Electrophysiological responses of the cochlea to transient asphyxia are influenced by arachidonate metabolites

The influence of a transient asphyxia on cochlear potentials, i.e. endolymphatic potential (EP), summating potential (SP) and cochlear microphonics (CM) was investigated in guinea pigs when pretreating the animals with various substances interacting with the arachidonic acid (AA) cascade at the level of thromboxane. The controls showed the well-known decline of the EP, CM and the SP increase. When infusing a thromboxane synthetase inhibitor (dazoxiben) or two different thromboxane receptor blockers (daltroban or sulotraban) before the 3-minutes' period of asphyxia was started, the electrophysiological responses of the inner ear (cochlea) could significantly be influenced. The results indicate that a shift of the thromboxane (TXA₂)/prostacyclin (PGI₂)-balance in favour of the last improve the metabolic conditions for a survival of the cochlea when it is challenged.     

Electrophysiological responses of osteoclasts to hormones

Electrophysiological measurements were carried out on osteoclasts in vitro. Such isolated osteoclasts are able to resorb bone in vitro and contract in response to calcitonin (CT). Our measurements show that individual osteoclasts respond to CT with a significant transient hyperpolarization of membrane potential. Application of parathyroid hormone (PTH) and dibutyryl cAMP produced a transient hyperpolarization in some osteoclasts. Measurements on an osteoblastlike line (ROS 17/2.8) showed a sustained hyperpolarizing response to CT, which is similar to but smaller than the hyperpolarizing response to PTH and dibutyryl cAMP in this and some other osteoblastlike lines. In contrast to osteoblastlike cells, the osteoclasts have no long term membrane potential response to CT, to PTH, or to dibutyryl cAMP. These results show that there are distinct differences between osteoclasts and osteoblasts in their ion transport responses to hormones.     

Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in humans.

Short-term intermittent hypoxia leads to sustained sympathetic activation and a small increase in blood pressure in healthy humans. Because obstructive sleep apnea, a condition associated with intermittent hypoxia, is accompanied by elevated sympathetic activity and enhanced sympathetic chemoreflex responses to acute hypoxia, we sought to determine whether intermittent hypoxia also enhances chemoreflex activity in healthy humans. To this end, we measured the responses of muscle sympathetic nerve activity (MSNA, peroneal microneurography) to arterial chemoreflex stimulation and deactivation before and following exposure to a paradigm of repetitive hypoxic apnea (20 s/min for 30 min; O(2) saturation nadir 81.4 +/- 0.9%). Compared with baseline, repetitive hypoxic apnea increased MSNA from 113 +/- 11 to 159 +/- 21 units/min (P = 0.001) and mean blood pressure from 92.1 +/- 2.9 to 95.5 +/- 2.9 mmHg (P = 0.01; n = 19). Furthermore, compared with before, following intermittent hypoxia the MSNA (units/min) responses to acute hypoxia [fraction of inspired O(2) (Fi(O(2))) 0.1, for 5 min] were enhanced (pre- vs. post-intermittent hypoxia: +16 +/- 4 vs. +49 +/- 10%; P = 0.02; n = 11), whereas the responses to hyperoxia (Fi(O(2)) 0.5, for 5 min) were not changed significantly (P = NS; n = 8). Thus 30 min of intermittent hypoxia is capable of increasing sympathetic activity and sensitizing the sympathetic reflex responses to hypoxia in normal humans. Enhanced sympathetic chemoreflex activity induced by intermittent hypoxia may contribute to altered neurocirculatory control and adverse cardiovascular consequences in sleep apnea.     

Cardiovascular responses to forskolin in the ovine fetus

Six near-term ewes were instrumented to measure regional blood flows in the maternal and fetal subthoracic structures and allowed to recover for 5 days. Control blood flows were measured and 10(-3) molar forskolin was infused in the fetal hindlimb vein at 1 ml/min. After 10 min of infusion, maternal and fetal regional blood flows were measured. The fetal blood pressure was 44 +/- 3 mmHg in the control state and 40 +/- 4 mmHg after forskolin, P less than 0.056. The fetal renal vascular resistance changed from 24.4 +/- 2.4 to 17.5 +/- 1.7 mmHg.ml-1.min.g, P less than 0.005. The placenta had a control resistance of 27.7 +/- 5.0 and 25.6 +/- 5.1 mmHg.ml-1.min.g after forskolin, P less than 0.05. The placental membranes showed vasodilation: control resistance was 261 +/- 49 and 168 +/- 39 mmHg.ml-1.min.g after forskolin, P less than 0.02. The generalized vasodilation of the fetal circulation was paralleled in the maternal circulation. Forskolin, a lipid soluble diterpene, apparently had a placental clearance close to the theoretical maximum. Vasodilation was seen in the maternal renal, placental and uterine vasculatures. Maternal blood pressure was unchanged. Maternal placental vascular resistance was 47.4 +/- 3.0 mmHg.ml-1.min.g in the control state and 40.6 +/- 3.3 mmHg.ml-1.min.g after forskolin, P less than 0.02. Forskolin is a vasodilator in both the fetal and maternal circulations. The maintenance of a relatively normal blood pressure in the face of regional vasodilation shows that forskolin may have a positive inotropic effect on the fetal heart. These results indicate that neither the fetal nor the maternal ovine placental vasculature is maximally dilated in the control state.     

