T-cell phenotypes in bronchoalveolar lavage fluid, blood and lymph nodes in pulmonary sarcoidosis--indication for an airborne antigen as the triggering factor in sarcoidosis.

BACKGROUND: An increased percentage of CD4+ T cells is usually observed in bronchoalveolar lavage fluid (BALF) from patients with sarcoidosis. In HLA-DRB1*03-positive patients, such T cells express the T-cell receptor (TCR) AV2S3+ gene segment. It is not known whether cells found in BALF reflect those in enlarged regional lymph nodes (LNs). Therefore, the aim of this study was to compare T-cell phenotypes in BALF, blood and mediastinal LNs. METHODS: Fifteen patients underwent clinical investigation including bronchoscopy with bronchoalveolar lavage. Blood samples were drawn, and endoscopic ultrasound-guided fine-needle aspiration of enlarged mediastinal LNs was performed via the oesophagus. T cells from all three compartments were analysed by flow cytometry for markers of activity, differentiation and T regulatory function. RESULTS: The CD4/CD8 ratio was significantly higher in BALF compared with regional LNs and was also significantly higher in LNs than in blood. The CD4+ T cells were recently activated and more differentiated in BALF than in blood and LNs. There was an accumulation of T regulatory cells (FOXP3+) in LNs and a correlation between high levels of FOXP3+ cells in BALF and in LNs. In HLA-DRB1*03-positive patients, TCR AV2S3+ CD4+ T cells were predominantly localized within BALF. CONCLUSIONS: The CD4+ T-cell phenotype in BALF indicates an active ongoing specific immune response primarily localized to the alveolar space.

Renal function in hypoxaemic chronic obstructive pulmonary disease: effects of long-term oxygen treatment.

UNLABELLED: Impaired renal function is an important cause for the oedema formation, which often occurs in severe chronic obstructive pulmonary disease (COPD). In the present study, the importance of nocturnal hypoxaemia (measured by a nocturnal pulse oximetry) for the renal function was determined in 19 COPD patients, with normal levels of serum creatinine. The effects on kidney function of alleviating the nocturnal hypoxaemia [using 6 months of long-term oxygen treatment (LTOT)], was assessed in 12 patients. Renal function was assessed by determining the clearances of intravenously administered inulin (C(In)) and para-amino-hippurate (C(PAH)) and orally supplemented lithium (C(Li)) and of circulating sodium (C(Na)). The 19 patients had a mean PaO2 of 7.63 +/- 1.08 kPa, a PaCO2 of 5.98 +/- 0.85 kPa, a mean nocturnal oxygen saturation (MnSaO2) of 87.7 +/- 2.8% and an FEV1 in %P of 25.6 +/- 14.6%. C(In) and C(PAH) were 35 and 45% lower than normal, respectively, whereas C(In)/C(PAH)=filtration fraction (FF) was 31% higher than normal. Six months of LTOT in 12 of the patients was not followed by any significant change in renal function in the entire study group. However, low pretreatment MnSaO2 correlated with reductions in post-treatment (FF) (r=0.73, P<0.05). Post-treatment PaCO2 did not change significantly in patients treated with oral diuretics, but increased (P<0.05) in patients without diuretics. C(Na) decreased after LTOT in six patients with an increase in PaCO2>6%, but C(Na) increased in four patients with unchanged or decreased PaCO2 following LTOT. CONCLUSIONS: Renal function (including filtration fraction) is impaired in hypoxaemic COPD. Filtration fraction is decreased following 6 months of LTOT solely in patients with severe pretreatment hypoxaemia and sodium clearance seems to be increased if improved oxygenation is not accompanied by increased PaCO2.

Atracurium and vecuronium block nicotine-induced carotid body chemoreceptor responses.

