Pulmonary arterial pressure-flow plots in dogs: effects of isoflurane and nitroprusside

We investigated the effects of nitroprusside and isoflurane on multipoint pulmonary arterial pressure (PAP)/cardiac index (Q) plots in pentobarbital sodium-anesthetized dogs ventilated alternatively in hyperoxia (fraction of inspired O2, FIO2, 0.4) and hypoxia (FIO2 0.1). Over the entire range of Q studied, 2-5 l.min-1.m-2, hypoxia increased PAP in 16 dogs ("responders") and did not affect PAP in 16 other dogs ("nonresponders"). A hypoxic pulmonary vasoconstriction (HPV) was restored in the nonresponders by intravenous administration of 1 g of acetylsalicylic acid (ASA). Nitroprusside (5 micrograms.kg-1.min-1) inhibited HPV in responders (n = 8) and nonresponders treated with ASA (n = 8). End-tidal 1.41% isoflurane (a minimal alveolar concentration equal to one for dogs) did not affect HPV in responders (n = 8) and nonresponders treated with ASA (n = 8). In the latter group isoflurane increased PAP at the highest Q studied (3-5 l.min-1.m-2) in hyperoxia and hypoxia. In a final group of eight dogs with Q kept constant, PAP remained unchanged during two consecutive sequences of alternated 30-min periods (maximum time to generate a PAP/Q plot) successively at FIO2 0.4 and 0.1, and the hypoxia-induced increase in PAP was reproducible. Thus the present experimental model appeared suitable for the study of the effects of hypoxia and drugs on pulmonary vascular tone of intact dogs. At the given doses HPV was inhibited by nitroprusside and not affected by isoflurane. Products of arachidonic acid metabolism possibly could be implicated in the pulmonary vascular effects of isoflurane.     

PEEP inhibits hypoxic pulmonary vasoconstriction in dogs

The effects of an increase in alveolar pressure on hypoxic pulmonary vasoconstriction (HPV) have been reported variably. We therefore studied the effects of positive end-expiratory pressure (PEEP) on pulmonary hemodynamics in 13 pentobarbital-anesthetized dogs ventilated alternately in hyperoxia [inspired O2 fraction (FIO2) 0.4] and in hypoxia (FIO2 0.1). In this intact animal model, HPV was defined as the gradient between hypoxic and hyperoxic transmural (tm) mean pulmonary arterial pressure [Ppa(tm)] at any level of cardiac index (Q). Ppa(tm)/Q plots were constructed with mean transmural left atrial pressure [Pla(tm)] kept constant at approximately 6 mmHg (n = 5 dogs), and Ppa(tm)/PEEP plots were constructed with Q kept constant approximately 2.8 l.min-1.m-2 and Pla(tm) kept constant approximately 8 mmHg (n = 8 dogs). Q was manipulated using a femoral arteriovenous bypass and a balloon catheter in the inferior vena cava. Pla(tm) was held constant by a balloon catheter placed by left thoracotomy in the left atrium. Increasing PEEP, from 0 to 12 Torr by 2-Torr increments, at constant Q and Pla(tm), increased Ppa(tm) from 14 +/- 1 (SE) to 19 +/- 1 mmHg in hyperoxia but did not affect Ppa(tm) (from 22 +/- 2 to 23 +/- 1 mmHg) in hypoxia. Both hypoxia and PEEP, at constant Pla(tm), increased Ppa(tm) over the whole range of Q studied, from 1 to 5 l/min, but more at the highest than at the lowest Q and without change in extrapolated pressure intercepts. Adding PEEP to hypoxia did not affect Ppa(tm) at all levels of Q.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sinoaortic deafferentation reduces intrapulmonary shunt in dogs with oleic acid lung injury

