Effect of resistive loading on ventilatory response to hypoxia.

Ventilatory responses to hypoxia, with and without an inspiratory resistive load, were measured in eight normal subjects, using a rebreathing technique. During the studies, the end-tidal P-CO2 was kept constant at mixed venous level (Pv-CO2) by drawing expired gas through a variable CO2-absorbing bypass. The initial bag O2 concentration was 24% and rebreathing was continued until the O2 concentration in the bag fell to 6% or the subject's arterial oxygen saturation (Sa-O2), monitored continuously by ear oximetry, fell to 70%. Studies with and without the load were performed in a formally randomized order for each subject. Linear regressions for rise in ventilation against fall in Sa-O2 were calculated. The range of unloaded responses was 0.78-3.59 1/min per 1% fall in Sa-O2 and loaded responses 0.37-1.68 1/min per 1% fall in Sa-O2. In each subject, the slope of the response curve during loading fell by an almost constant fraction of the unloaded response, such that the ratio of loaded to unloaded slope in all subjects ranged from 0.41 to 0.48. However, the extrapolated intercept of the response curve on the Sa-O2 axis did not alter significantly indicating that the P-CO2 did not alter between experiments. These results suggest that the change in ventilatory response to hypoxia during inspiratory resistive loading is related to the mechanical load applied, with the loaded slope being directly proportional to the unloaded one.     

Effect of elastic loading on ventilatory response to hypoxia in conscious man.

Ventilatory responses to isocapnic hypoxia, with and without an inspiratory elastic load (12.1 cmH2O/l), were measured in seven healthy subjects using a rebreathing technique. During each experiment, the end-tidal PCO2 was held constant using a variable-speed pump to draw gas from the rebreathing bag through a CO2 absorbing bypass. Studies with and without the load were performed in a formally randomized order for each subject. Linear regressions for rise in ventilation against fall in SaO2 were calculated. The range of unloaded responses was 0.74-1.38 1/min per 1% fall in SaO2 and loaded responses 0.71-1.56 1/min per 1% fall in SaO2. Elastic loading did not significantly alter the ventilatory response to progressive hypoxia (P greater than 0.2). In all subjects there was, however, a change in breathing pattern during loading, whereby increments in ventilation were attained by smaller tidal volumes and higher frequencies than in the control experiments. These results support the hypothesis previously proposed in our studies of resistive loading during progressive hypoxia, that a similar control pathway appears to be involved in response to the application of loads to breathing, whether ventilation is stimulated by hypoxia or hypercapnia.     

Pseudorandom testing of ventilatory response to inspired carbon dioxide in man

A new method of testing the transient ventilatory response to inspired CO2 in humans has been developed in an attempt to improve the resolution and reproducibility of measures of peripheral chemoreceptor-mediated dynamics. The test input consisted of varying the level of inspired CO2 between 0 and 6-8% on a pseudorandom breath-by-breath basis. Cross-correlating this input with responses of end-tidal CO2, tidal volume, durations of inspiration and expiration, and respiratory rate yielded estimates of impulse responses. Computer simulation results and data collected in two subjects showed that reliable estimates of circulatory time lags and rapid dynamics are possible with this method. In one subject, the response dynamics observed were consistent with peripheral chemoreceptor rate sensitivity or adaptation. The rapid changes in inspiratory and expiratory durations also observed are probably mediated by peripheral chemoreceptors and appear to depend on the phase of the breathing cycle at which the CO2 stimulus arrives.     

Effect of hypoxia on immediate ventilatory load response in dogs.

The effective elastance of the respiratory system (which has been previously shown to provide an index of the ability of the respiratory musculature to compensate rapidly for transient mechanical ventilatory loads) was measured in six hypoxic dogs to determine whether hypoxia hindered immediate load-compensatory mechanisms. The effective elastance value was computed from measurements of control tidal volume and the pressure developed at the airway opening during the first inspiratory effort following airway occlusion at FRC. The mean effective elastance was 197 cmH2O/l while the animals were breathing room air and did not change significantly when the animals were rendered hypoxic by reducing the inspired oxygen concentration, in five dogs, or by controlled hemorrhage, in two dogs. It was concluded that inasmuch as effective elastance measurements remain constant during hypoxia, the stability of ventilation is not significantly impaired in this situation.     

