture was used to produce hypoxic, hypercapnic acidosis. Force-frequency curves were generated using twitches and maximal tetanic contractions produced by stimulating with 0.2-ms pulses at 10 to 120 Hz for 300 to 500 ms. Moderate fatigue was then induced by repeated submaximal contractions (25 Hz, 160 ms, at the rate of 1/s for 45 contractions). Muscle strips exposed to hypoxic, hypercapnic acidosis had a decreased force response at all frequencies. The decrease in force was not different from that seen with hypoxia alone but was significantly worse than with hypercapnia alone. In the combined hypercapnic, hypoxia solution, tension produced by stimulating at 25 Hz for 160 ms was decreased to 52 +/- 11% of control (p less than 0.001). For these submaximal contractions, hypercapnic acidosis had a greater negative inotropic effect than did hypoxia alone. With repeated contractions, tension declined at a faster rate than in control, hypoxia alone, or hypercapnia alone. In the combined hypoxic, hypercapnic solution, the time constant of relaxation (tau) was increased prior to the start of the fatigue run compared to the control (tau = 35 +/- 6 versus 45 +/- 5 ms; p less than 0.001), and the tau increased at a faster rate than in control. These studies suggest that hypoxic, hypercapnic acidosis has a greater detrimental effect on the muscle than either abnormality alone and makes the muscle more susceptible to fatigue.