Hypoxic stimulation of the peripheral chemoreceptors has been reported to inhibit hypoxic pulmonary vasoconstriction. To evaluate the pathophysiological importance of this observation, we investigated the effects of surgical peripheral chemoreceptor denervation on pulmonary vascular tone and gas exchange in 17 pentobarbital-anesthetized dogs with oleic acid pulmonary edema. Pulmonary arterial pressure-cardiac index (Ppa/Q) plots, blood gases, and intrapulmonary shunt measured by the SF6 method were obtained at base line, after peripheral chemodenervation (n = 9) or after sham operation (n = 8), and again after 0.09 ml.kg-1 intravenous oleic acid. Over the range of Q studied (2-5 l.min-1.m-2), Ppa/Q plots were best fitted as first-order polynomials in most dogs in all experimental conditions. Chemoreceptor denervation increased Ppa at the lowest Q, while sham operation did not affect the Ppa/Q plots. Oleic acid increased Ppa over the entire range of Q and increased intrapulmonary shunt. This latter was measured at identical Q during the construction of the Ppa/Q plots. Chemoreceptor-denervated dogs, compared with sham-operated dogs, had the same pulmonary hypertension but lower intrapulmonary shunt (36 +/- 4 vs. 48 +/- 5%, means +/- SE, P less than 0.04) and venous admixture (43 +/- 4 vs. 54 +/- 3%, P less than 0.02). We conclude that in intact dogs chemoreceptor denervation attenuates the rise in intrapulmonary shunt after oleic acid lung injury. Whether this improvement in gas exchange is related to an enhanced hypoxic pulmonary vasoconstriction is uncertain.     

The response of few-fiber carotid chemoreceptor preparations to almitrine in the dog

Almitrine, a long-lasting peripheral chemoreceptor stimulant, was given to nine dogs via intracarotid injection. Carotid chemoreceptor activity was recorded from single or few-fiber afferent nerve preparations. Doses of 10-20 microgram/kg were generally sufficient to produce a brisk stimulatory response of less than 30 min duration. In four dogs decreasing arterial PO2 was found to allow a greater than additive response to almitrine. Infusions of NaHCO3 appeared to depress the response to almitrine whereas changing arterial PCO2 had little effect on the carotid chemoreceptor response to almitrine. Neither dopamine infusion nor dopamine receptor blockade altered the responsiveness of the carotid chemoreceptors to almitrine.     

Almitrine mimics hypoxia in fetal sheep with lateral pontine lesions

Almitrine bimesylate is a potent and long-lasting respiratory stimulant in adult species. It acts by stimulating the peripheral chemoreceptors, where it has been shown to accumulate specifically, although its exact mechanism of action is uncertain. In the fetal lamb, however, it produces a profound inhibition of breathing even after denervation of the peripheral chemoreceptors. In this respect its action is similar to hypoxia. To investigate whether almitrine is hypoxia mimetic, we examined the effect of almitrine in nine fetal lambs of 120-130 days gestation. Five had lesions in the lateral pons that changed the fetal depressive response to hypoxia to one of stimulation. In the remaining four fetuses, the lesions did not bilaterally encompass the appropriate area of the pons; thus they still showed the normal fetal depressive response to hypoxia and so acted as controls. Almitrine (10 mg iv) caused a pronounced stimulation of breathing that lasted 406 +/- 26 min in all five fetuses with lesions that caused a stimulatory response to hypoxia. However, in the remaining four fetuses, in which the response to hypoxia was inhibitory, almitrine caused an inhibition of breathing that lasted 184 +/- 28 min. We conclude that the action of almitrine is like that of hypoxia and that, because it acts specifically on the chemoreceptors, it may prove to be a useful tool in the study of possible central chemoreceptor mechanisms.     

Ventilatory, circulatory, endocrine, and renal effects of almitrine infusion in man: a contribution to high altitude physiology

Diuresis at altitude was thought to be the result of chemoreceptor stimulation leading to a reduction of cardiac volume overload. This hypothesis was tested in ten young, healthy subjects by infusion of almitrine (0.5 mg.kg-1 body mass within 30 min) assuming analogous sites of action, i.e. arterial chemoreceptors and pulmonary vessels, for almitrine as for hypoxic hypoxia. The results show that almitrine increases ventilation, heart rate, systolic blood pressure, central venous pressure and natriuresis, but fails to increase significantly atrial natriuretic peptide plasma concentration and diuresis. It is concluded: (1) that almitrine has similar sites of action as hypoxic hypoxia at about 5000 m, (2) that natriuresis during arterial chemoreceptor stimulation might reduce cardiac volume overload, (3) that the volume excretion hypothesis, in particular the pathways from the cardiac volume overload to the water diuresis, need, for an understanding of the hypoxia-induced diuresis, further direct investigations at altitude.     