Effects of human pregnancy on the ventilatory chemoreflex response to carbon dioxide

This study examined the effects of human pregnancy on the central chemoreflex control of breathing. Subjects were two groups (n=11) of pregnant subjects (PG, gestational age, 36.5+/-0.4 wk) and nonpregnant control subjects (CG), equated for mean age, body height, prepregnant body mass, parity, and aerobic fitness. All subjects performed a hyperoxic CO2 rebreathing procedure, which includes prior hyperventilation and maintenance of iso-oxia. Resting blood gases and plasma progesterone and estradiol concentrations were measured. During rebreathing trials, end-tidal Pco2 increased, whereas end-tidal Po2 was maintained at a constant hyperoxic level. The point at which ventilation (Ve) began to rise as end-tidal Pco2 increased was identified as the central chemoreflex ventilatory recruitment threshold for CO2 (VRTco2). Ve levels below (basal Ve) and above (central chemoreflex sensitivity) the VRTco2 were determined. The VRTco2 was significantly lower in the PG vs. CG (40.5+/-0.8 vs. 45.8+/-1.6 Torr), and both basal Ve (14.8+/-1.1 vs. 9.3+/-1.6 l/min) and central chemoreflex sensitivity (5.07+/-0.74 vs. 3.16+/-0.29 l.min-1.Torr-1) were significantly higher in the PG vs. CG. Pooled data from the two groups showed significant correlations for resting arterial Pco2 with basal Ve, central chemoreflex sensitivity, and the VRTco2. The VRTco2 was also correlated with progesterone and estradiol concentrations. These data support the hypothesis that pregnancy decreases the threshold and increases the sensitivity of the central chemoreflex response to CO2. These changes may be due to the effects of gestational hormones on chemoreflex and/or nonchemoreflex drives to breathe.     

Effect of atrial natriuretic factor on the plasma aldosterone response to potassium infusion in rats--in vivo study

Previous in vitro studies have shown that atrial natriuretic factor inhibits the secretion of aldosterone stimulated by AII, ACTH, and potassium in adrenal cell suspensions. The present study investigated the effects of atriopeptin II on the plasma aldosterone response to a potassium infusion in conscious unrestrained rats in vivo. The infusion of potassium chloride solution increased plasma aldosterone level from 20.4 +/- 3.7 to 168.4 +/- 27.3 ng/dl. The simultaneous administration of atriopeptin II reduced the increase in plasma aldosterone level (16.0 +/- 2.1 to 63.3 +/- 10.4 ng/dl). There was no significant difference in the plasma renin activity, corticosterone, or serum potassium levels between the two groups. These results suggest that atriopeptin II may be important in the regulation of aldosterone secretion.     

Intermittent hypoxia augments carotid body and ventilatory response to hypoxia in neonatal rat pups.

Carotid bodies are functionally immature at birth and exhibit poor sensitivity to hypoxia. Previous studies have shown that continuous hypoxia at birth impairs hypoxic sensing at the carotid body. Intermittent hypoxia (IH) is more frequently experienced in neonatal life. Previous studies on adult animals have shown that IH facilitates hypoxic sensing at the carotid bodies. On the basis of these studies, in the present study we tested the hypothesis that neonatal IH facilitates hypoxic sensing of the carotid body and augments ventilatory response to hypoxia. Experiments were performed on 2-day-old rat pups that were exposed to 16 h of IH soon after the birth. The IH paradigm consisted of 15 s of 5% O2 (nadir) followed by 5 min of 21% O2 (9 episodes/h). In one group of experiments (IH and control, n = 6 pups each), sensory activity was recorded from ex vivo carotid bodies, and in the other (IH and control, n = 7 pups each) ventilation was monitored in unanesthetized pups by plethysmography. In control pups, sensory response of the carotid body was weak and was slow in onset (approximately 100 s). In contrast, carotid body sensory response to hypoxia was greater and the time course of the response was faster (approximately 30 s) in IH compared with control pups. The magnitude of the hypoxic ventilatory response was greater in IH compared with control pups, whereas changes in O2 consumption and CO2 production during hypoxia were comparable between both groups. The magnitude of ventilatory stimulation by hyperoxic hypercapnia (7% CO2-balance O2), however, was the same between both groups of pups. These results demonstrate that neonatal IH facilitates carotid body sensory response to hypoxia and augments hypoxic ventilatory chemoreflex.     

