Hypoxic Pulmonary Vasoconstriction In Dogs Research Articles

The role of prostaglandins on hypoxic pulmonary vasoconstriction in dogs--especially the role of PGI2

The role of prostaglandins on hypoxic pulmonary vasoconstriction in dogs--especially the role of PGI2

Effects of posture on blood flow diversion by hypoxic pulmonary vasoconstriction in dogs

We used differential excretion of sulphur hexafluoride from the left and right lung to measure blood flow diversion by hypoxic pulmonary vasoconstriction (HPV) in the prone and supine positions in dogs (n = 9). Gas exchange was assessed using the multiple inert gas elimination technique. Blood flow diversion from the hypoxic (3% oxygen) left lung was mean 70.7 (SD 11.2)% in the supine compared with 57.0 (12.1)% in the prone position (P < 0.02). The supine position was associated with increased perfusion to low VA/Q regions (P < 0.05). The increased flow diversion with hypoxia in the supine position was associated with more ventilation to high VA/Q regions (P < 0.05). We conclude that flow diversion by hypoxic pulmonary vasoconstriction is greater in the supine position. This effect could contribute to the variable response in gas exchange with positioning in patients with ARDS.

Prostaglandin E1 antagonizes hypoxic pulmonary vasoconstriction but reduces systemic blood pressure in dogs

To investigate whether prostaglandin E1 (PGE1) directly inhibits hypoxic pulmonary vasoconstriction in dogs. Prospective, longitudinal study. University research laboratory. Six mongrel dogs in vivo. The left thorax of anesthetized and ventilated dogs was opened and the left lower lobe was separately ventilated. The tip of the thermodilution pulmonary artery catheter was introduced into the left lower lobe pulmonary artery. The left lower lobe was ventilated with hyperoxic (95% oxygen and 5% CO2) or hypoxic (95% nitrogen and 5% CO2) gas. By manipulating the occluders placed on both pulmonary arteries, blood flow in the left lower lobe was regulated. Continuous pressure-flow plots for the left lower lobe were then obtained. Measurements included continuous pressure-flow plot generation, thermodilution cardiac output and blood flow in the left lower lobe, and blood gas analysis. Alveolar hypoxia of the left lower lobe caused blood flow in the left lower lobe to decrease from 371.8 +/- 63.4 to 95.0 +/- 23.4 mL/min and shifted the pressure-flow plot to the right, with a decreased slope and with an increase in the pressure-axis intercept. Subsequently, systemic venous infusion of PGE1 at a rate of 0.3 microg/kg/min had no effect on the pressure-flow plot configuration, blood flow in the left lower lobe, pulmonary vascular resistance, systemic vascular resistance, and PaO2. However, there was a decrease in the pressure-axis intercept of the pressure-flow plot. Infusion of PGE1 at a rate of 3.0 microg/kg/min (high-dose) during hypoxia reduced pulmonary vascular resistance and systemic vascular resistance by 19% and 25%, respectively, and returned the pressure-flow plot toward normal while blood flow in the left lower lobe increased to 122.6 +/- 21.0 mL/min. Consequently, PaO2 decreased from 270 +/- 31 to 144 +/- 32 torr (36.0 +/- 4.1 to 19.2 +/- 4.3 kPa). High-dose PGE1 essentially inhibits hypoxic pulmonary vasoconstriction, at the expense of a deterioration in pulmonary gas exchange and systemic blood pressure in dogs.

Effects of chronic dexfenfluramine treatment on pulmonary hemodynamics in dogs.

