Hypoxic Pulmonary Vasoconstriction Response Research Articles

EFFECTS OF THE PATTERN OF VENTILATION AND OF AN INCREASE IN CARDIAC OUTPUT ON THE DISTRIBUTION OF BLOOD FLOW TO A HYPOXIC LUNG LOBE

Electromagnetic flow probes were used to measure the fraction of the pulmonary blood flow perfusing the left lower lobe (Ql/Qt) in 16 anaesthetized, open-chest dogs in order to study the effects of right lung airway pressure on the distribution of blood flow to a hypoxic lung lobe. Ventilation of the lobe with 7% oxygen in nitrogen resulted in a 37% reduction in Ql/Qt at the beginning and end of the main procedure, thus confirming that the hypoxic pulmonary vasoconstrictor response was unchanged throughout the study. The effects of varying mean airway pressure to the right lung by changing inspiratory:expiratory time ratio and by the addition of a positive end-expiratory pressure were studied when the left lower lobe was insufflated with oxygen or 7% oxygen in nitrogen, or was collapsed. Insufflation of the lobe with 7% oxygen in nitrogen and collapse reduced Ql/Qt by 61% and 66%, respectively. However, changing mean airway pressure in the right lung produced no significant changes in Ql/Qt in any of the different lobar conditions or when collapse was produced after fluid loading. Fluid loading during collapse increased cardiac output and pulmonary vascular pressures and increased Ql/Qt to a value which was not significantly different from lobar ventilation with 7% oxygen in nitrogen. It is concluded that moderate increases in mean airway pressure do not increase Ql/Qt when this has been reduced by exposure of the lobe to mixed venous blood-gas tensions.

Pulmonary and systemic vascular effects of serotonin in conscious newborn lambs.

There is evidence that serotonin (5-hydroxytryptamine) may be released from pulmonary neuroendocrine cells during hypoxia in animals. Because there are few data regarding serotonin's effect on the immature pulmonary circulation, we studied the direct pulmonary (and systemic) vascular effects of this amine in awake lambs. As has been observed in mature animals, we found that serotonin is a powerful pulmonary and systemic vasoconstrictor, with a threshold of 3 micrograms/kg in immature lambs. However, unlike in mature animals, phenoxybenzamine, 2 mg/kg, prevented both the pulmonary (and systemic) vasoconstriction seen with serotonin. Serotonin is a powerful pulmonary vasoconstrictor in immature lambs, which is consistent with the idea that release of serotonin from pulmonary neuroendocrine cells may play a role in the hypoxic pulmonary vasoconstrictor response.

Specificity of FPL 57231 for leukotriene D4 receptors in fetal pulmonary circulation.

The effects of leukotriene D4 and the putative leukotriene receptor antagonist FPL 57231 were studied on the pulmonary circulation of alpha-chloralose-anesthetized fetal lambs close to term. At constant pulmonary inflow leukotriene D4 (LTD4, 0.1-10 micrograms), as bolus injections, caused dose-dependent increases in pulmonary vascular resistance. FPL 57231 (1.0-10 mg/kg) not only blocked the pressor responses to LTD4 but also lowered the normal pulmonary vascular resistance in a dose-dependent fashion. However, FPL 57231 also decreased the pulmonary pressor response to U 46619, a thromboxane A2 mimic, as well as the pressor response to phenylephrine HCl. Furthermore, the pressor responses to LTD4 were markedly reduced by cyclooxygenase inhibition. In preliminary experiments we demonstrated that the phenidone derivative, BW755C, which is a dual inhibitor of both cyclooxygenase and 5-lipoxygenase enzymes, did not block the pressor response to hypoxia. We conclude that FPL 57231 decreases fetal pulmonary vascular resistance by nonspecific mechanisms. Also the action of LTD4, is indirect and by way of the cyclooxygenase system. Although exogenous leukotrienes are able to produce a marked pulmonary pressor response, endogenous leukotrienes are probably not responsible for the hypoxic pulmonary pressor response of the fetal lung or its normally high pulmonary vascular resistance.

High-dose almitrine bismesylate inhibits hypoxic pulmonary vasoconstriction in closed-chest dogs.