The prolactin response to intravenous dextroamphetamine in normal young men and postmenopausal women

D-amphetamine was administered intravenously in doses of 0.1 mg/kg and 0.15 mg/kg to normal young men and postmenopausal women in both morning and evening. No suppression of PRL secretion after amphetamine was found, and, in the postmenopausal women, no significant change in PRL levels in any dose or time condition occured. However, a significant and relatively consistent PRL release was induced in the young men in the evening by the higher dose. This latter response suggests that, in humans, dextroamphetamine can actually stimulate prolactin perhaps by a mechanism other than alteration in dopaminergic tone.     

Renal response to intravenous phosphate infusion in the sheep.

Renal clearance experiments were performed on six Merino ewes in which plasma phosphate concentrations were increased by the intravenous infusion of isohydric sodium phosphate. As the phosphate load to the kidney increased, the renal tubular reabsorptive capacity became saturated and a definite tubular maximum for phosphate reabsorption (Tmp) was demonstrated. The Tmp was directly related to the glomerular filtration rate and had a mean value of 333-1+/-27-0 (s.e.m.) mumol/min or 416-6+/-13-5 mumol/100 ml glomerular filtrate. Calcium infused concurrently with phosphate in order to maintain plasma total calcium levels did not alter the Tmp. Ultrafilterability of calcium and phosphate in the plasma decreased with phosphate infusion and this was accentuated by an accompanying calcium infusion. The Tmp in sheep's kidney is higher than in non-ruminant animals and the implications of this are discussed.     

Naloxone accelerates the rate of ventilatory acclimatization to hypoxia in awake rats

During ventilatory acclimatization to hypoxia in rats, PaCO2 progressively falls from about 40 torr in normoxia (PIO2 approximately equal to 150 torr) to a new steady-state at about 23 torr in chronic hypoxia (24 or more hours at PIO2 approximately equal to 90 torr). In acute (20 or 60 minutes) hypoxia naloxone treatment caused a hyperventilation greater than that caused by acute hypoxia alone. Following 20 minutes hypoxia, naloxone treated rats had a PaCO2 = 28.6 +/- 0.7 torr (mean +/- 95% confidence limits) which was significantly lower (P less than .001) than the saline treated PaCO2 = 31.0 +/- 0.6 torr. In contrast, in normoxia and at 24 hour hypoxia and at 20 minute return to normoxia following 24 hours hypoxia, naloxone treatment had no effect on PaCO2. We conclude that in the rat about one third of the ventilatory acclimatization to hypoxia is due to a progressively decreasing endogenous opioid-like inhibition of ventilation.     

Effect of intravenous epinephrine infusion on plasma renin activity in adrenalectomized dogs

Previous experiments have shown that circulating epinephrine stimulates renin secretin and increases plasma renin activity (PRA) when it is infused intravenously, but not when it is infused directly into the renal artery at similar infusion rates. The present experiments were designed to test the hypothesis that the adrenal glands mediate the PRA response to intravenous epinephrine infusion. Accordingly, anesthetized dogs were prepared with either an acute bilateral adrenalectomy or a sham-adrenalectomy procedure. Epinephrine was then infused intravenously into each animal for 45 minutes at a rate of 25 ng X kg-1 X min-1. Time control experiments in which epinephrine was not infused were also conducted. In sham-adrenalectomized dogs, PRA (in nanograms per ml h-1) rose from 4.1 +/- 1.4 in the control period to 13.0 +/- 3.0 during intravenous epinephrine infusion (means +/- SE; p less than 0.01). In adrenalectomized dogs, PRA rose from 2.1 +/- 0.4 during the control period to 5.5 +/- 0.9 during intravenous epinephrine infusion (p less than 0.01). Neither the absolute increments in PRA nor the percent increases in PRA were significantly different between the two groups receiving epinephrine. PRA remained unchanged in time control experiments. These data demonstrate that the adrenal glands need not be present in order for intravenous epinephrine infusion to elicit an increase in PRA. The data do not support the hypothesis, therefore, that epinephrine-induced increases in PRA are initiated by receptors located within the adrenal glands.     

Time course of air hunger mirrors the biphasic ventilatory response to hypoxia.