BACKGROUND: Vecuronium depresses carotid body chemosensitivity during hypoxia. We hypothesized that this is caused by inhibition of cholinergic transmission of the carotid body. METHODS: The carotid body with its sinus nerve was removed en bloc from thiopentone-anaesthetized adult male New Zealand rabbits and perfused in vitro with modified Tyrodes buffer solution at constant perfusion pressure, temperature, a buffer pH of 7.4 and normocapnia. Chemoreceptor discharge and spike frequencies (fx) were recorded from the whole sinus nerve after administration of 500 microg nicotine, given as duplicated controls and thereafter following 30 min perfusion of equipotent concentrations of atracurium (28.1 microM) or vecuronium(10 microM), after 30 min of neostigmine perfusion (9.2 microM) and finally after 30 min wash-out with buffer solution only. A short-lasting hypoxic test was performed before and at the end of the experimental period to confirm the responsiveness and validity of the preparation. RESULTS: Atracurium (n = 7) and vecuronium (n = 6) reduced chemoreceptor responses to nicotine by 70 +/- 30% and 66 +/- 19% (SEM) (P<0.05). Chemoreceptor discharges showed full recovery after neostigmine in the atracurium group and partial recovery in the vecuronium group (P<0.05). Finally, after wash-out the chemoreceptor responses to nicotine had fully recovered in both groups. CONCLUSION: Atracurium and vecuronium in equipotent concentrations block nicotine-induced chemoreceptor responses of the carotid body.

Contrast radiography in small intestinal obstruction, a valuable diagnostic tool?

OBJECTIVE: To investigate the diagnostic and therapeutic potential of plain abdominal radiographs and contrast radiography in patients with suspected small intestinal obstruction. DESIGN: Retrospective study. SETTING: General hospital, Sweden. MATERIAL: 2357 sets of plain abdominal radiographic casenotes. MAIN OUTCOME MEASURES: Analysis of plain abdominal radiographs for small intestinal obstruction. Establishment of the time that subsequent contrast radiography medium took to reach the caecum, and its success rate. RESULTS: Of the 2357 plain abdominal films 1599 (68%) did not show small intestinal obstruction, 425 (18%) showed intermediate obstruction, and 333 (14%) showed small intestinal obstruction. The water-soluble contrast medium reached the colon in 394/591 (67%) of the cases with intermediate or complete small intestinal obstruction. Although the contrast medium passed to the colon there was remaining abnormality with dilated small intestine in 71/212 (33%) of the cases with intermediate obstruction and in 95/143 (66%) of the small intestinal obstruction group. The time for the contrast medium to reach the colon was 3.4 hours in the normal group, 5.5 hours in the intermediate group and 8.9 hours in the obstruction group. CONCLUSION: The plain abdominal radiographs seem to predict the success of follow-through examinations. Contrast radiography is safe and may have a therapeutic potential in small intestinal obstruction.

Hypoxic-ischaemic brain damage in immature rats: effects of adrenoceptor modulation.

The purpose of the present study was to evaluate the role of adrenergic receptors in the cascade leading to hypoxic-ischaemic brain injury in neonatal rats. The effect of adrenergic agents (prazosin, yohimbine, idazoxan and clonidine) administered before or after hypoxia-ischaemia was evaluated with respect to mortality and brain injury. Rat pups of either 7 or 8 days of age were subjected to unilateral carotid artery ligation combined with hypoxia (6% or 8% O2 in N2). The mortality was higher in hypoxic-ischaemic groups pre-treated with the alpha-adrenergic receptor antagonists prazosin (48%) or yohimbine (53%) than in saline controls (7%). After 2 weeks the severity of the brain injury was evaluated in the surviving rats. Unilateral brain injury, evaluated by brain weight deficit of the injured ipsilateral hemisphere compared with the contralateral hemisphere, was 17.8 +/- 4.9% and 27.1 +/- 4.0% in pre- and post-treated saline groups, respectively. Post-treatment with clonidine, an alpha2-adrenergic agonist, reduced brain injury by 45% (p < 0.05) compared with saline controls. Pre-treatment with the same drug was not effective. Idazoxan had no effect on brain injury in this animal model. The results indicate that activation of central alpha2-adrenergic or imidazole receptors provides neuroprotection during reperfusion after hypoxic-ischaemic brain injury in neonatal rats.