An epidemic of primary pulmonary hypertension occurred in Europe in the 1960s, after the introduction of the appetite suppressant aminorex. Recently, a cluster of cases of pulmonary hypertension was observed in France in relation to the intake of the appetite suppressant dexfenfluramine. We previously reported that intravenous dexfenfluramine enhances hypoxic pulmonary vasoconstriction in dogs. We therefore investigated the pulmonary hemodynamic effects of chronic oral intake of this drug. Twenty-four dogs with a strong (n = 12) and a weak hypoxic pulmonary vasoconstriction (n = 12) respectively were randomly allocated in a double blind manner to a twice daily oral intake of either a placebo or dexfenfluramine 1.5 mg/kg for 20 d. A strong hypoxic vasoconstriction was defined as a hypoxia-induced increase in pulmonary artery pressure by more than 3 mm Hg at a standardized cardiac output of 3 L/min/m2. Pulmonary hemodynamics were studied in hyperoxia (fraction of inspired O2 [F(I)O2] 0.4) and in hypoxia (F(I)O2 0.1) before and after treatment. Venous return was manipulated at post-treatment evaluation for isoflow comparisons of pulmonary vascular pressures. Dexfenfluramine had no effect on systemic hemodynamics or blood gases, but increased pulmonary vascular resistance from 155 +/- 17 to 192 +/- 14 dyne x s x cm(-5) in hyperoxia (mean +/- SE, p < 0.05) and from 237 +/- 27 to 293 +/- 47 dyne x s x cm(-5) in hypoxia (p < 0.01). Dexfenfluramine, and not placebo, increased the isoflow pulmonary vascular pressure gradient in hyperoxia and in hypoxia. This effect was unrelated to the magnitude of pretreatment hypoxic vasoconstriction. We conclude that the chronic intake of dexfenfluramine in dogs is associated with a moderate increase in pulmonary vascular resistance which is unrelated to pulmonary vasoreactivity to hypoxia.

The Effect of Thoracic Epidural Anesthesia on Hypoxic Pulmonary Vasoconstriction in Dogs

The aim of the present study was to examine whether hypoxic pulmonary vasoconstriction (HPV) is preserved during one-lung ventilation combined with thoracic epidural anesthesia (TEA) in dogs. Using a separately ventilated left lower lobe (LLL) in situ, the pressure-flow (P-Q) curve was obtained. The HPV response was assessed by the shift of the P-Q curve, changes in blood flow diversion rate (FDR) and decrease in PaO2 during hypoxic gas ventilation of LLL. In the control group (n = 7), the shift of P-Q curve, changes in FDR, and decrease in PaO2 remained constant during four consecutive hypoxic stimulations. In the TEA group (n = 6), the P-Q curve shifted to the left during hyperoxia, but the magnitude of the shift during hypoxia was unchanged. FDR and decrease in PaO2 were significantly reduced compared with baseline values (P < 0.05 with analysis of variance). TEA reduced heart rate, cardiac output, mean arterial pressure, mean pulmonary arterial pressure, and mixed venous oxygen tension. Our results suggest that TEA did not affect the primary pulmonary vascular tone at baseline or during lobar hypoxia, but enhanced the diversion of blood flow and arterial blood oxygenation during lobar hypoxia. This enhanced HPV response probably reflects hemodynamic changes, such as decreased cardiac output with resultant low mixed venous oxygen tension, due to sympathetic nerve activity blockade by TEA. (Anesth Analg 1996;82:1049-55)

Prostacyclin aerosol and inhaled nitric oxide fail to reverse pulmonary vasoconstriction induced by thromboxane analogue in dogs