Effects of increased pulmonary vascular tone on gas exchange in canine oleic acid pulmonary edema

Pulmonary gas exchange was investigated before and after an increase in pulmonary vascular tone induced by administration of acetylsalicylic acid (ASA), indomethacin, or almitrine in 32 pentobarbital-anesthetized and ventilated (fraction of inspired O2 0.4) dogs with oleic acid lung injury. Pulmonary vascular tone was evaluated by five-point pulmonary arterial pressure (PAP)/cardiac index (Q) plots and intrapulmonary shunt was measured using a SF6 infusion. PAP/Q plots were rectilinear in all experimental conditions. In control dogs (n = 8), oleic acid (0.09 ml/kg iv) increased PAP over the range of Q studied (1-5 l.min-1.m-2). At the same Q, arterial PO2 fell from 186 +/- 11 to 65 +/- 8 (SE) Torr and intrapulmonary shunt rose from 5 +/- 1 to 50 +/- 6% 90 min after oleic acid injection. These changes remained stable during the generation of two consecutive PAP/Q plots. ASA (1 g iv, n = 8), indomethacin (2 mg/kg iv, n = 8), and almitrine (8 micrograms.kg-1.min-1 iv, n = 8) produced a further increase in PAP at each level of Q. ASA and indomethacin, respectively, increased arterial PO2 from 61 +/- 4 to 70 +/- 3 Torr (P less than 0.05) and from 70 +/- 6 to 86 +/- 6 Torr (P less than 0.05) and decreased intrapulmonary shunt from 61 +/- 5 to 44 +/- 4% (P less than 0.05) and from 44 +/- 5 to 29 +/- 4% (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Absence of neural modulation of hypoxic pulmonary vasoconstriction in conscious dogs

Our objectives were 1) to quantify the magnitude of the hypoxic pulmonary vasoconstrictor (HPV) response in conscious dogs by utilizing pulmonary vascular pressure-cardiac index (P/Q) plots and 2) to assess the extent to which the autonomic nervous system (ANS) modulates the HPV response. Multipoint P/Q plots were constructed in conscious dogs during normoxia and during bilateral alveolar hypoxia by stepwise constriction of the thoracic inferior vena cava to reduce Q. With the ANS intact, the pulmonary vascular pressure gradient (pulmonary arterial pressure-pulmonary capillary wedge pressure) increased (P less than 0.01) approximately twofold during hypoxia over a broad range of Q. The absolute magnitude of the HPV response was related (P less than 0.01) to the level of Q. We hypothesized that if ANS activation reduces the magnitude of HPV in intact dogs, then we would expect the magnitude of HPV to be increased both after combined sympathetic alpha-(phentolamine) and beta-(propranolol) adrenergic block and after total autonomic ganglionic block (hexamethonium). A marked HPV response (P less than 0.01) was observed after both combined sympathetic block and ganglionic block over a broad range of Q during alveolar hypoxia. The magnitude of the HPV response with the ANS intact, however, was not significantly different from the magnitude of HPV after combined sympathetic block (P = 0.45) or after ganglionic block (P = 0.64) at any level of Q. Thus, during bilateral alveolar hypoxia, the ANS does not appear to attenuate the HPV response of intact conscious dogs.     

Effect of a synthetic progestin on ventilatory response to hypoxia in anesthetized rats

Effects on ventilatory responses to progressive isocapnic hypoxia of a synthetic potent progestin, chlormadinone acetate (CMA), were determined in the halothane-anesthetized male rat. Ventilation during the breathing of hyperoxic gas was largely unaffected by treatment with CMA when carotid chemoreceptor afferents were kept intact. The sensitivity to hypoxia evaluated by hyperbolic regression analysis of the response curve did not differ between the control and CMA groups. The reduction of ventilation after bilateral section of the carotid sinus nerve (CSN) in hyperoxia was less severe in CMA-treated than in untreated animals. Furthermore, the CMA-treated rats showed a larger increase in ventilation during the hypoxia test and a lower PO2 break point for ventilatory depression. Inhibition of hypoxic ventilatory depression by CMA persisted even after the denervation of CSN. We conclude that exogenous progestin likely protects regulatory mechanism(s) for respiration against hypoxic depression through a stimulating action independent of carotid chemoreceptor afferents and without a change in the sensitivity of the ventilatory response to hypoxia.     