Adrenalectomy reduces the ability of newborn rats to gasp and survive anoxia.

The ventilatory response to anoxia in unanaesthetized rat pups of 1 and 8 days of age was studied. Ventilation was recorded by barometric plethysmography. During acute anoxia (100% N2), animals of both ages responded with hyperpnoea, primary apnoea, hypoxic gasping and secondary apnoea. After secondary gasping, occasional gasps occurred. If oxygen was administered during the gasping period, all animals survived through autoresuscitation. The duration of the period of hypoxic gasping was significantly longer in the 1-day-old animals. Adrenalectomy reduced the length of this period in both 1- and 8-day-old animals. In a second series of experiments, the effect of adrenergic antagonists on autoresuscitation was examined. Pretreatment with the non-selective alpha-receptor antagonist phentolamine reduced the duration of gasping in 1-day-old rats, but prolonged this duration in 8-day-old rats. The non-selective beta-receptor antagonist propranolol did not affect the duration of gasping in 1-day-old rats, whereas it prolonged this period in the older animals. We conclude that proper duration of gasping during anoxia is dependent on intact adrenal function and that the adrenal glands therefore play an important role in autoresuscitation from anoxia during postnatal life. The underlying mechanism appears to involve alpha-adrenergic receptors.

Effects of hyperglycemia on gasping and autoresuscitation in newborn rats.

The aim of this study was to test the effects of glucose on the gasping ability and survival in a rat pup model during acute anoxia. Newborn rat pups of both 1 and 8 days of age were given glucose (30 and 60 mg/animal) or saline intraperitoneally and subsequently subjected to anoxia (100% N2). Glucose supplement induced hyperglycemia. Respiration was recorded by barometric plethysmography. The rat pups responded to acute anoxia with a robust sequence of respiratory pattern: hyperpnea, primary apnea, hypoxic gasping and secondary apnea. During anoxia the 1-day-old rats gasped much longer than the 8-day-old rats (23.4 +/- 1.0 vs. 6.1 +/- 0.5 min, p < 0.001). No difference was found in gasping duration between the saline control and the glucose-supplemented 1-day-old rat pups. The 8-day-old supplemented rats gasped much longer (9.3 +/- 0.5 min) than the control rats (6.1 +/- 0.5 min, p < 0.01). The animals autoresuscitated when they received oxygen (100%) during the gasping period. When oxygen was given after the gasping period, the survival rate was 33.3% in control and 0% in supplemented 1-day-old rats, and 100% in control and 50% in glucose-supplemented 8-day-old rats (p < 0.02). Further controlled experiments for a fixed period of anoxia to 13.5 min resulted in survival rates of 50.0% for controls and 28.6% for supplemented animals, respectively. The overall survival rate was then 85.2% in control and 52.9% in supplemented 8-day-old rats (p < 0.05). Lactate concentration in blood rapidly increased in the first 6 min of anoxia and thereafter gradually increased to 22.1 mmol/l around the last gasp in the 1-day-old rats. Hyperglycemia did not cause further accumulation of lactate despite a transient elevation over the control rats at 6 min of anoxia. In the 8-day-old supplemented animals the lactate level was only modestly increased, probably due to the prolonged gasping period. In conclusion, we found that gasping performance was well preserved in the 8-day-old glucose-supplemented rats, whereas the autoresuscitation mechanism after the last gasp might be altered due to hyperglycemia. In addition, the accumulation of lactate in the blood did not affect the gasping performance and the mechanisms of autoresuscitation.

Cerebral and ventilatory depression during hypoxia in anaesthetized newborn guinea-pigs.