Effects of naloxone on the breathing, electrocortical, heart rate, glucose and cortisol responses to hypoxia in the sheep fetus

Continuous infusions of naloxone HC1 (0.5 mg/kg or 3.8 mg/kg) or saline were given intravenously to fetal sheep at 119 to 137 days of gestation during a one hour period of air administration and a one hour period of hypoxia induced by having ewes breathe 9% O2, 3% CO2 and 88% N2. Fetal carotid PaO2 fell to 13.0 +/- 0.5 mmHg during hypoxia with no change in pH. During hypoxia, plasma cortisol concentration increased significantly more in naloxone-infused fetuses than controls. Ewes, whose fetuses received naloxone, showed a significant increase in cortisol during hypoxia whereas no increase was observed in controls. There were no significant differences between saline and naloxone-infused fetuses during hypoxia in fetal breathing incidence, amplitude, frequency, number of deep inspiratory efforts per hour, heart rate, electrocortical activity or in the rise in plasma glucose caused by hypoxia. Results suggest that endogenous opiates may have a role in modulating cortisol production in the ewe and fetus during hypoxia but do not have a role in mediating the decrease in incidence of breathing activity or rise in plasma glucose. During air administration, naloxone significantly increased fetal breath amplitude, fetal and maternal plasma glucose, fetal heart rate, and the number of electrocortical changes per hour. This suggests endogenous opiates may have a more important role in the normoxic pregnant ewe and fetus.     

Cardiorespiratory and cerebrovascular responses to acute poikilocapnic hypoxia following intermittent and continuous exposure to hypoxia in humans.

We tested the hypothesis that intermittent hypoxia (IH) and/or continuous hypoxia (CH) would enhance the ventilatory response to acute hypoxia (HVR), thereby altering blood pressure (BP) and cerebral perfusion. Seven healthy volunteers were randomly selected to complete 10-12 days of IH (5-min hypoxia to 5-min normoxia repeated for 90 min) before ascending to mild CH (1,560 m) for 12 days. Seven other volunteers did not receive any IH before ascending to CH for the same 12 days. Before the IH and CH, following 12 days of CH and 12-13 days post-CH exposure, all subjects underwent a 20-min acute exposure to poikilocapnic hypoxia (inspired fraction of O(2), 0.12) in which ventilation, end-tidal gases, arterial O(2) saturation, BP, and middle cerebral artery blood flow velocity (MCAV) were measured continuously. Following the IH and CH exposures, the peak HVR was elevated and was related to the increase in BP (r = 0.66 to r = 0.88, respectively; P < 0.05) and to a reciprocal decrease in MCAV (r = 0.73 to r = 0.80 vs. preexposures; P < 0.05) during the hypoxic test. Following both IH and CH exposures, HVR, BP, and MCAV sensitivity to hypoxia were elevated compared with preexposure, with no between-group differences following the IH and/or CH conditions, or persistent effects following 12 days of sea level exposure. Our findings indicate that IH and/or mild CH can equally enhance the HVR, which, by either direct or indirect mechanisms, facilitates alterations in BP and MCAV.     

Electrophysiological responses of crayfish oocytes to biogenic amines

Intracellular recordings were made from immature, growing oocytes of the crayfish Pacifastacus leniusciulus. Oocytes had a relatively negative resting potential of -74.7+/-2.2 mV (n=26; range -53 to -90) and a mean input resistance of 0.86+/-0.19 MOmega (n=22; range 0.17-3.3). Octopamine induced a long-lasting response involving biphasic changes in input resistance, together with bi- or multiphasic changes in membrane potential. The resistance-decreasing phase involved (in different oocytes) membrane hyperpolarization, depolarization or both. The resistance-increasing phase was usually a depolarization. The hyperpolarizing form of the resistance-decreasing response, and the depolarizing resistance-increasing response reversed in polarity at membrane potentials of (respectively) -90 and -92 mV, suggesting increases and decreases in K(+) conductance underly the biphasic changes in input resistance. The threshold concentration for the response was remarkably low (>10(-12) M) and showed little or no dose-dependence over the concentration range 10(-12)-10(-6) M. Similar responses were evoked by dopamine and serotonin (at 10(-9) M), although a higher proportion of oocytes responded to octopamine and/or dopamine than to serotonin.     