The effect of almitrine bismesylate on the hypoxic pulmonary vasoconstrictor (HPV) response was studied in seven closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2, while the left lung was ventilated with either 100% O2 ("hyperoxia") or with an hypoxic gas mixture ("hypoxia": end-tidal PO2 = 50.1 +/- 0.1 mmHg). Cardiac output (CO) was altered from a "normal" value of 3.10 +/- 0.18 l . min-1 to a "high" value of 3.92 +/- 0.16 l . min-1 by opening arteriovenous fistulae which allowed measurements of two points along a pressure-flow line. These four phases of left lung hypoxia or hyperoxia with normal and high cardiac output were repeated in the presence and absence of almitrine. Almitrine bismesylate was administered as a constant infusion of 14.3 micrograms . kg-1 . min-1 for a mean plasma concentration of 219.5 +/- 26.4 ng . ml-1. Relative blood flow to each lung was measured with a differential CO2 excretion (VCO2) method corrected for the Haldane effect. With both lungs hyperoxic, the percent left lung blood flow (%QL-VCO2) was 44 +/- 1%. When the left lung was exposed to hypoxia, the %QL-VCO2 decreased significantly to 22 +/- 1%. However, with the administration of almitrine, the %QL-VCO2 during left lung hypoxia increased significantly to 36 +/- 2%. The arterial oxygen tension decreased significantly between hyperoxia (PaO2 = 633 +/- 6 mmHg) and hypoxia (271 +/- 31 mmHg). With the addition of almitrine, there was no change during hyperoxia; however, during hypoxia, the PaO2 decreased significantly to 124 +/- 15 mmHg. Cardiac output did not influence these findings. The pulmonary vascular conductance (G) is the slope of the pressure-flow line.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of leukotrienes in acute hypoxic pulmonary vasoconstriction in rats.

In this study, we investigated the possible role of leukotrienes in the mediation of hypoxic pulmonary vasoconstriction (HPV) in rats. Diethylcarbamazine citrate (DEC), an inhibitor of leukotriene synthesis, can block HPV, while minimally affecting the angiotensin II pressor response. The inhibition of HPV by DEC was not affected by cyclooxygenase or histamine H1-receptor blocker, and the HPV response could be increased by cyclooxygenase blocker. It is suggested that the inhibitory effect of DEC on HPV may not be related to the actions of prostaglandins, histamine and angiotensin II. HPV in male Sprague-Dawley rats and female Hilltop rats was completely and significantly counteracted by the leukotriene receptor blocker FPL55712, respectively. This lends further support to the hypothesis that leukotrienes might be the most important mediators of HPV in rats.

Ozone inhibits prostacyclin synthesis in pulmonary endothelium

The effects of ozone on lung arachidonate metabolism in-vitro were studied in cultured bovine pulmonary endothelial cells exposed for 2 hours to ozone in concentrations up to 1.0 ppm. A concentration-dependent decrease in prostacyclin synthesis was found (90% decrease at the highest ozone level of 1.0 ppm). The inhibition of prostacyclin synthesis was not due to a decreased release of arachidonic acid from membrane lipids. We also examined the hypoxic pulmonary vasoconstrictive response to 10% oxygen inhalation in anesthetized dogs in-vivo after exposure to 1.0 ppm ozone for 1 hour. Pulmonary vascular resistance was significantly increased after ozone exposure, similar to the findings in dogs given indomethacin (15 mg/kg). The percentage change in the hypoxic pulmonary pressor response was similar between the ozone exposure and indomethacin-treated groups, although due to the variance of the pulmonary vascular resistance values during hypoxia the results did not reach statistical significance. These results suggest that ozone inhalation affects pulmonary endothelial arachidonate metabolism in-vivo as well as in-vitro .

Pulmonary and systemic vascular effects of SRS-A blockade in conscious lambs.