The effects of hypoxia on ventilation and cerebral activity were studied in urethane-anaesthetized newborn guinea-pigs. Ventilation was measured by a pneumotachograph, and cerebral activity by a cerebral function monitor (CFM). All animals were subjected to either 9% O2 or 6% O2 in N2 for 10 minutes or until apnoea occurred. Hypoxia produced a biphasic response in ventilation, that is, an increase followed by a decrease. The initial increase was attributed to the elevation of the respiratory rate, whereas the tidal volume showed a pure decline. The respiratory rate reached its peak at 3 minutes of hypoxia (170 +/- 12% during 9% O2 and 169 +/- 12% during 6% O2). Cerebral activity during both 9 and 6% O2 breathing showed a small increase followed by a decrease. In the group subjected to 9% O2 the maximum CFM activity increased to 114 +/- 8% of the control level and the minimum activity increased to 113 +/- 7%, while in the group subjected to 6% O2 the maximum CFM activity increased to 104 +/- 5% and the minimum CFM activity to 101 +/- 3%. The depression of CFM activity was more pronounced with 6% O2 than with 9% O2. Regression analysis showed a linear correlation between ventilation and cerebral activity during both 9 and 6% O2 breathing. The results suggest that hypoxic ventilatory depression may be the consequence of cerebral depression produced by acute severe hypoxia.

Tachykinin antagonists in carotid body responses to hypoxia and substance P in the rat.

In the present study, we tested the hypothesis that substance P (SP) is an excitatory peptide to the rat carotid body and plays an important role in chemosensory excitation by hypoxia. Chemosensory discharge was recorded from the cut carotid sinus nerve in 19 anaesthetized, paralyzed and mechanically ventilated rats. Intracarotid administration of SP augmented the chemoreceptor activity in a dose-dependent manner. Maximal excitation was seen with 10 nmol SP. Carotid body stimulation by SP was independent of its effects on arterial blood pressure. The effect of SP antagonists, D-Pro2-D-Trp7,9-SP (DPDT-SP) or Spantide, on chemoreceptor responses to SP and hypoxia was examined in 12 rats. Close carotid body administration of either antagonist at doses of 40 micrograms.kg-1.min-1 elicited an augmentation followed by a progressive depression of baseline carotid body activity. SP antagonists significantly reduced peptide-induced carotid body stimulation and also markedly attenuated the chemoreceptor response to hypoxia. Systemic administration of sodium bicarbonate stimulated the carotid bodies, presumably by releasing CO2, and the bicarbonate-induced chemoreceptor stimulation was not affected by SP antagonists. From these results we conclude that in rats (a) SP stimulates the carotid bodies independently of its effects on arterial blood pressure, and (b) SP is associated with the chemosensory stimulation by hypoxia but not with other excitatory stimuli.

Enhanced in vivo release of substance P in the nucleus tractus solitarii during hypoxia in the rabbit: role of peripheral input.

In the adult, pentobarbitone-anaesthetized rabbit, the in vivo release of substance P-like immunoreactivity was measured in the nucleus tractus solitarii using microdialysis and radioimmunoassay. Increased 160 +/- 16%) extracellular concentrations of substance P-like immunoreactivity were observed during hypoxic provocations of 9% O2 in N2 which also resulted in an increase in phrenic nerve activity. In bilateral carotid sinus nerve-denervated animals no enhanced release of substance P was seen in response to hypoxic challenges (105 +/- 6%) and the phrenic nerve activity was not significantly affected. Perfusion of the nucleus tractus solitarii region with the dopamine agonist, apomorphine (10(-5) M) resulted in a significant decrease in the extracellular level of substance P. These results provide further evidence that substance P is involved in the mediation of the hypoxic drive inputs from the peripheral chemoreceptors. The interactions of apomorphine with substance P release might also suggest a presynaptic modulation of substance Pergic neurons by dopamine in the nucleus tractus solitarii.