Pulmonary maturation in the hypophysectomised ovine fetus. Differential responses to adrenocorticotrophin and cortisol

Pulmonary maturation in six ovine fetuses hypophysectomised by a cryosurgical method at 0.7-0.8 of pregnancy and delivered by hysterotomy at 152.2 +/- 2.9 (SD) days was compared with that in seven control fetuses delivered at 144.5 +/- 3.5 days. Both the wet and the dry weight of the lungs was less in the hypophysectomised fetuses but total DNA did not differ. Lung volumes at 40 cm of H2O and at 5 cm of H2O on deflation in hypophysectomised fetuses were less than one-third that of controls. Saturated phosphatidylcholine, as an estimate of surfactant, was lower in both lung tissue and lavage fluid. A further group of hypophysectomised fetuses was infused intravenously either with cortisol at 1 mg/h for 72 h (n = 6), or with ACTH1-24 at 5 microgram/h for 84 h (n = 6) before delivery at 155.0 +/- 2.1 days and 154.2 +/- 3.9 days respectively. None of the indices of pulmonary maturation in the cortisol-treated fetuses differed from those in untreated hypophysectomised fetuses whereas values for lung volumes at 40 and 5 cm of H2O in ACTH-treated fetuses were more than twice those of untreated hypophysectomised fetuses and did not differ significantly from controls. In addition, the amount of saturated phosphatidylcholine in lavage fluid was greater in ACTH-treated fetuses (0.13 +/- 0.10 mg/g) than in untreated hypophysectomised fetuses (0.04 +/- 0.48 mg/g). Lung volume at 40 cm of H2O in four fetuses that were thyroidectomised at the time of hypophysectomy responded to ACTH as in hypophysectomised fetuses with intact thyroids but other indices were unaffected. We conclude that hypophysectomy retards pulmonary maturation in fetal sheep. Since ACTH restores distensibility and increases alveolar surfactant in the absence of other pituitary hormones it is likely that ACTH has a major role in lung maturation. The lack of response to cortisol suggests that the effect of ACTH is not mediated only by circulating cortisol.     

Developmental responses to high altitude hypoxia

From a review of published literature on developmental responses to high altitude, three major conclusions are derived. First, the small birth weight of high altitude native populations are adaptive responses to reduce the oxygen requirements, while the relative increase in the placental weight is a compromise mechanism to increase the volume and surface area for a better oxygenation. Second, the small stature of the high altitude native is due to slow prenatal and postnatal growth. Third, the enlarged chest size, increased lung volumes and predominance of the right ventricle of the heart are due to accelerated development during childhood and adolescence. However, there is not adequate information to determine whether or not the developmental responses of the high altitude native are population-specific, based on a genetic structure different from that of sea level populations. Hence, the need for further study of developmental factors is emphasized.     

Adrenocortical responses to adrenocorticotrophin in the hypophysectomized ovine fetus

Fetal adrenocortical responsiveness to ACTH declines during 90-120 days gestation and fetal pituitary peptides have been implicated in this refractoriness. In these studies the ACTH-induced cortisol responses were measured in 11 ovine fetuses of 114 days gestation. Five animals were hypophysectomized as evidenced by prolonged gestation, pituitary histology, TRH-testing, delayed maturation and decreasing fetal plasma prolactin concentrations (less than 1 ng.ml-1) (P less than 0.005). Resting cortisol concentrations decreased from 22.4 to 8.1 ng.ml-1 in the hypophysectomy group and were not different from the control group (19.6-14.9 ng.ml-1) over the 5 days of study. Responses measured as increments in plasma cortisol concentrations increased equally and successively in both groups. Since pituitary ablation fails to enhance fetal adrenal responsiveness to ACTH we conclude that refractoriness is unlikely to be caused by an inhibitor of pituitary origin.     

