Cardiorespiratory responses of the facultative air-breathing fish jeju, Hoplerythrinus unitaeniatus (Teleostei, Erythrinidae), exposed to graded ambient hypoxia

The jeju, Hoplerythrinus unitaeniatus, is equipped with a modified part of the swim bladder that allows aerial respiration. On this background, we have evaluated its respiratory and cardiovascular responses to aquatic hypoxia. Its aquatic O2 uptake (V(O2)) was maintained constant down to a critical P(O2) (P(cO2)) of 40 mm Hg, below which V(O2) declined linearly with further reductions of P(iO2). Just below P(cO2), the ventilatory tidal volume (V(T)) increased significantly along with gill ventilation (V(G)), while respiratory frequency changed little. Consequently, water convection requirement (V(G)/V(O2)) increased steeply. The same threshold applied to cardiovascular responses that included reflex bradycardia and elevated arterial blood pressure (P(a)). Aerial respiration was initiated at water P(O2) of 44 mm Hg and breathing episodes and time at the surface increased linearly with more severe hypoxia. At the lowest water P(O2) (20 mm Hg), the time spent at the surface accounted for 50% of total time. This response has a character of a temporary emergency behavior that may allow the animal to escape hypoxia.     

Cardiorespiratory responses to hypoxia in intact and bilaterally vagotomized pigeons

Bilateral, cervical vagotomy in birds denervates, among other receptors, the carotid bodies. To test whether such neural section removes sensitivity to hypoxia, we measured respiratory, cardiovascular, and blood gas responses to hypoxia at 84-, 70-, and 49-Torr inspiratory O2 partial pressure (PIO2) in five pigeons with intact vagi and in five bilaterally, cervically vagotomized pigeons. Normoxic respiratory frequency (fresp) and expiratory flow rate (VE) were decreased after vagotomy. Intact pigeons showed large increases in VE in response to hypoxia, effected mostly by increases in fresp. VE also increased greatly in response to hypoxia in vagotomized pigeons, but increases were largely the result of tidal volume. O2 consumption, CO2 production, and respiratory exchange ratio increased slightly in all pigeons during hypoxia. Normoxic heart rate was greater after vagotomy; cardiac output increased in all pigeons in response to hypoxia, but stroke volume increased only in intact pigeons. During normoxia, arterial and mixed venous O2 partial pressure, O2 concentration, and pH were lower and arterial and mixed venous CO2 partial pressure was higher, after vagotomy. In all pigeons during hypoxia, arterial and mixed venous O2 and CO2 partial pressure and O2 concentration decreased and arterial and mixed venous pH increased; changes were roughly parallel in intact and vagotomized pigeons. The arteriovenous O2 concentration differences during normoxia and hypoxia were similar in all pigeons. We conclude that bilateral, cervical vagotomy in the pigeon causes hypoventilation and tachycardia during normoxia, but strong respiratory and cardiovascular responses to hypoxia are still present.     

A comparison of adrenergic stress responses in three tropical teleosts exposed to acute hypoxia