Chemoreflex blunting of hypoxic pulmonary vasoconstriction is vagally mediated

We investigated the role of the autonomic nervous system in the arterial chemoreceptor attenuation of hypoxic pulmonary vasoconstriction (HPV) using anesthetized dogs. Total pulmonary blood flow (Qt) and left pulmonary blood flow (Ql) were determined using electromagnetic flow probes. Carotid body chemoreceptors were perfused using blood pumped from an extracorporeal circuit containing an oxygenator. Four groups were used: 1) prevagotomy (control), 2) bilateral vagotomy, 3) post-atropine, and 4) post-propranolol. Left lung hypoxia decreased Ql/Qt from 42.9 +/- 2.9 to 28.1 +/- 3.0%, from 41.1 +/- 5.3 to 26.7 +/- 4.2%, from 38.6 +/- 1.3 to 22.2 +/- 2.4%, and from 48.2 +/- 4.2 to 28.5 +/- 3.7% in the four groups, respectively. Chemoreceptor stimulation during unilateral hypoxia increased Ql/Qt from 28.1 +/- 3.0 to 39.1 +/- 4.9% and from 28.5 +/- 3.7 to 40.6 +/- 3.7% in the control and propranolol groups. However, chemoreceptor stimulation had no effect on Ql/Qt during left lung hypoxia after vagotomy or atropine, as Ql/Qt went from 26.7 +/- 4.2 to 29.3 +/- 5.2% and from 22.2 +/- 2.4 to 24.1 +/- 1.5% in groups 2 and 3, respectively. Because chemoreceptor stimulation did not affect HPV in groups 2 and 3, we conclude that the chemoreceptor attenuation of HPV is mediated by the parasympathetic nervous system.     

Exponential and diphasic ventilatory response to hypoxia in conscious lambs

This study was undertaken to test the hypothesis that in the neonate the hypoxic chemoreflex drive adapts to steady-state hypoxia but not to progressive hypoxia. First we have compared the ventilatory (VE) response of 2-day-old conscious lambs to steady-state hypoxia with their response to progressive hypoxia. Second, we have quantified the chemoreceptor excitatory function operating at the end of each period of hypoxia by studying the immediate VE response to the withdrawal of the hypoxic stimulus. Lambs responded to steady-state hypoxia [fractional concentration of inspired O2 (FIO2) = 0.08] by a diphasic VE response but responded to progressive hypoxia (FIO2 0.21-0.08) by an exponential VE increase. Hyperventilation in steady-state hypoxia was transient; VE increased immediately from 532 to a mean peak response of 712 ml X kg-1 X min-1 and decreased to 595 ml X kg-1. min-1 within 10 min. With progressive hypoxia, VE increased within 13 min from 514 to 705 ml X kg-1 X min-1. At the end of steady-state and progressive hypoxia the abrupt withdrawal of the hypoxic drive caused an instantaneous VE decrease to 390 and 399 ml X kg-1 X min-1, respectively; the VE decrease was respectively 306 and 205 ml X kg-1 X min-1 (P less than 0.05). This demonstrates that during steady-state hypoxia the lambs had suffered a loss of one third of the chemoreceptor excitatory function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral chemoreceptor contributions to sympathetic and cardiovascular responses during hypercapnia

We tested the hypothesis that integrated sympathetic and cardiovascular reflexes are modulated by systemic CO2 differently in hypoxia than in hyperoxia (n = 7). Subjects performed a CO2 rebreathe protocol that equilibrates CO2 partial pressures between arterial and venous blood and that elevates end tidal CO2 (PET(CO2)) from approximately 40 to approximately 58 mmHg. This test was repeated under conditions where end tidal oxygen levels were clamped at 50 (hypoxia) or 200 (hyperoxia) mmHg. Heart rate (HR; EKG), stroke volume (SV; Doppler ultrasound), blood pressure (MAP; finger plethysmograph), and muscle sympathetic nerve activity (MSNA) were measured continuously during the two protocols. MAP at 40 mmHg PET(CO2) (i.e., the first minute of the rebreathe) was greater during hypoxia versus hyperoxia (P < 0.05). However, the increase in MAP during the rebreathe (P < 0.05) was similar in hypoxia (16 +/- 3 mmHg) and hyperoxia (17 +/- 2 mmHg PET(CO2)). The increase in cardiac output (Q) at 55 mmHg PET(CO2) was greater in hypoxia (2.61 +/- 0.7 L/min) versus hyperoxia (1.09 +/- 0.44 L/min) (P < 0.05). In both conditions the increase in Q was due to elevations in both HR and SV (P < 0.05). Systemic vascular conductance (SVC) increased to similar absolute levels in both conditions but rose earlier during hypoxia (> 50 mmHg PET(CO2)) than hyperoxia (> 55 mmHg). MSNA increased earlier during hypoxic hypercapnia (> 45 mmHg) compared with hyperoxic hypercapnia (> 55 mmHg). Thus, in these conscious humans, the dose-response effect of PET(CO2) on the integrated cardiovascular responses was shifted to the left during hypoxic hypercapnia. The combined data indicate that peripheral chemoreceptors exert important influence over cardiovascular reflex responses to hypercapnia.     