Electrophysiological and contractile responses of canine atrial tissue to adrenocorticotropin

The direct extra-adrenal actions of adrenocorticotropin 1-39 (ACTH) on electrical (E) and mechanical (M) characteristics of canine atrial tissues (AT) were investigated in in vitro experiments. One hundred twenty-five mU/ml of ACTH 1-39 significantly augmented the catecholamine induced positive inotropism as seen by shortening the time to peak tension (10.6%, p = 0.01) and increasing peak isometric tension (3.5 times, p = 0.001). Effects on the M responses were inhibited by propranolol (10(-6) M) (P). ACTH did not significantly modify action potential E or M parameters during cholinergic receptor antagonism or alpha-adrenergic receptor antagonism. Existence of a specific ACTH receptor was demonstrated using 125I radioiodinated ACTH 1-24. Significant binding of 125I-ACTH to AT was observed. Intracellular C-AMP levels were also measured in AT using radioimmunoassay. Tissues were exposed to 125mU/ml ACTH 1-39 plus combinations of norepinephrine (10(-6) M) (NE) and P. ACTH alone did not elevate intracellular C-AMP levels. NE increased C-AMP levels were not further increased by ACTH. Exposure to antagonist returned elevated C-AMP levels to control values. In conclusion (1) ACTH augments the NE induced M positive inotropism of the beta adrenergic receptor system. (2) ACTH specifically binds to AT and (3) ACTH does not utilize the C-AMP second messenger system.     

Chronic hypoxia attenuates nitric oxide-dependent hemodynamic responses to acute hypoxia

Alterations in the nitric oxide (NO) pathway have been implicated in the pathogenesis of chronic hypoxia-induced pulmonary hypertension. Chronic hypoxia can either suppress the NO pathway, causing pulmonary hypertension, or increase NO release in order to counteract elevated pulmonary arterial pressure. We determined the effect of NO synthase inhibitor on hemodynamic responses to acute hypoxia (10% O(2)) in anesthetized rats following chronic exposure to hypobaric hypoxia (0.5 atm, air). In rats raised under normoxic conditions, acute hypoxia caused profound systemic hypotension and slight pulmonary hypertension without altering cardiac output. The total systemic vascular resistance (SVR) decreased by 41 +/- 5%, whereas the pulmonary vascular resistance (PVR) increased by 25 +/- 6% during acute hypoxia. Pretreatment with N(omega)-nitro-L-arginine methyl ester (L-NAME; 25 mg/kg) attenuated systemic vasodilatation and enhanced pulmonary vasoconstriction. In rats with prior exposure to chronic hypobaric hypoxia, the baseline values of mean pulmonary and systemic arterial pressure were significantly higher than those in the normoxic group. Chronic hypoxia caused right ventricular hypertrophy, as evidenced by a greater weight ratio of the right ventricle to the left ventricle and the interventricular septum compared to the normoxic group (46 +/- 4 vs. 28 +/- 3%). In rats which were previously exposed to chronic hypoxia (half room air for 15 days), acute hypoxia reduced SVR by 14 +/- 6% and increased PVR by 17 +/- 4%. Pretreatment with L-NAME further inhibited the systemic vasodilatation effect of acute hypoxia, but did not enhance pulmonary vasoconstriction. Our results suggest that the release of NO counteracts pulmonary vasoconstriction but lowers systemic vasodilatation on exposure to acute hypoxia, and these responses are attenuated following adaptation to chronic hypoxia.     

Dopamine does not limit fetal cerebrovascular responses to hypoxia.

Dopamine is used clinically to stabilize mean arterial blood pressure (MAP) in sick infants. One goal of this therapeutic intervention is to maintain adequate cerebral blood flow (CBF) and perfusion pressure. High-dose intravenous dopamine has been previously demonstrated to increase cerebrovascular resistance (CVR) in near-term fetal sheep. We hypothesized that this vascular response might limit cerebral vasodilatation during acute isocapnic hypoxia. We studied nine near-term chronically catheterized unanesthetized fetal sheep. Using radiolabeled microspheres to measure fetal CBF, we calculated CVR at baseline, during fetal hypoxia, and then with the addition of an intravenous dopamine infusion at 2.5, 7.5, and 25 microg.kg(-1).min(-1) while hypoxia continued. During acute isocapnic fetal hypoxia, CBF increased 73.0 +/- 14.1% and CVR decreased 38.9 +/- 4.9% from baseline. Dopamine infusion at 2.5 and 7.5 microg.kg(-1).min(-1), begun during hypoxia, did not alter CVR or MAP, but MAP increased when dopamine infusion was increased to 25 microg.kg(-1).min(-1). Dopamine did not alter CBF or affect the CBF response to hypoxia at any dose. However, CVR increased at a dopamine infusion rate of 25 microg.kg(-1).min(-1). This increase in CVR at the highest dopamine infusion rate is likely an autoregulatory response to the increase in MAP, similar to our previous findings. Therefore, in chronically catheterized unanesthetized near-term fetal sheep, dopamine does not alter the expected cerebrovascular responses to hypoxia.     