Chemoreceptor responses to substance P, physalaemin and eledoisin: evidence for neurokinin-1 receptors in the cat carotid body.

Substance P (SP) belongs to a group of peptides called tachykinins. Biological effects of SP are mediated by tachykinin receptors that have been classified as neurokinin-1 (NK-1), NK-2 and NK-3 subtypes. The aim of the present study is to elucidate the tachykinin receptor subtype(s) that mediate the excitatory effects of SP in the carotid body. For this purpose, we compared the carotid body responses elicited by SP with that of physalaemin and eledoisin. In other tissues, physalaemin exhibits equi or greater potency at NK-1 receptors and eledoisin exerts its effects more on NK-2 and NK-3 subtypes compared to SP. Experiments were performed on eight cats that were anaesthetized, paralyzed and artificially ventilated with room air. Close carotid body administration of SP and physalaemin produced dose-dependent augmentation of the chemoreceptor afferent activity. Chemoreceptor discharge, however, was unaffected by eledoisin. Compared to that by SP, the magnitude of excitation produced by physalaemin was the same at lower doses but significantly greater with the highest dose (100 nmol). The time course of the response induced by physalaemin, however, was the same as that by SP. The present results demonstrate that in the carotid body physalaemin is also either equi or relatively more potent than SP, whereas eledoisin has no effect on the chemoreceptor discharge. It is suggested that stimulation of the carotid body by SP is mediated by NK-1 but not NK-2 or NK-3 receptors.

Occurrence of neutral endopeptidase activity in the cat carotid body and its significance in chemoreception.

The carotid body contains both tachykinins and enkephalins. Neutral endopeptidase (NEP, E.C. 3.4.24.11), has been suggested to involve in the metabolism of these neuropeptides in several organs. In the present study we determined neutral endopeptidase activity of the cat carotid body and assessed its significance in chemoreception. The cytosolic and membrane fractions of the carotid body contained NEP-like activity whereas it occurred only in the membrane fractions of the superior cervical and the nodose ganglia. Phosphoramidon, thiorphan and metal ion chelators inhibited NEP-like activity of all the 3 tissues studied; other protease inhibitors, however, were ineffective. Close carotid body administration of phosphoramidon significantly potentiated the carotid body response to low PO2 but not to hypercapnia. The enhanced response to hypoxia following phosphoramidon was further augmented by naloxone, an enkephalin antagonist. These results demonstrate that the glomus tissue contains detectable amounts of NEP-like activity and its inhibition selectively affects the hypoxic response of the carotid body.

Effect of adenosine on isolated and superfused cat carotid body activity.

Adenosine is known to increase carotid chemoreceptor discharge in vivo. Since adenosine has powerful vascular effects it is possible that this chemoexcitation is indirectly caused by changes in carotid body blood flow. To evaluate this possibility the effect of adenosine (0.02-2.0 mumol) was assessed on the chemoreceptor activity of the cat carotid bodies in vitro. All three doses of adenosine produced an increase in chemoreceptor discharge which reached its maximum within 10-20 s and subsequently returned to preinjection controls within 1 min. The chemoreceptor excitation caused by adenosine was dose-dependent. These results suggest that adenosine induces chemoexcitation without changes in blood pressure and blood flow.

Effect of adenosine on chemosensory activity of the cat aortic body.

Adenosine, which is released during hypoxia, increases carotid chemoreceptor discharge. It is not known if adenosine also may stimulate the aortic chemoreceptors. The purpose of this study was to investigate if adenosine also can stimulate aortic chemoreceptors. The effect of adenosine (0.01, 0.1 and 1.0 mumol/kg) on aortic chemoreceptor discharge was studied in seven anesthetized, paralyzed and artificially ventilated adult cats. Intra-aortic injections of adenosine produced an increase in chemoreceptor discharge, which reached its peak between 10 and 20 s. The chemoreceptor augmentation increased with higher doses of adenosine. Adenosine also caused a fall in blood pressure. The increase of chemoreceptor discharge was not related to fall in arterial blood pressure. Since adenosine is released during hypoxia, it is suggested that part of the cardiovascular changes induced by hypoxia is due to stimulation of aortic chemoreceptors by adenosine.