Ventilatory response to hyperoxia in the chick embryo

In the avian embryo at term we measured the ventilatory response to hyperoxia, which lowers the chemoreceptor activity, to test the hypothesis that the peripheral chemoreceptors are tonically functional. Measurements of pulmonary ventilation (VE) were conducted in chicken embryos during the external pipping phase, at 38 degrees C, during air and hyperoxia, and during hypercapnia in air or in hyperoxia. Hyperoxia (95% O2) maintained for 30 min lowered VE by 15-20%, largely because of a reduction in breathing frequency (f). The oxygen consumption and carbon dioxide production of the embryo were not altered. The hyperoxic drop of VE was more marked in those embryos, which had higher values of normoxic VE. Hypercapnia, whether 2 or 5% CO2, increased VE, almost exclusively because of the increase in tidal volume (VT). The increase in VT was less pronounced when hypercapnia was associated with hyperoxia, and f slightly decreased. Hence, in hyperoxia, the VE response to CO2 was less than in air. The results are in support of the hypothesis that in the avian embryo, after the onset of breathing, the peripheral chemoreceptors exert a tonic facilitatory input on . This differs from neonatal mammals, where the chemoreceptors have minimal or no activity at birth, presumably because the increased arterial oxygenation with the onset of air breathing is a much more sudden phenomenon in mammals than it is in birds.     

Effects of almitrine on hypoglossal and phrenic electroneurograms

Almitrine increases breathing by stimulating peripheral chemoreceptors. Previous studies suggest clinical usefulness in the adult with chronic obstructive pulmonary disease, but little data are available to decide whether almitrine would be helpful in diseases involving pharyngeal airway obstruction, such as apnea of prematurity or obstructive sleep apnea. We investigated the effect of intravenous almitrine on hypoglossal (HG), an upper airway nerve, and phrenic (PHR) neural activity in eight alpha-chloralose-urethan anesthetized, paralyzed, vagotomized, and artificially ventilated cats. Recordings were made of raw and integrated HG and PHR electroneurograms (ENGs), alveolar PCO2, arterial PO2, arterial blood pressure, and rectal temperature. A dose-response study of cumulative almitrine doses ranging from 0.1 to 4.0 mg/kg was performed in three cats. The interactive effects of almitrine and hypoxic stimulation were investigated in four cats. The interactive effects of almitrine and hypercapnic stimulation were investigated in five cats. The interactive effects of almitrine and ventilatory timing were investigated in six cats. We found that 1) almitrine doses as low as 0.1 mg/kg iv increased both HG and PHR ENG activity, with a maximum effect at approximately 1.0 mg/kg; 2) almitrine markedly increased HG and PHR ENG activity at all arterial PO2 values from 35-175 Torr; 3) almitrine increased HG and PHR ENG activity at all arterial PCO2 values from 30-70 Torr; and 4) almitrine increased the ratio of tidal volume to inspiratory time and decreased the inspiratory muscle duty cycle at normoxia and eucapnia.     