Experiments were performed to assess the afferent and efferent limbs of the hypoxia-mediated humoral adrenergic stress response in selected hypoxia-tolerant tropical fishes that routinely experience environmental O(2) depletion. Plasma catecholamine (Cat) levels and blood respiratory status were measured during acute aquatic hypoxia [water Po(2) (Pw(O(2))) = 10-60 mmHg] in three teleost species, the obligate water breathers Hoplias malabaricus (traira) and Piaractus mesopotamicus (pacu) and the facultative air breather Hoplerythrinus unitaeniatus (jeju). Traira displayed a significant increase in plasma Cat levels (from 1.3 +/- 0.4 to 23.3 +/- 15.1 nmol/l) at Pw(O(2)) levels below 20 mmHg, whereas circulating Cat levels were unaltered in pacu at all levels of hypoxia. In jeju denied access to air, plasma Cat levels were increased markedly to a maximum mean value of 53.6 +/- 19.1 nmol/l as Pw(O(2)) was lowered below 40 mmHg. In traira and jeju, Cat release into the circulation occurred at abrupt thresholds corresponding to arterial Po(2) (Pa(O(2))) values of approximately 8.5-12.5 mmHg. A comparison of in vivo blood O(2) equilibration curves revealed low and similar P(50) values (i.e., Pa(O(2)) at 50% Hb-O(2) saturation) among the three species (7.7-11.3 mmHg). Thus Cat release in traira and jeju occurred as blood O(2) concentration was reduced to approximately 50-60% of the normoxic value. Intravascular injections of nicotine (600 nmol/kg) elicited pronounced increases in plasma Cat levels in traira and jeju but not in pacu. Thus the lack of Cat release during hypoxia in pacu may reflect an inoperative or absent humoral adrenergic stress response in this species. When allowed access to air, jeju did not release Cats into the circulation at any level of aquatic hypoxia. The likeliest explanation for the absence of Cat release in these fish was that air breathing, initiated by aquatic hypoxia, prevented Pa(O(2)) values from falling to the critical threshold required for Cat secretion. The ventilatory responses to hypoxia in each species were similar, consisting generally of increases in both frequency and amplitude. These responses were not synchronized with or influenced by plasma Cat levels. Thus the acute humoral adrenergic stress response does not appear to stimulate ventilation during acute hypoxia in these tropical species.     

Reflex cardiovascular responses originating in exercising muscles of mice.

The cardiovascular responses induced by exercise are initiated by two primary mechanisms: central command and reflexes originating in exercising muscles. Although our understanding of cardiovascular responses to exercise in mice is progressing, a murine model of cardiovascular responses to muscle contraction has not been developed. Therefore, the purpose of this study was to characterize the cardiovascular responses to muscular contraction in anesthetized mice. The results of this study indicate that mice demonstrate significant increases in blood pressure (13.8 +/- 1.9 mmHg) and heart rate (33.5 +/- 11.9 beats/min) to muscle contraction in a contraction-intensity-dependent manner. Mice also demonstrate 23.1 +/- 3.5, 20.9 +/- 4.0, 21.7 +/- 2.6, and 25.8 +/- 3.0 mmHg increases in blood pressure to direct stimulation of tibial, peroneal, sural, and sciatic hindlimb somatic nerves, respectively. Systemic hypoxia (10% O(2)-90% N(2)) elicits increases in blood pressure (11.7 +/- 2.6 mmHg) and heart rate (42.7 +/- 13.9 beats/min), while increasing arterial pressure with phenylephrine decreases heart rate in a dose-dependent manner. The results from this study demonstrate the feasibility of using mice to study neural regulation of cardiovascular function during a variety of autonomic stimuli, including exercise-related drives such as muscle contraction.     

Importance of fatty acid oxidation in the neonatal pig heart with hypoxia and reoxygenation

We investigated mechanical and metabolic responses in isolated, isovolumically-beating, pig hearts (n = 7), 12 h to 2 days of age; subjected to hypoxia followed by reoxygenation. Hearts were perfused with an erythrocyte-enriched (hematocrit approximately 15%) solution during 3 consecutive 30-min periods: pre-hypoxia, arterial perfusate [O2] = 7.6 +/- 0.2 vol% (PO2 approximately 270 torr); hypoxia, [O2] = 0.6 +/- 0.1 vol% (approximately 10% hemoglobin saturation) and reoxygenation. Prehypoxia parameters averaged: left ventricular peak systolic pressure, 107.1 +/- 2.9 mmHg and end-diastolic pressure, 0.9 +/- 0.3 mmHg; coronary flow, 2.8 +/- 0.2 ml/min per g; myocardial O2 consumption, 59.4 +/- 1.6 microliters/min per g and fatty acid oxidation, 37.1 +/ 1.1 nmol/min per g. Fatty acid oxidation was determined using [14C]palmitate. Early in hypoxia, coronary flow increased 3-4 fold but then decreased. Throughout hypoxia, hearts released lactate yet continued to oxidize fatty acids (45-50% of myocardial O2 consumption). By the end of the hypoxia period, hearts exhibited mechanical failure (peak systolic pressure approximately 55 mmHg and end-diastolic pressure approximately 19 mmHg). After 30 min of reoxygenation, peak systolic pressure recovered to 80.6 +/- 2.6 mmHg and end-diastolic pressure remained elevated at 6.1 +/- 1.9 mmHg. However, fatty acid oxidation rates were 90-95% above pre-hypoxia values. Thus, during 30 min of severe hypoxia neonatal pig hearts exhibited mechanical dysfunction, yet continued to oxidize exogenously supplied fatty acids. Moreover, fatty acid oxidation was enhanced during reoxygenation.     