There is preliminary evidence suggesting that hypoxic pulmonary vasoconstriction may be mediated by slow-reacting substance of anaphylaxis (SRS-A), which is comprised of leukotrienes C4, D4, and E4. We studied the effects of the SRS-A antagonist FPL 57231 (FPL) on the hypoxic pulmonary vasoconstrictor response and on systemic vascular resistance in awake, chronically instrumented young lambs. Two other studies were performed to ascertain whether FPL's vasodilation was specific for hypoxic pulmonary vasoconstriction: the effect of FPL infusion in pulmonary and systemic vascular resistance was measured in six normoxic lambs, and the effect of FPL on 5-hydroxytryptamine (5-HT)-mediated vasoconstriction was determined. In seven lambs, mean pulmonary arterial pressure was 21 mmHg in room air and 28 mmHg in hypoxia (Po2 = 43 Torr). During hypoxia, FPL infusion (2 mg X kg-1 X min-1) reversibly decreased pulmonary arterial pressure to 15 mmHg; pulmonary arteriolar resistance also fell below normoxia levels with FPL. FPL also caused a fall in aortic pressure and systemic vascular resistance in these hypoxic lambs, but the decrease in systemic resistance was less than the fall in pulmonary resistance. beta-Adrenergic blockade using propranolol (1 mg/kg) did not affect the pulmonary vasodilation caused by FPL. In six normoxic lambs, FPL infusion also significantly decreased pulmonary and systemic vascular resistance (29% in each case). These data are consistent with the idea that leukotrienes may be involved in adjusting both pulmonary and systemic vascular tone, but further work is necessary to establish whether FPL's vasodilation is mediated via its leukotriene antagonism or is a nonspecific effect of FPL.

High-frequency ventilation attenuation of hypoxic pulmonary vasoconstriction. The role of prostacyclin.

In order to determine the effects of high-frequency ventilation on the pulmonary vascular response to hypoxia, we assessed pulmonary vascular resistance at 2 levels of inspired oxygen tension (PlO2), 200 and 30 mmHg, during conventional and high-frequency ventilation in the isolated, blood-perfused lungs of 10 sheep, 5 treated with indomethacin (40 micrograms/ml of perfusate) and 5 untreated. Resistance was assessed by measuring pulmonary artery pressure-flow curves generated over a wide range of flows (20 to 140 ml X min-1 X kg body wt-1). Conventional ventilation was provided by an animal ventilator at a rate of 10 min-1 and a tidal volume of 10 ml X kg body wt-1. High-frequency ventilation was provided by a flow interrupter at a rate of 1,200 min-1 and a tidal volume less than 1.5 ml X kg body wt-1. In the 5 untreated lungs, the normoxic pressure-flow curve was unaltered by high-frequency ventilation, but the hypoxic pulmonary vasoconstrictor response was significantly attenuated. Furthermore, the net rate of change of 6-keto-prostaglandin F1 alpha concentration in the perfusate during hypoxia was significantly greater with high-frequency ventilation (65.4 +/- 8.9 pg X ml-1 X min-1) than with conventional ventilation (2.8 +/- 18.7 pg X ml-1 X min-1). In the 5 indomethacin-treated lungs, production of 6-keto-prostaglandin F1 alpha was markedly depressed, and the attenuation of the hypoxic vasoconstrictor response by high-frequency ventilation was abolished.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxic pulmonary vasoconstriction in man: effects of hyperventilation.

The pulmonary vasoconstriction response to hypoxia was studied in eight anaesthetized supine subjects. One lung was made hypoxic while the other was ventilated with 100% oxygen. This was achieved by separating the tidal gas-distribution to the lungs by means of a double-lumen tracheal catheter. The hypoxic pulmonary vasoconstriction (HPV) response was estimated from the blood flow diversion away from the hypoxic lung. Blood flow distribution between the lungs was calculated from the regional expired carbon dioxide production, assuming regional carbon dioxide production to be proportional to blood flow. The subjects were studied during six different conditions. Firstly, when ventilated with 100% oxygen to both lungs at a PaCO2 of about 6 kPa. Secondly, with 100% oxygen to the left lung and 5% oxygen in nitrogen to the right (test) lung. The ratio between carbon dioxide output from right and left lung was calculated. These measurements were repeated during two states of hyperventilation (PaCO2 of about 4.5 kPa and 3.5 kPa, respectively) with and without hypoxia (conditions 3-6). During normoventilation, blood flow distribution between the lungs was equal. During hypoxia, blood flow distribution to the hypoxic lung decreased by 35% of the pre-hypoxic value. Furthermore, a decrease in arterial oxygen tension from 51.5 +/- 4.5 to 11.5 +/- 2.1 kPa was observed. During excessive hyperventilation (PaCO2 3.2 +/- 0.2 kPa), blood flow distribution to the hypoxic right lung decreased by only 10% of its pre-hypoxic value. A further decrease in arterial oxygen tension to 8.5 +/- 1.8 kPa was observed. This decrease in PaO2 was possibly due to an increased venous admixture caused by an abolished HPV response. It is concluded that hyperventilation counteracts hypoxic pulmonary vasoconstriction in man.