Substance P and mitochondrial oxygen consumption: evidence for a direct intracellular role for the peptide.

Substance P (SP), a member of the tachykinin group of peptides, has been shown to augment the sensory discharge of the carotid body, an oxygen sensing chemoreceptor. In this study we present evidence that the excitatory effect of SP, in part, could arise from a direct effect of the peptide on mitochondrial oxidative phosphorylation. Measurement of the partition coefficient of SP showed that the peptide has a relatively high apolar partition, which could be consistent with its distribution across lipid bilayers and in intracellular organelles. In addition, the effects of three concentrations of SP were tested on oxygen consumption of mitochondria isolated from rat hearts. The results showed that while the lower concentration of the peptide (0.5 microM) did not affect O2 consumption, higher concentrations, i.e., 1 and 2 microM, enhanced the rate of state 4 respiration by 52 and 64%, respectively. The rate of state 3 respiration, on the other hand, was unaltered with 0.5 and 1 microM, and was only slightly decreased with 2 microM of the peptide. The ADP:O ratio was unaffected by any concentrations of SP tested. The peptide-induced effect on state 4 respiration was even more pronounced with glutamate as a respiratory substrate and in presence of K+ in the medium. These results indicate that SP, in addition to its more accepted role as a neurotransmitter or modulator in the carotid body, may elicit intracellular response by interfering directly with oxidative phosphorylation.

Role of adenosine in hypoxic ventilatory depression.

The role of adenosine in the ventilatory depression induced by hypoxia was studied in 82 spontaneously breathing urethan-anesthetized 4-day-old rabbit pups. Respiration was monitored with a pneumotachograph. The animals were exposed to hypoxia (6% O2 in N2) for 30 min or until the occurrence of terminal apnea. In all animals hypoxia produced an initial increase in ventilation followed by a decrease. In the control group 52% of the animals became apneic after 7 min of hypoxic exposure. By contrast, pretreatment with dipyridamole (10 or 20 mg/kg), an adenosine uptake blocker, significantly shortened the time needed to reach apnea. Thus at 7 min of hypoxia 93% of the animals that received dipyridamole became apneic. On the other hand, administration of adenosine antagonists 8-p-sulfophenyltheophylline (5 or 8 mg/kg) and aminophylline (10 or 25 mg/kg) significantly prolonged the time required to produce apnea. Only 20% of the animals that received these antagonists became apneic at 7 min of hypoxia. These results suggest that adenosine is potentially involved in the ventilatory depression produced by hypoxia in neonatal rabbit pups.

Somatostatin in the control of respiration.

Somatostatin has been found to induce apnoea when applied into the brain ventricular system (Fuxe et al. 1982, Härfstrand et al. 1985). The site of action of somatostatin was suggested to be in the dorsal respiratory neurons in the medulla oblongata of the rat (Fuxe et al. 1982) where high somatostatin-like immunoreactivity has been detected (Kalia et al. 1984a). In the present study we wanted to further localize the site(s) of action of somatostatin on respiration by microinjection of somatostatin into the medulla oblongata of the cats. We could not detect any inhibitory effect of somatostatin on respiration after microinjection into the nuclear complex of the solitary tract. On the other hand microinjection of somatostatin into the region of nucleus paragigantocellularis lateralis consistently caused apnoea. This finding further supports the idea that this structure functions as an integrative area of respiratory drive inputs.

Respiratory and neuroendocrine responses of piglets to hypoxia during postnatal development.