Defining hypoxia: a systems view of VO2, glycolysis, energetics, and intracellular PO2

The necessity for defining hypoxia as O2-limited energy flux rather than low partial pressure is explored from a systems perspective. Oxidative phosphorylation, the Krebs cycle, glycolysis, substrate supply, and cell energetics interact as subsystems; the set point is a match between ATP demand and aerobic ATP production. To this end the transport subsystem must match the transcapillary and mitochondrial O2 fluxes. High transcapillary O2 flux requires intracellular PO2 in the range 1-10 Torr. In this range the O2 drive on electron transport must be compensated by adaptive changes in the phosphorylation and redox drives. Thus the metabolic subsystem supports diffusive O2 transport by maintaining O2 flux at intracellular partial pressures required for O2 release from blood. Since responses to stress are distributed according to the state of the entire system, several simultaneous metabolic measurements, including intracellular PO2 (or a known direction of change in intracellular PO2) and the O2 dependence of a measurable function are required to judge the adequacy of O2 supply. ATP demand and aerobic capacity must also be evaluated, because the hypoxic threshold depends on the ratio of ATP demand to aerobic capacity. The application and limitation of commonly used criteria of hypoxia are discussed, and a more precise terminology is proposed.     

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 acclimatization to hypoxia is not dependent on arterial hypoxemia

Goats were prepared so that one carotid body (CB) could be perfused with blood in which the gas tensions could be controlled independently from the blood perfusing the systemic arterial system, including the brain. Since one CB is functionally adequate, the nonperfused CB was excised. To determine whether systemic arterial hypoxemia is necessary for ventilatory acclimatization to hypoxia (VAH), the CB was perfused with hypoxic normocapnic blood for 6 h [means +/- SE: partial pressure of carotid body O2 (PcbO2), 40.6 +/- 0.3 Torr; partial pressure of carotid body CO2 (PcbCO2), 38.8 +/- 0.2 Torr] while the awake goat breathed room air to maintain systemic arterial normoxia. In control periods before and after CB hypoxia the CB was perfused with hyperoxic normocapnic blood. Changes in arterial PCO2 (PaCO2) were used as an index of changes in ventilation. Acute hypoxia (0.5 h of hypoxic perfusion) resulted in hyperventilation sufficient to reduce average PaCO2 by 6.7 Torr from control (P less than 0.05). Over the subsequent 5.5 h of hypoxic perfusion, average PaCO2 decreased further, reaching 4.8 Torr below that observed acutely (P less than 0.05). Acute CB hyperoxic perfusion (20 min) following 6 h of hypoxia resulted in only partial restoration of PaCO2 toward control values; PaCO2 remained 7.9 Torr below control (P less than 0.05). The progressive hyperventilation that occurred during and after 6 h of CB hypoxia with concomitant systemic normoxia is similar to that occurring with total body hypoxia. We conclude that systemic (and probably brain) hypoxia is not a necessary requisite for VAH.     

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.     