Inhalation of either prostacyclin (PGI2) as an aerosol or nitric oxide (NO) has been shown to elicit selective pulmonary vasodilation during hypoxic pulmonary vasoconstriction in dogs. Hypoxia may produce cardiovascular changes confounding interpretation of drug effects. Therefore, we investigated the effects of PGI2-aerosol and inhaled NO (50 p.p.m.) on pulmonary pressure-flow relationships (P/Q plots) during thromboxane analogue (U46619) induced pulmonary vasoconstriction. In eight anaesthetized dogs infusion of U46619 (0.33 +/- 0.18 micrograms kg-1 min-1) increased the slope (3.5 +/- 1.1 to 8.4 +/- 1.7 mmHg L-1 min-1, P < 0.001) and the intercept (4.4 +/- 2.3 to 10.2 +/- 4.6 mmHg, P < 0.01) of P/Q plots indicating pulmonary vasoconstriction. Inhalation of both aerosolized PGI2 solution (10 micrograms mL-1) and NO (50 p.p.m.) reduced neither the slope nor the intercept of the P/Q plots. Increasing the concentration of the aerosolized PGI2 solution to 50 micrograms mL-1 (n = 3) did not enhance the effect on pulmonary circulation but systemic vascular resistance fell by 23%. Oxygenation and intrapulmonary shunt remained unchanged during both PGI2-aerosol and inhaled NO. The failure of PGI2-aerosol to induce pulmonary vasodilation indicates that during aerosolization PGI2-concentrations at receptor sites on pulmonary vessels were insufficient to surmount U46619 induced vasoconstriction; this notion is supported by unchanged arterial plasma concentrations of the PGI2 degradation product 6-keto-PGF1 alpha. Considering that NO inhaled at comparable concentrations in sheep reversed U46619 induced pulmonary vasoconstriction, species differences may account for the failure of both PGI2-aerosol and NO to dilate pulmonary vessels in dogs.

Inhaled Nitric Oxide Reverses Hypoxic Pulmonary Vasoconstriction in Dogs: A Practical Nitric Oxide Delivery and Monitoring System

Nitric oxide (NO) is a potent dilator of vascular smooth muscle that likely represents an important endothelium-dependent relaxing factor. Recent interest has focused on inhaled NO as a pulmonary vasodilator. The purpose of this study was to design a reliable NO delivery system with on-line monitoring of NO and nitrogen dioxide (NO2) concentrations, and to test the effects of inhaled NO in a dog model of acute hypoxic pulmonary vasoconstriction (HPV). Six canines were studied. Marked HPV was induced using a hypoxic gas mixture. Using a standard blender. NO was delivered through a volume-cycled ventilator. We were able to rapidly adjust the delivered NO concentration using this system. An on-line chemoluminescence analyzer was used to continuously measure NO and NO2 concentrations. Inhaled NO at 40 and 80 ppm for 30 min rapidly reversed HPV in all animals (PVR 502 +/- 154 dynes.s.cm-5 with hypoxia, 244 +/- 52 with 40 ppm NO, 227 +/- 47 with 80 ppm NO). No significant NO2 or methemoglobin production was noted during the study. We conclude that inhaled NO can be easily delivered through a ventilator and the dose rapidly adjusted, NO and NO2 concentrations can be monitored continuously on-line, inhaled NO rapidly reverses HPV in dogs, and with short-term NO inhalation, there is no significant NO2 or methemoglobin formation. Inhaled NO may, therefore, have a future clinical role as a new agent in the diagnosis and treatment of other forms of pulmonary hypertension.

Effects of acute ingestion of ethanol on hemodynamics and hypoxic pulmonary vasoconstriction in dogs--role of leukotrienes.

The effects of acute intragastric administration of ethanol on hemodynamics and hypoxic pulmonary vasoconstriction were studied in spontaneously breathing dogs. The dogs were given 0.5 g/kg of 10% ethanol (v/v) in 5 min. Hemodynamic measurements were obtained before and 30 min after ingestion of ethanol. Mean pulmonary arterial pressure and pulmonary vascular resistance increased markedly after ingestion of ethanol, and hypoxic pulmonary vasoconstriction was augmented significantly by ethanol as well. Diethylcarbamazine citrate (DEC), a lipoxygenase inhibitor, inhibited these effects of ethanol in a dosage of 200 mg/kg. The above findings suggest that ethanol can induce pulmonary vasoconstriction, which may be predominantly mediated by leukotrienes (LTs).