Thermoregulatory and metabolic responses of Japanese quail to hypoxia

Common responses to hypoxia include decreased body temperature (T_b) and decreased energy metabolism. In this study, the effects of hypoxia and hypercapnia on T_b and metabolic oxygen consumption (V.O₂) were investigated in Japanese quail (Coturnix japonica). When exposed to hypoxia (15, 13, 11 and 9% O₂), T_b decreased only at 11% and 9% O₂ compared to normoxia; quail were better able to maintain T_b during acute hypoxia after a one-week acclimation to 10% O₂. V.O₂ also decreased during hypoxia, but at 9% O₂ this was partially offset by increased anaerobic metabolism. T_b and V.O₂ responses to 9% O₂ were exaggerated at lower ambient temperature (T_a), reflecting a decreased lower critical temperature during hypoxia. Conversely, hypoxia had little effect on T_b or V.O₂ at higher T_a (36 °C). We conclude that Japanese quail respond to hypoxia in much the same way as mammals, by reducing both T_b and V.O₂. No relationship was found between the magnitudes of decreases in T_b and V.O₂ during 9% O₂, however. Since metabolism is the source of heat generation, this suggests that Japanese quail increase thermolysis to reduce T_b. During hypercapnia (3, 6 and 9% CO₂), T_b was reduced only at 9% CO₂ while V.O₂ was unchanged.     

Fetal cardiovascular responses to asphyxia induced by decreased uterine perfusion

Cardio-respiratory responses to asphyxia produced by decreased uterine perfusion were studied in 15 sheep fetuses. In chronic (spinal-anesthetized) and acute (inhalation-anesthetized) preparations, we measured fetal PO2, PCO2, pH, heart rate, arterial and umbilical venous pressures at rest and 5 min after controlled reductions of maternal aortic blood flow. Umbilical blood flow was determined by electromagnetic flow transducer on the fetal descending aorta with the iliac arteries ligated, in conjunction with radionuclide-labelled microspheres. In contrast to previous studies in which fetal hypoxaemia was produced by decreased maternally inspired O2 concentrations, decreasing degrees of uterine perfusion were associated with increasing degrees of hypercapnea and acidemia, as well as hypoxaemia. In chronic experiments, heart rate and umbilical blood flow fell significantly in response to decreased uterine perfusion with all degrees of hypoxaemia studied. In acute experiments, during the control period, PO2 values were similar to those of chronic experiments while values for pH and umbilical blood flow were lower and those for umbilical vascular resistance were higher. In the acute experiments, hypoxic stresses identical to those in the chronic studies failed to produce significant hemodynamic changes, except for bradycardia in response to severe hypoxaemia. These differences were apparently due to the pharmacologic effects of halothane and the operative stresses.     

Cardiorespiratory responses of the woodchuck and porcupine to CO2 and hypoxia

Summary The burrow-dwelling woodchuck (Marmota monax) (mean body wt.=4.45±1 kg) was compared to a similar-sized (5.87±1.5 kg) but arboreal rodent, the porcupine (Erithrizon dorsatum), in terms of its ventilatory and heart rate responses to hypoxia and hypercapnia, and its blood characteristics.V _T,f,T _I andT _E were measured by whole-body plethysmography in four awake individuals of each species. The woodchuck has a longerT _E/T _TOT (0.76±0.03) than the porcupine (0.61±0.03). The woodchuck had a higher threshold and significantly smaller slope to its CO₂ ventilatory response compared to the porcupine, but showed no difference in its hypoxic ventilatory response. The woodchuck P₅₀ of 27.8 was hardly different from the porcupine value of 30.7, but the Bohr factor, –0.72, was greater than the porcupine's, –0.413. The woodchuck breathing air has PaCO₂=48 (±2) torr, PaO₂=72 (±6), pHa=7.357 (±0.01); the porcupine blood gases are PaCO₂=34.6 (±2.8), PaO₂=94.9 (±5), pHa=7.419 (±0.03), suggesting a difference in PaCO₂/pH set points. The woodchuck exhibited no reduction in heart rate with hypoxia, nor did it have the low normoxic heart rate observed in other burrowing mammals.