Tolerance of acute hypercapnic acidosis by the European eel (<Emphasis Type="Italic">Anguilla anguilla</Emphasis>)

European eels ( Anguilla anguilla) were exposed sequentially to partial pressures of CO(2) in the water ( PwCO(2)) of 5, 10, 20, 40, 60 then 80 mm Hg (equivalent to 0.66-10.5 kPa), for 30 min at each level. This caused a profound drop in arterial plasma pH, from 7.9 to below 7.2, an increase in arterial PCO(2) from 3.0 mm Hg to 44 mm Hg, and a progressive decline in arterial blood O(2) content (caO(2)) from 10.0% to 1.97% volume. Gill ventilation rate increased significantly at water PwCO(2)s of 10, 20 and 40 mm Hg, followed by a decline at PwCO(2)s of 60 and 80 mm Hg, due to periodic breathing. Mean opercular pressure amplitude increased steadily throughout hypercapnic exposure and was significantly elevated at a PwCO(2) of 80 mm Hg. Hypercapnia caused a tachycardia between PwCO(2)s of 5 mmHg and 10 mm Hg, followed by a progressive decline in heart rate. Cardiac output (CO) remained unchanged throughout, as a consequence of a significant increase in stroke volume at PwCO(2)s of 40, 60 and 80 mm Hg. The eels maintained O(2) uptake at routine normocapnic levels throughout hypercapnic exposure. A comparison of the rates of blood O(2) delivery (calculated from CO and caO(2)) against O(2) consumption at PwCO(2)s of 60 mm Hg and 80 mm Hg indicated that a portion of O(2) uptake was due to cutaneous respiration. Thus, the European eel's exceptional tolerance of acute hypercapnia is probably a consequence of the tolerance of its heart to acidosis and hypoxia, and a contribution to O(2) uptake from cutaneous respiration.     

Peripheral chemoreflex responsiveness is increased at elevated levels of carbon dioxide after episodic hypoxia in awake humans.

We hypothesized that the acute ventilatory response to hypoxia is enhanced after exposure to episodic hypoxia in awake humans. Eleven subjects completed a series of rebreathing trials before and after exposure to eight 4-min episodes of hypoxia. During the rebreathing trials, subjects initially hyperventilated to reduce the partial pressure of carbon dioxide (Pet(CO(2))) below 25 Torr. Subjects then breathed from a bag containing normocapnic (42 Torr), low (50 Torr), or high oxygen (140 Torr) gas mixtures. During the trials, Pet(CO(2)) increased while a constant oxygen level was maintained. The point at which ventilation began to rise in a linear fashion as Pet(CO(2)) increased was considered to be the ventilatory recruitment threshold. The ventilatory response below and above the recruitment threshold was determined. Ventilation did not persist above baseline values immediately after exposure to episodic hypoxia; however, Pet(CO(2)) levels were reduced compared with baseline. In contrast, compared with baseline, the ventilatory response to progressive increases in carbon dioxide during rebreathing trials in the presence of low but not high oxygen levels was increased after exposure to episodic hypoxia. This increase occurred when carbon dioxide levels were above but not below the ventilatory recruitment threshold. We conclude that long-term facilitation of ventilation (i.e., increases in ventilation that persist when normoxia is restored after episodic hypoxia) is not expressed in awake humans in the presence of hypocapnia. Nevertheless, despite this lack of expression, the acute ventilatory response to hypoxia in the presence of hypercapnia is increased after exposure to episodic hypoxia.     

Circulating catecholamines and cardiorespiratory responses in hypoxic lungfish (Protopterus dolloi): a comparison of aquatic and aerial hypoxia