Effects of hyperoxia on vasoconstriction and VA/Q matching in the neonatal lung

Exposure of adult animals to 48-72 h of 100% O2 breathing is associated with a blunting of hypoxic pulmonary vasoconstriction (HPV) (Newman et al. J. Appl. Physiol. 54: 1379-1386, 1983). It is unknown whether HPV is also diminished in neonates after hyperoxic exposure and if so to what extent such suppression might interfere with pulmonary gas exchange during hypoxic gas breathing. We tested the possibility that hyperoxia would suppress HPV and interfere with ventilation-perfusion (VA/Q) matching and therefore gas exchange in neonatal piglets. Twelve 2- to 4-wk-old piglets were exposed for an average of 68 h to greater than 90% inspired O2. A control group of eight piglets was exposed to room air for a similar period of time. Immediately after exposure the animals were anesthetized and instrumented. Pulmonary hemodynamics and respiratory and inert gas exchange were assessed while the animals inspired an O2 fraction of 1.0, 0.21, and 0.12. After 20 min of hypoxic gas breathing, pulmonary arterial pressure rose to a lesser degree in the hyperoxia (H)-exposed animals than in the control (C) animals (P less than 0.02). The increase in pulmonary vascular resistance was similarly blunted. Venous admixture of the insoluble inert gas, sulfur hexafluoride, an index of extremely low VA/Q areas, was increased during hypoxic gas breathing compared with room air breathing in the H-preexposed animals (P less than 0.02). Standard deviation of pulmonary blood flow was increased (P less than 0.02), indicating an increase in mismatching of VA/Q during hypoxic breathing in the H-preexposed animals compared with the C animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of substance P in hypercapnic excitation of carotid chemoreceptors

Experiments were performed on 17 anesthetized, paralyzed, and artificially ventilated cats to evaluate the importance of substance P-like peptide (SP) on the carotid body responses to CO2. Single or paucifiber carotid chemoreceptor activity was recorded from the peripheral end of the cut carotid sinus nerve. In eight of the cats the influence of SP on hyperoxic hypercapnic responses was studied. While the animals breathed 100% O2, intracarotid infusion of SP (1 microgram.kg-1.min-1, 3 min) increased chemoreceptor activity by +4.8 +/- 0.3 impulses/s. After SP infusion, inhalation of CO2 in O2 caused a rapid increase in activity that reached a peak and then adapted to a lower level, whereas similar levels of CO2 before SP caused only a gradual increase in carotid body discharge rate without any overshoot in response. Furthermore SP significantly increased the magnitude and slope of the CO2 response. In the other nine cats the effect of intracarotid infusion of an SP antagonist, [D-Pro2,D-Trp7,9] SP (10-15 micrograms.kg-1.min-1), on carotid body responses to 1) hyperoxic hypercapnia (7% CO2-93% O2), 2) isocapnic hypoxia (11% O2-89% N2), and 3) hypoxic hypercapnia (11% O2-7% CO2-82% N2) was examined. SP antagonist had no effect on carotid body response to hyperoxic hypercapnia but significantly attenuated the chemoreceptor excitation caused by isocapnic hypoxia and hypoxic hypercapnia. These results suggest that 1) SP may play an important role in carotid body responses to hypoxia but not to CO2, and 2) the mechanisms of stimulation of the carotid body by hypercapnia and by hypoxia differ.     

Effects of dopamine on chemoreflexes in breathing

The effects of intravenous infusion of dopamine (20 microgram.min) on the steady-state ventilatory and carotid chemoreceptor responses to successive levels of isocapnic hypoxia and hyperoxic hypercapnia were investigated in cats anesthetized with alpha-chloralose. Dopamine infusion was followed by a maximal decrease in ventilation in about 20 s. Thereafter, the effect diminished and stabilized. Termination of dopamine infusion was promptly followed by an increase in ventilation. These ventilatory responses were smaller than the corresponding carotid chemoreceptor responses. The steady-state effect of dopamine infusion was to diminish ventilation at all levels of arterial O2 tension, the decrease being greater during hypoxia than that during hyperoxia. Bilateral section of the carotid sinus nerves significantly diminished but did not abolish the inhibitory effect of dopamine on ventilation during hyperoxia. Thus the ventilatory depression due to dopamine infusion is not entirely due to its effect on the carotid chemoreceptors. Dopamine decreased ventilatory responses to successive levels of hypercapnia by the same magnitude without changing the slope of the response curves. The steady-state relationship between chemoreceptor activity and ventilation shows that the ventilatory equivalent for carotid chemoreceptor activity is increased during dopamine infusion because of its greater inhibitory effect on carotid chemoreceptor activity than on ventilation with the decrease of arterial O2 tension.     