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)

Restored Hypoxic Pulmonary Vasoconstriction by Peripheral Chemoreceptor Agonists in Dogs

Hypoxic stimulation of the peripheral chemoreceptors inhibits hypoxic pulmonary vasoconstriction (HPV). On the other hand, almitrine, a peripheral chemoreceptor agonist, has been reported in some studies to enhance HPV. To further explore this apparent contradiction, we investigated the effects of two different low intravenous doses of almitrine on pulmonary arterial pressure (Ppa) versus cardiac index (Q) plots in 32 pentobarbital-anesthetized dogs ventilated alternatively in hyperoxia (FIO2, 0.4) and in hypoxia (FIO2 0.1). HPV, defined as a hypoxia-induced increase in Ppa over the entire range of Q studied, from 2 to 5 L/min/m2, was elicited in 16 dogs. In the first eight of these "responders," almitrine 2 micrograms/kg/min had no vascular effect, and in the other eight, almitrine 4 micrograms/kg/min inhibited HPV. In 16 other dogs, hypoxia did not affect Ppa over the entire range of Q. In these "nonresponders," almitrine 2 micrograms/kg/min (n = 8) as well as 4 micrograms/kg/min (n = 8) restored HPV. To answer the question whether the ability to restore HPV would be specific to almitrine, we administered intravenously the structurally unrelated chemoreceptor agonist doxapram at the dose of 20 micrograms/kg/min to an additional group of eight "nonresponders," and this treatment also restored HPV. Intravenous infusion of the malic acid solution solvent of almitrine had no effect on Ppa/Q plots in a final group of eight "nonresponders". We conclude that low dose almitrine and doxapram restore HPV in dogs with a naturally absent hypoxic pulmonary pressor response, probably by a direct effect at the pulmonary vessels.

Effects of acidosis and alkalosis on hypoxic pulmonary vasoconstriction in dogs

We studied the effects of metabolic and respiratory acidosis (pH 7.20) and alkalosis (pH 7.60) on pulmonary vascular tone in 32 pentobarbital-anesthetized dogs ventilated with hyperoxia (inspired oxygen fraction, FIO2 0.40) and with hypoxia (FIO2 0.10). Ventilation, pulmonary capillary wedge pressure (Ppw), and cardiac output (3 l.min-1.m-2) were maintained constant to prevent passive changes in pulmonary arterial pressure (Ppa). Metabolic acidosis and alkalosis were induced with HCl (2 mmol.kg-1.h-1) and NaHCO3-Na2CO3 (5 mmol.kg-1.h-1) infusions, respectively, and respiratory acidosis and alkalosis by modifying the inspiratory CO2 fraction. The hypoxia-induced rise in Ppa-Ppw gradient increased from 5 to 9 mmHg in metabolic acidosis (P less than 0.001), decreased from 6 to 1 mmHg in metabolic alkalosis (P less than 0.001), remained unchanged in respiratory acidosis, and decreased from 5 to 2 mmHg in respiratory alkalosis (P less than 0.001). Linear relationships were found between pH and Ppa-Ppw gradients. These data indicate that in intact anesthetized dogs, metabolic acidosis and alkalosis, respectively, enhance and reverse hypoxic pulmonary vasoconstriction (HPV). Respiratory acidosis did not affect HPV and respiratory alkalosis blunted HPV, which suggests an pH-independent vasodilating effect of CO2.

Relationship of leukotriene C4 and D4 to hypoxic pulmonary vasoconstriction in dogs.

Leukotrienes C4 and D4 have been implicated as possible mediators of hypoxic pulmonary vasoconstriction. To test this hypothesis, the relationship between pulmonary leukotriene (LT) synthesis in response to hypoxia and alterations in pulmonary hemodynamics was evaluated in pentobarbital sodium-anesthetized, neuromuscular-blocked, male, mongrel dogs. A reduction in the fraction of inspired O2 (FIO2) in vehicle-treated animals (n = 12) from 0.21 to 0.10 was associated with increases in LTC4 and LTD4 in bronchoalveolar lavage fluid (BALF). After 30 min of continuous hypoxia, LTC4 and LTD4 increased from control values of 59.4 +/- 10.4 and 91.7 +/- 18.1 ng/lavage to 142.7 +/- 31.8 (P less than 0.05) and 156.3 +/- 25.3 (P less than 0.01) ng/lavage, respectively. Concomitantly, mean pulmonary arterial pressure (Ppa) and pulmonary vascular resistance (PVR) were increased over control by 67 +/- 7 (P less than 0.001) and 62 +/- 7% (P less than 0.001), respectively. In contrast, in animals treated with diethylcarbamazine (n = 5), a leukotriene A4 synthase inhibitor, identical reductions in FIO2 were not associated with increases in LTC4 and LTD4 in BALF, although at the same time period, Ppa and PVR were increased over control by 60 +/- 13 (P less than 0.05) and 112 +/- 31% (P less than 0.05), respectively. These results, therefore, do not support the contention that leukotrienes mediate hypoxic pulmonary vasoconstriction in dogs.