Circulating catecholamine levels and a variety of cardiorespiratory variables were monitored in cannulated bimodally breathing African lungfish (Protopterus dolloi) exposed to aquatic or aerial hypoxia. Owing to the purported absence of external branchial chemoreceptors in lungfish and the minor role played by the gill in O2 uptake, it was hypothesized that plasma catecholamine levels would increase only during exposure of fish to aerial hypoxia. The rapid induction of aquatic hypoxia (final PWo2 = 25.9+/-1.6 mmHg) did not affect the levels of adrenaline (A) or noradrenaline (NA) within the plasma. Similarly, none of the measured cardiorespiratory variables--including heart rate (fH), blood pressure, air-breathing frequency (fV), O2 consumption (Mo2), CO2 excretion (Mco2), or blood gases--were influenced by acute aquatic hypoxia. In contrast, however, the rapid induction of aerial hypoxia (inspired Po2=46.6+/-3.3 mmHg) caused a marked increase in the circulating levels of A (from 7.9+/-2.0 to 18.8+/-6.1 nmol L(-1)) and NA (from 7.7+/-2.2 to 19.7+/-6.3 nmol L(-1)) that was accompanied by significant decreases in Mo2, arterial Po2 (Pao2), and arterial O2 concentration (Cao2). Air-breathing frequency was increased (by approximately five breaths per hour) during aerial hypoxia and presumably contributed to the observed doubling of pulmonary Mco2 (from 0.25+/-0.04 to 0.49+/-0.07 mmol kg(-1) h(-1)); fH and blood pressure were unaffected by aerial hypoxia. An in situ perfused heart preparation was used to test the possibility that catecholamine secretion from cardiac chromaffin cells was being activated by a direct localized effect of hypoxia. Catecholamine secretion from the chromaffin cells of the heart, while clearly responsive to a depolarizing concentration of KCl (60 mmol L(-1)), was unaffected by the O2 status of the perfusion fluid. The results of this study demonstrate that P. dolloi is able to mobilize stored catecholamines and increase f(V) during exposure to aerial hypoxia while remaining unresponsive to aquatic hypoxia. Thus, unlike in exclusively water-breathing teleosts, P. dolloi would appear to rely solely on internal/airway O2 chemoreceptors for initiating catecholamine secretion and cardiorespiratory responses.     

Respiratory, circulatory and neuropsychological responses to acute hypoxia in acclimatized and non-acclimatized subjects

Respiratory, circulatory and neuropsychological responses to stepwise, acute exposure at rest to simulated altitude (6,000 m) were compared in ten acclimatized recumbent mountaineers 24 days, SD 11 after descending from Himalayan altitudes of at least 4,000 m with those found in ten non-acclimatized recumbent volunteers. The results showed that hypoxic hyperpnoea and O2 consumption at high altitudes were significantly lower in the mountaineers, their alveolar gases being, however, similar to those of the control group. In the acclimatized subjects the activation of the cardiovascular system was less marked, systolic blood pressure, pulse pressure, heart rate and thus (calculated) cardiac output being always lower than in the controls; diastolic blood pressure and peripheral vascular resistance, however, were maintained throughout in contrast to the vasomotor depression induced by central hypoxia which occurred in the non-acclimatized subjects at and above 4,000 m [alveolar partial pressure of O2 less than 55-50 mmHg (7.3-6.6 kPa)]. It was concluded that in the acclimatized subjects at high altitude arterial vasodilatation and neurobehavioural impairment, which in the non-acclimatized subjects reflect hypoxia of the central nervous system, were prevented; that acclimatization to high altitude resulted in a significant improvement of respiratory efficiency and cardiac economy, and that maintaining diastolic blood pressure (arterial resistance) at and above 4,000 m may represent a useful criterion for assessing hypoxia acclimatization.     

Analysis of pulmonary vasodilator responses to the Rho-kinase inhibitor fasudil in the anesthetized rat

The small GTP-binding protein Rho and its downstream effector, Rho-kinase, are important regulators of vasoconstrictor tone. Rho-kinase is upregulated in experimental models of pulmonary hypertension, and Rho-kinase inhibitors decrease pulmonary arterial pressure in rodents with monocrotaline and chronic hypoxia-induced pulmonary hypertension. However, less is known about responses to fasudil when pulmonary vascular resistance is elevated on an acute basis by vasoconstrictor agents and ventilatory hypoxia. In the present study, intravenous injections of fasudil reversed pulmonary hypertensive responses to intravenous infusion of the thromboxane receptor agonist, U-46619 and ventilation with a 10% O(2) gas mixture and inhibited pulmonary vasoconstrictor responses to intravenous injections of angiotensin II, BAY K 8644, and U-46619 without prior exposure to agonists, which can upregulate Rho-kinase activity. The calcium channel blocker isradipine and fasudil had similar effects and in small doses had additive effects in blunting vasoconstrictor responses, suggesting parallel and series mechanisms in the lung. When pulmonary vascular resistance was increased with U-46619, fasudil produced similar decreases in pulmonary and systemic arterial pressure, whereas isradipine produced greater decreases in systemic arterial pressure. The hypoxic pressor response was enhanced by 5-10 mg/kg iv nitro-L-arginine methyl ester (L-NAME), and fasudil or isradipine reversed the pulmonary hypertensive response to hypoxia in control and in L-NAME-treated animals, suggesting that the response is mediated by Rho-kinase and L-type Ca(2+) channels. These results suggest that Rho-kinase is constitutively active in regulating baseline tone and vasoconstrictor responses in the lung under physiological conditions and that Rho-kinase inhibition attenuates pulmonary vasoconstrictor responses to agents that act by different mechanisms without prior exposure to the agonist.     

Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in humans

Recurrent and intermittent nocturnal hypoxia is characteristic of several diseases including chronic obstructive pulmonary disease, congestive heart failure, obesity-hypoventilation syndrome, and obstructive sleep apnea. The contribution of hypoxia to cardiovascular morbidity and mortality in these disease states is unclear, however. To investigate the impact of recurrent nocturnal hypoxia on hemodynamics, sympathetic activity, and vascular tone we evaluated 10 normal volunteers before and after 14 nights of nocturnal sustained hypoxia (mean oxygen saturation 84.2%, 9 h/night). Over the exposure, subjects exhibited ventilatory acclimatization to hypoxia as evidenced by an increase in resting ventilation (arterial Pco(2) 41.8 +/- 1.5 vs. 37.5 +/- 1.3 mmHg, mean +/- SD; P < 0.05) and in the isocapnic hypoxic ventilatory response (slope 0.49 +/- 0.1 vs. 1.32 +/- 0.2 l/min per 1% fall in saturation; P < 0.05). Subjects exhibited a significant increase in mean arterial pressure (86.7 +/- 6.1 vs. 90.5 +/- 7.6 mmHg; P < 0.001), muscle sympathetic nerve activity (20.8 +/- 2.8 vs. 28.2 +/- 3.3 bursts/min; P < 0.01), and forearm vascular resistance (39.6 +/- 3.5 vs. 47.5 +/- 4.8 mmHg.ml(-1).100 g tissue.min; P < 0.05). Forearm blood flow during acute isocapnic hypoxia was increased after exposure but during selective brachial intra-arterial vascular infusion of the alpha-blocker phentolamine it was unchanged after exposure. Finally, there was a decrease in reactive hyperemia to 15 min of forearm ischemia after the hypoxic exposure. Recurrent nocturnal hypoxia thus increases sympathetic activity and alters peripheral vascular tone. These changes may contribute to the increased cardiovascular and cerebrovascular risk associated with clinical diseases that are associated with chronic recurrent hypoxia.     

Sex differences in the respiratory response to hemorrhage in the conscious, New Zealand white rabbit

In conscious animals, the response to hemorrhage is biphasic. During phase 1, arterial pressure is maintained. Phase 2 is characterized by profound hypotension. Despite allied roles, less is known about the integrated cardiovascular and respiratory response to blood loss in conscious animals. We evaluated cardiorespiratory changes during hemorrhage to test the hypotheses that 1) respiratory rate (RR) and blood gases do not change during phase 1; 2) RR increases during phase 2; and 3) RR and blood gas changes during hemorrhage are similar in males and females. We measured mean arterial pressure, RR, and blood gases during hemorrhage in 16 conscious, chronically prepared, male and female New Zealand white rabbits. We removed venous blood until mean arterial pressure was < or =40 mmHg. Sex did not affect mean arterial pressure, heart rate, Pa(O(2)), Pa(CO(2)), or pH during hemorrhage or the blood loss required to induce phase 2. Pa(CO(2)) decreased significantly from 37 +/- 1 to 33 +/- 1 and 29 +/- 1 mmHg (P < 0.001) during phase 1 and 2, respectively. Before hemorrhage, Pa(O(2)) was 87 +/- 2 mmHg. Pa(O(2)) was unchanged in phase 1 (92 +/- 2 mmHg) but increased in phase 2 (101 +/- 2 mmHg; P < 0.001). Body temperature, Pv(CO(2)) (thoracic vena cava), and ventilation-perfusion mismatch (A-a gradient) were unchanged during phases 1 and 2. Neither sex increased RR during phase 1. While males doubled RR during phase 2, RR in females did not change (P < 0.001). Thus, while Pa(CO(2)) decreases in phase 1 and phase 2, the decreases are achieved in different ways across the two phases and in the two sexes.     