Stimulus interaction between CO2 and almitrine in the cat carotid chemoreceptors

The hypothesis that augmentation of the carotid chemoreceptor response to hypoxia by almitrine is due in part to an increased response to CO2 was tested by using single or few fiber preparation of carotid body chemosensory fibers in 12 cats anesthetized with alpha-chloralose. To differentiate between the plausible mechanisms of effects, we also tested the responsiveness of the afferents to cyanide and nicotine before and after almitrine. After a saturation dose of almitrine (1 mg.kg-1 followed by 0.5 mg.kg-1.h-1) the chemosensory responses to CO2 strikingly increased even during hyperoxia: the afferents showing an increased transient peak activity at the onset of hypercapnia, an augmented steady-state response to CO2 stimulus, and a decreased arterial PCO2 stimulus threshold. Thus, the effect of almitrine on carotid chemoreceptor response to hypoxia could be explained, at least in part, by its multiplicative stimulus interaction with CO2. After almitrine, the chemoreceptor response to cyanide, which is dependent on arterial PO2, was not particularly augmented relative to those of nicotine. Accordingly, the O2-sensing mechanism does not appear to be the primary site of almitrine effect. The results also indicate that the site of CO2 chemoreception resides downstream from those of hypoxia.     

Peripheral chemoreceptor function after carbonic anhydrase inhibition during moderate-intensity exercise.

The effect of carbonic anhydrase inhibition with acetazolamide (Acz, 10 mg/kg) on the ventilatory response to an abrupt switch into hyperoxia (end-tidal PO2 = 450 Torr) and hypoxia (end-tidal PO2 = 50 Torr) was examined in five male subjects [30 +/- 3 (SE) yr]. Subjects exercised at a work rate chosen to elicit an O2 uptake equivalent to 80% of the ventilatory threshold. Ventilation (VE) was measured breath by breath. Arterial oxyhemoglobin saturation (%SaO2) was determined by ear oximetry. After the switch into hyperoxia, VE remained unchanged from the steady-state exercise prehyperoxic value (60.6 +/- 6.5 l/min) during Acz. During control studies (Con), VE decreased from the prehyperoxic value (52.4 +/- 5.5 l/min) by approximately 20% (VE nadir = 42.4 +/- 6.3 l/min) within 20 s after the switch into hyperoxia. VE increased during Acz and Con after the switch into hypoxia; the hypoxic ventilatory response was significantly lower after Acz compared with Con [Acz, change (Delta) in VE/DeltaSaO2 = 1.54 +/- 0.10 l. min-1. SaO2-1; Con, DeltaVE/DeltaSaO2 = 2.22 +/- 0.28 l. min-1. SaO2-1]. The peripheral chemoreceptor contribution to the ventilatory drive after acute Acz-induced carbonic anhydrase inhibition is not apparent in the steady state of moderate-intensity exercise. However, Acz administration did not completely attenuate the peripheral chemoreceptor response to hypoxia.     

Increased nitric oxide production accompanies blunted hypoxic pulmonary vasoconstriction in hyperoxic rat lung

Hyperoxia may affect lung physiology in different ways. We investigated the effect of hyperoxia on the protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, and hypoxic pulmonary vasoconstriction (HPV) in rat lung. Twenty-four male rats were divided into hyperoxic and normoxic groups. Hyperoxic rats were placed in > 90% F1O2 for 60 h prior to experiments. After baseline in vitro analysis, the rats underwent isolated, perfused lung experiments. Two consecutive hypoxic challenges (10 min each) were administered with the administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), in between. We measured intravascular NO production, pulmonary arterial pressure, and protein expression of eNOS and iNOS by immunohistochemistry. We found that hyperoxia rats exhibited increased baseline NO production (P < 0.001) and blunted HPV response (P < 0.001) during hypoxic challenges compared to normoxia rats. We also detected a temporal association between the attenuation in HPV and increased NO production level with a negative pre-L-NAME correlation between HPV and NO (R = 0.52, P < 0.05). After L-NAME administration, a second hypoxic challenge restored the HPV response in the hyperoxic group. There were increased protein expression of eNOS (12.6 +/- 3.1-fold, n = 3) (X200) and iNOS (8.1 +/- 2.6-fold, n = 3) (X200) in the hyperoxia group. We conclude that hyperoxia increases the protein expression of eNOS and iNOS with a subsequent increased release of endogenous NO, which attenuates the HPV response.