Leukotriene inhibitors do not block hypoxic pulmonary vasoconstriction in dogs.

We studied whether intravenously administered inhibitors of leukotriene synthesis (diethylcarbamazine, DEC) or end-organ effect (FPL-55712) would change the distribution of regional pulmonary blood flow (rPBF) caused by left lower lobe (LLL) alveolar hypoxia in dogs. Both drugs failed to alter rPBF. In addition, the pressor response to whole-lung hypoxia was not blocked by an FPL-55712 infusion. On the other hand, nitroprusside, as a nonspecific vasodilator also administered intravenously, was able to partially reverse the effects of LLL hypoxia on rPBF. Thus our data do not support a role for leukotriene mediation of hypoxic pulmonary vasoconstriction in dogs.

The role of leukotrienes in hypoxic pulmonary vasoconstriction in dogs

The role of leukotrienes in hypoxic pulmonary vasoconstriction in dogs

Hypoxic pulmonary vasoconstriction in dogs: effects of lung segment size and oxygen tension.

Six pentobarbital-anesthetized dogs were prepared with endobronchial tubes and electromagnetic flow probes. The effects of changing inspired oxygen concentrations (FIO2 = 1, 0.21, 0.15, 0.1, 0.075, 0.05, and 0) were tested on test segments of different size corresponding to left lower lobe, left upper lobe-lingula, left lung, right lung, right lung plus left lower lobe, right lung plus left upper lobe-lingula, and whole lung. In each test the rest of the lung received oxygen. Hypoxic pulmonary vasoconstriction is demonstrated by both diversion of blood flow away from hypoxic test segments and by increased perfusion pressure. Flow diversion (FD%) decreases with the size of the hypoxic test segment (%QSN) from a maximum of 75% for very small segments to zero when the whole lung is hypoxic. FD% increases linearly as alveolar oxygen tension (PAO2) of the test segment is decreased in the range of 130--28 Torr. When mixed venous oxygen tension (PVO2) is less than 45 Torr FD% is reduced. These relationships are described by FD% = [74.99 - 0.0778 (%QSN) - 0.00661 (%QSN)2] [1.268 - 0.0096 (PAO2)] [0.47 + 0.012 (PVO2)], with r = 0.92 and standard error for prediction of 8.4%. Pulmonary perfusion pressure changes (PPH/PPN) increase with the size of the hypoxic test segments from 0 with very small segments to approximately 2.2 for the hypoxic whole lung. For all test segments PPH/PPN increases linearly with PAO2. These relationships are described by PPH/PPN = 1 + [0.0043 (%QSN) + 0.000072 (%QSN)2] [1.234 - 0.0096 (PAO2)], with r = 0.91 and standard error for prediction of 0.3 units. Responses to hypoxic pulmonary vasoconstriction in dogs are therefore shown to be predictable and continuous, and the physiological basis for action of each of the variables is discussed.

Stability of alveolar hypoxic vasoconstriction with intermittent hypoxia.