Cerebral and intestinal perfusion and metabolism in normocythemic hyperviscous hypoxic newborn pigs.

We studied the effects of hypoxia on cerebral cortical and intestinal perfusion and metabolism in normocythemic hyperviscous newborn pigs. Seven pigs were made hyperviscous by an injection of cryoprecipitate, increasing viscosity from 5.8 +/- 0.9 to 9.0 +/- 1. 2 (SD) cycles/s. Six normoviscous pigs received 0.9% NaCl. Reducing the inspired O(2) decreased the arterial O(2) content (Ca(O(2))) from 9.5 +/- 1.6 to 3.6 +/- 1.3 ml O(2)/100 ml. Increases in brain and decreases in gastrointestinal blood flow at the lower Ca(O(2)) values were similar between the groups. During hypoxia, blood flow to stomach, distal intestinal mucosa, and large intestines was lower (-50, -23, and -28%, respectively) in the hyperviscous than normoviscous group. At the lower Ca(O(2)) values, cerebral cortical vascular resistance decreased in both groups and intestinal vascular resistance increased (+257%) in the hyperviscous but not in the normoviscous group. During hypoxia, systemic oxygen delivery decreased, extraction increased, and uptake did not change; cerebral cortical O(2) delivery, extraction, and uptake did not change; and intestinal O(2) delivery decreased, extraction increased, and uptake did not change in both groups. Our study demonstrated that 1) during hypoxia, increases in systemic O(2) extraction compensated for decreases in delivery and systemic uptake did not change; vasodilation sustained cerebral cortical O(2) delivery and preserved metabolism; increases in intestinal oxygen extraction offset decreases in delivery and uptake was preserved; and 2) nonpolycythemic hyperviscosity did not have a major influence on cardiovascular or metabolic responses to hypoxia, except for modest effects on intestinal resistance and perfusion to certain gastrointestinal regions. We conclude that, under normocythemic conditions, a moderate increase in viscosity does not have a major impact on hemodynamic or metabolic adjustments to hypoxia in newborn pigs.     

Respiratory and cardiovascular responses to acute hypoxia and hyperoxia in internally pipped chicken embryos.

During the first day of hatching, the developing chicken embryo internally pips the air cell and relies on both the lungs and chorioallantoic membrane (CAM) for gas exchange. Our objective in this study was to examine respiratory and cardiovascular responses to acute changes in oxygen at the air cell or the rest of the egg during internal pipping. We measured lung (VO2(lung)) and CAM (VO2(CAM)) oxygen consumption independently before and after 60 min exposure to combinations of hypoxia, hyperoxia, and normoxia to the air cell and the remaining egg. Significant changes in VO2(total) were only observed with combined egg and air cell hypoxia (decreased VO2(total)) or egg hyperoxia and air cell hypoxia (increased VO2(total)). In response to the different O2 treatments, a change in VO2(lung) was compensated by an inverse change in VO2(CAM) of similar magnitude. To test for the underlying mechanism, we focused on ventilation and cardiovascular responses during hypoxic and hyperoxic air cell exposure. Ventilation frequency and minute ventilation (V(E)) were unaffected by changes in air cell O2, but tidal volume (V(T)) increased during hypoxia. Both V(T) and V(E) decreased significantly in response to decreased P(CO2). The right-to-left shunt of blood away from the lungs increased significantly during hypoxic air cell exposure and decreased significantly during hyperoxic exposure. These results demonstrate the internally pipped embryo's ability to control the site of gas exchange by means of altering blood flow between the lungs and CAM.     

Oxygen-conserving effects of apnea in exercising men.