Breathing response to 12% and 6% O2 in N2 (at isocapnia) was measured in anaesthetized piglets, 1-5 and 19-25 days old, before and after 3 mg kg-1 i.v. naltrexone. The degree of interaction between the anaesthetic and naltrexone was assessed. At the end of each hypoxic trial, arterial blood was sampled for measurements of pH and gas tensions, (Met)enkephalin-Arg6-Phe7, adenosine, noradrenaline and adrenalin. Whereas respiration in older animals was stimulated by hypoxia, young piglets had a biphasic response with a pronounced ventilatory decrease in response to severe hypoxia (6% O2/N2). In young animals there was a greater ventilatory response with naltrexone than without the drug, and the biphasic hypoxic response was ameliorated or reversed by naltrexone. Levels of adrenalin increased and those of encephalin, adenosine and noradrenaline tended to increase during hypoxia in the younger age group. Levels of adenosine showed significant increase when data from both age groups and levels of hypoxia were pooled. Combined with previously reported physiological evidence regarding adenosine in hypoxic depression, we conclude that the present results are compatible with a role of opioid peptides and adenosine in the early postnatal response to hypoxia.

Role of the vagal afferents in substance P-induced respiratory responses in anaesthetized rabbits.

Since substance P (SP)-like immunoreactivity has been demonstrated in vagal sensory fibres of bronchopulmonary origin, it was considered of interest to (1) characterize the pattern of responses to SP injected into the pulmonary as well as the systemic arterial system, and (2) assess the types of vagal afferents that are affected by SP. Experiments were performed on 15 pentobarbital-anaesthetized, spontaneously breathing rabbits. Efferent phrenic nerve activity was monitored as an index of central respiratory neural output. Intra-atrial injections of SP into the pulmonary circulation (100 ng kg-1) increased the respiratory rate, and peak integrated phrenic amplitude by 47 +/- 8 and 40 +/- 4%, respectively, above the controls. In addition, SP elicited augmented breaths (ABs) within 2-3 s in 67% of the trials. In contrast to right atrial injections, no ABs and no significant changes in respiratory rate were observed in response to intra-aortic injections of SP (100 ng kg-1). Tidal phrenic activity rise after aortic injections of SP was significantly less as compared with right atrial administrations of SP. Since both routes of administration decreased the arterial blood pressure to the same extent, these respiratory responses were not likely secondary to cardiovascular changes. After administration of an SP antagonist (D-Arg-D-Trp7,9, Leu11, SP), respiratory responses to SP were significantly attenuated. Also, the rate of occurrence of ABs elicited by releasing the tracheal occlusions was reduced (control 95 vs. 14% SP antagonist). Bilateral vagotomy abolished the tachypnoeic response and reduced the magnitude of the phrenic nerve increments caused by right atrial injection of SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventilatory effect of an adenosine analogue in unanesthetized rabbits during development.

The effect of an adenosine analogue N6-L-(R-phenylisopropyl)adenosine (R-PIA) on respiration was studied in rabbit pups (1-8 days old). Respiration was monitored by a noninvasive barometric method during natural sleep. The adenosine analogue was given by an indwelling intraperitoneal catheter. R-PIA given in a dose of 0.1 mumol/kg (380 micrograms/kg) body wt caused a decrease of the ventilation. The respiratory decrease could be reversed or prevented by pretreatment with theophylline (10 mg/kg). R-PIA caused a considerably more pronounced effect in 1- to 3-day-old animals than in 8-day-old animals. This effect was seen both when the ambient temperature was held at 28 (P less than 0.01) and 32 degrees C (P less than 0.05). Determination of R-PIA receptors in whole brains of rabbit pups of various ages showed that R-PIA bound with higher affinity to membranes from newborn animals (Kd 0.53 nM) than older animals (Kd 0.7-1.26). Since adenosine is released during hypoxia, it may be involved in "hypoxic depression" of respiration in neonates and apnea of prematurity. This might also explain the potent therapeutic effect of the adenosine antagonist theophylline on recurrent apnea in preterm infants.