Determining response dynamics of hypoxic air hunger may provide information of use in clinical practice and will improve understanding of basic dyspnea mechanisms. It is hypothesized that air hunger arises from projection of reflex brain stem ventilatory drive ("corollary discharge") to forebrain centers. If perceptual response dynamics are unmodified by events between brain stem and cortical awareness, this hypothesis predicts that air hunger will exactly track ventilatory response. Thus, during sustained hypoxia, initial increase in air hunger would be followed by a progressive decline reflecting biphasic reflex ventilatory drive. To test this prediction, we applied a sharp-onset 20-min step of normocapnic hypoxia and compared dynamic response characteristics of air hunger with that of ventilation in 10 healthy subjects. Air hunger was measured during mechanical ventilation (minute ventilation = 9 +/- 1.4 l/min; end-tidal Pco(2) = 37 +/- 2 Torr; end-tidal Po(2) = 45 +/- 7 Torr); ventilatory response was measured during separate free-breathing trials in the same subjects. Discomfort caused by "urge to breathe" was rated every 30 s on a visual analog scale. Both ventilatory and air hunger responses were modeled as delayed double exponentials corresponding to a simple linear first-order response but with a separate first-order adaptation. These models provided adequate fits to both ventilatory and air hunger data (r(2) = 0.88 and 0.66). Mean time constant and time-to-peak response for the average perceptual response (0.36 min(-1) and 3.3 min, respectively) closely matched corresponding values for the average ventilatory response (0.39 min(-1) and 3.1 min). Air hunger response to sustained hypoxia tracked ventilatory drive with a delay of approximately 30 s. Our data provide further support for the corollary discharge hypothesis for air hunger.     

The metabolism of prostaglandin D2 after inhalation or intravenous infusion in normal men

Tritium-labelled prostaglandin D2 (PGD2) was administered to normal volunteers by either intravenous infusion or inhalation in order to establish which metabolites of PGD2 are initially found in human plasma. Inhaled PGD2 was rapidly absorbed from the airways, as indicated by the rapid appearance of tritium in the plasma. Metabolites chromatographically similar to 9 alpha,11 beta-PGF2 and 13,14-dihydro-15-keto-9 alpha,11 beta-PGF2 were found after both routes of administration. At later time points, other unidentified compounds were present. Only after intravenous infusion was there evidence of metabolites with 9 alpha,11 alpha stereochemistry of the ring hydroxyl functions. In human lung, 9 alpha,11 beta-PGF2 was metabolized in the presence of NAD+ to compounds tentatively identified by gas chromatography/mass spectrometry (GC/MS) as 15-keto-9 alpha,11 beta-PGF2 and 13,14-dihydro-15-keto-9 alpha,11 beta-PGF2. Thus, after 11-ketoreductase-dependent metabolism of PGD2 to the biologically active compound 9 alpha,11 beta-PGF2, further metabolism probably proceeds by the combined action of 15-hydroxyprostaglandin dehydrogenase/15-ketoprostaglandin-delta 13-reductase (15-PGDH/delta 13R). Both 9 alpha,11 beta-PGF2 and its 13,14-dihydro-15-keto metabolite may be useful analytes for the measurement of PGD2 turnover, and may therefore prove to be important in understanding the pathophysiological significance of this putative mediator.     

Effect of baroreceptor activity on ventilatory response to chemoreceptor stimulation.

This study tested the hypothesis that ventilatory responses to chemoreceptor stimulation are affected by the level of arterial pressure and degree of baroreceptor activation. Carotid chemoreceptors were stimulated by injection of nicotine into the common carotid artery of anesthetized dogs. Arterial pressure was reduced by bleeding the animals and raised by transient occlusion of the abdominal aorta. The results indicate that ventilatory responses to chemoreceptor stimulation were augmented by hypotension and depressed by hypertension. In additional studies we excluded the possibility that the findings were produced by a direct effect of changes in arterial pressure on chemoreceptors. Both carotid bifurcations were perfused at constant flow. In one carotid bifurcation, perfusion pressure was raised to stimulate carotid sinus baroreceptors. In the other carotid bifurcation, pressure was constant and nicotine was injected to stimulate carotid chemoreceptors. Stimulation of baroreceptors on one side attenuated the ventilatory response to stimulation of contralateral chemoreceptors. This inhibition was observed before and after bilateral cervical vagotomy. We conclude that there is a major central interaction between baroreceptor and chemoreceptor reflexes so that changes in baroreceptor activity modulate ventilatory responses to chemoreceptor stimulation.