Repeated intermittent global hypoxia has been reported to markedly enhance hypoxic pulmonary vasoconstriction in dogs. We have reexamined this phenomenon but with intermittent unilateral alveolar hypoxia, avoiding complications of systemic hypoxemia. Fifteen anesthetized dogs were intubated with a double-lumen endotracheal tube, allowing separate ventilation of one lung with 100% N2 as a hypoxic challenge and the other lung with 100% O2 to maintain adequate systemic oxygenation. Distribution of lung perfusion was determined with intravenous 133Xe and external chest detectors. Each dog alternately breathed air or the unilateral alveolar hypoxia combination for 15 min each for a total of 12 hypoxic challenges or 6 h. Two groups emerged on the basis of the strength of their vasoconstrictor responses to successive hypoxic challenge. In group I (n = 6), perfusion to the hypoxic lung decreased 29% with the first challenge and decreased comparably with successive challenges. In group II, vasoconstriction was initially weak with perfusion decreasing only 5%, but perfusion decreased further with time alone (n = 5) or successive challenges (n = 4), falling 35% on the 12th challenge (comparable to group I). Delayed achievement of hypoxic vasoconstriction in group II may be secondary to a vasodilating prostanoid that disappears with time.

Role of Cytochrome P-450 in Alveolar Hypoxic Pulmonary Vasoconstriction in Dogs

Alveolar hypoxia induces pulmonary vasoconstriction by an unknown mechanism. Cytochrome P-450 (C-P450) is found in the lung and may modify pulmonary vascular tone via its sensitivity to changes in oxygen tension or by affecting metabolism of a chemical mediator. Metyrapone and carbon monoxide are both inhibitors of C-P450. We tested alveolar hypoxic pulmonary vasoconstriction (AHPV) in 20 dogs before, during, and after separate administration of each inhibitor. Anesthetized dogs were ventilated through a double lumen endotracheal tube allowing ventilation of one lung with N(2) or CO as a hypoxic challenge and ventilation of the other lung with O(2) to maintain adequate systemic oxygenation. Distribution of lung perfusion was determined with intravenous (133)Xenon and external chest detectors. Before infusion of metyrapone, mean perfusion to the test lung decreased 30% with alveolar hypoxic challenge, but decreased only 10% during metyrapone infusion and returned to a base-line mean decrease of 31% after completion of metyrapone infusion. Prostaglandin F(2) alpha and angiotensin II infusions produced equivalent increases in pulmonary vascular resistance before and during metyrapone infusion. Before CO, mean test lung perfusion decreased 31% with alveolar hypoxia but was reduced only 10% from control when unilateral end-tidal CO% was >75%. Washout of alveolar CO with unilateral N(2) ventilation restored AHPV, with perfusion decreasing 29% from control. Thus, both metyrapone and carbon monoxide can reversibly inhibit AHPV. C-P450 may, therefore, be involved in the transduction process of the vasoconstrictor response to alveolar hypoxia.

Histamine receptor antagonism does not inhibit hypoxic pulmonary vasoconstriction in dogs

Histamine receptor antagonism does not inhibit hypoxic pulmonary vasoconstriction in dogs

Histamine Receptor Antagonism Does Not Inhibit Hypoxic Pulmonary Vasoconstriction in Dogs

Histamine Receptor Antagonism Does Not Inhibit Hypoxic Pulmonary Vasoconstriction in Dogs

Failure of histamine antagonists to prevent hypoxic pulmonary vasoconstriction in dogs

The role of histamine as a mediator of hypoxic pulmonary vasoconstriction was examined in intact anesthetized dogs. Antagonism of histamine vasoconstrictor (H1) receptors with a classic antihistaminic drug (chlorpheniramine) failed to prevent or modify the pulmonary vascular responses to hypoxia (10% O2). Blockade of histamine vasodilator (H2) receptors with a newly synthesized blocking agent (metiamide) potentiated the vasoconstriction induced by hypoxia and prevented the normal increase in heart rate. Combined H1- and H2-receptor blockade also did not prevent or reduce the hypoxic pulmonary pressor response, although it did effectively abolish the cardiovascular actions of infused histamine. In other dogs, histamine infused (3.6 mug/kg per min) during hypoxia attenuated the pulmonary vasoconstriction induced by hypoxia. The results imply that, in the dog, histamine does not mediate hypoxic pulmonary vasoconstriction. However, histamine does appear to be released during hypoxia, and it may play a role in modulating the pulmonary vascular responses to hypoxia by opposing the hypoxia induced vasoconstriction. The results also imply that histamine may be responsible for the increase in heart rate during hypoxia.