We sought to determine whether apnea-induced cardiovascular responses resulted in a biologically significant temporary O(2) conservation during exercise. Nine healthy men performing steady-state leg exercise carried out repeated apnea (A) and rebreathing (R) maneuvers starting with residual volume +3.5 liters of air. Heart rate (HR), mean arterial pressure (MAP), and arterial O(2) saturation (Sa(O(2)); pulse oximetry) were recorded continuously. Responses (DeltaHR, DeltaMAP) were determined as differences between HR and MAP at baseline before the maneuver and the average of values recorded between 25 and 30 s into each maneuver. The rate of O(2) desaturation (DeltaSa(O(2))/Deltat) was determined during the same time interval. During apnea, DeltaSaO(2)/Deltat had a significant negative correlation to the amplitudes of DeltaHR and DeltaMAP (r(2) = 0.88, P < 0.001); i.e., individuals with the most prominent cardiovascular responses had the slowest DeltaSa(O(2))/Deltat. DeltaHR and DeltaMAP were much larger during A (-44 +/- 8 beats/min, +49 +/- 4 mmHg, respectively) than during R maneuver (+3 +/- 3 beats/min, +30 +/- 5 mmHg, respectively). DeltaSa(O(2))/Deltat during A and R maneuvers was -1.1 +/- 0.1 and -2.2 +/- 0.2% units/s, respectively, and nadir Sa(O(2)) values were 58 +/- 4 and 42 +/- 3% units, respectively. We conclude that bradycardia and hypertension during apnea are associated with a significant temporary O(2) conservation and that respiratory arrest, rather than the associated hypoxia, is essential for these responses.     

The effects of endothelin-1 on the cardiorespiratory physiology of the freshwater trout (Oncorhynchus mykiss) and the marine dogfish (Squalus acanthias).

The aim of the present study was to evaluate the effects of endothelin-l-elicited cardiovascular events on respiratory gas transfer in the freshwater rainbow trout (Oncorhynchus mykiss) and the marine dogfish (Squalus acanthias). In both species, endothelin-1 (666 pmol kg(-1)) caused a rapid (within 4 min) reduction (ca. 30-50 mmHg) in arterial blood partial pressure of O2. The effects of endothelin-1 on arterial blood partial pressure of CO2 were not synchronised with the changes in O2 partial pressure and the responses were markedly different in trout and dogfish. In trout, arterial CO2 partial pressure was increased transiently by approximately 1.0 mmHg but the onset of the response was delayed and occurred 12 min after endothelin-1 injection. In contrast, CO2 partial pressure remained more-or-less constant in dogfish after injection of endothelin-1 and was increased only slightly (approximately 0.1 mmHg) after 60 min. Pre-treatment of trout with bovine carbonic anhydrase (5 mg ml(-1)) eliminated the increase in CO2 partial pressure that was normally observed after endothelin-1 injection. In both species, endothelin-1 injection caused a decrease in arterial blood pH that mirrored the changes in CO2 partial pressure. Endothelin-1 injection was associated with transient (trout) or persistent (dogfish) hyperventilation as indicated by pronounced increases in breathing frequency and amplitude. In trout, arterial blood pressure remained constant or was decreased slightly and was accompanied by a transient increase in systemic resistance, and a temporary reduction in cardiac output. The decrease in cardiac output was caused solely by a reduction in cardiac frequency; cardiac stroke volume was unaffected. In dogfish, arterial blood pressure was lowered by approximately 10 mmHg at 6-10 min after endothelin-1 injection but then was rapidly restored to pre-injection levels. The decrease in arterial blood pressure reflected an increase in branchial vascular resistance (as determined using in situ perfused gill preparations) that was accompanied by simultaneous decreases in systemic resistance and cardiac output. Cardiac frequency and stroke volume were reduced by endothelin-1 injection and thus both variables contributed to the changes in cardiac output. We conclude that the net consequences of endothelin-1 on arterial blood gases result from the opposing effects of reduced gill functional surface area (caused by vasoconstriction) and an increase in blood residence time within the gill (caused by decreased cardiac output.