1766 EFFECTS OF 17β ESTRADIOL ON THE PULMONARY CIRCULATION

Prior studies have shown that 1) mature ewes have an attenuated hypoxic pulmonary vasoconstrictor response (HPVR), 2) 17β estradiol (E2) administered 2-4 days prior to study of juvenile ewes reduces their HPVR to adult ewe levels, 3) E2 enhances prostaglandin production by systemic vessels. This study examined the effects of indomethacin (I) on the steady state pulmonary vascular response to graded hypoxia in isolated perfused lungs of 3 groups of juvenile ewes - controls (C and CI), E2 treated 36-60 hours before study (E2S, E2SI) and E2 treated 72-110 hours before study (E2L, E2LI). Mean pulmonary artery pressure (Ppa) at flow = 50 ml/kg·min for 3 levels of inspired O2 (PiO2) for each group (n) were: (* = less than C, p<.05).In all groups the peak response is seen at 30 torr. There was a time dependent attenuation of the HPVR caused by E2. While indomethacin had no effect on the HPVR in any group, it did return responsivity (Δ in Ppa 200→30) in E2L to C values (p<.05). These results suggest that although E2 may increase pulmonary prostaglandin synthesis, there is also an apparent time-dependent reduction in vascular resistance caused by non-prostaglandin dependent mechanisms.

Hypoxic pulmonary vasoconstriction in isolated rat lungs perfused with perfluorocarbon emulsion.

Eight rat lungs were perfused in an in vitro circuit with a blood-PS solution and then with a perfluorocarbon emulsion (perfluorotributylamine, FC-43). With perfusion flow constant, the hypoxic pulmonary vasoconstrictor (HPV) response was measured as changes in pulmonary artery pressure when F1,O2 was changed to 0.1, 0.06, 0.04, 0.03, 0.02 and zero with FI,CO2 of 0.05. The hypoxic response to an FI,O2 of 0.03, with the blood-PSS perfusate, was an increase from baseline pressure of 93.5 +/- 18% and, with the perfluorocarbon perfusate was 67.5 +/- 18%; these values were not significantly different (P greater than 0.2). A stimulus-response relationship was obtained with the FC-43 perfusate by plotting the response as a percentage of the maximum response (R%max) against the logarithm of the alveolar oxygen tension. The equation for the linear portion of the response was R%max = 257.9-140.2 X log (10) PA,O2 and r = 0.78. The PA,O2 corresponding to half of the maximum response (ED50) was 30.4 mmHg. The present study demonstrated that HPV is maintained in isolated rat lungs perfused with an FC-43 emulsion. The stimulus-response relationship as well as the ED50 with the FC-43 is similar to earlier results with blood perfusate. Lung oedema was not found after perfusion with the FC-43 emulsion.

Naloxone: Effects on hypoxic pulmonary vasoconstriction

To determine the effect of naloxone on the hypoxic pulmonary vasoconstrictive response, six mongrel dogs were rendered hypoxic with 10% oxygen and were given either saline or naloxone. Following hypoxia all dogs had significant increases in mean pulmonary artery pressure (PAP) and pulmonary arterial resistance index (PARI) without changes in cardiac output or systemic blood pressure. Beta endorphins did not change at any time following hypoxia. Dogs receiving naloxone had significant lowering of PAP and PARI without changes in plasma beta endorphin levels. We conclude that naloxone attenuates hypoxic pulmonary vasoconstriction without measurable alterations of plasma beta endorphin levels.

Comparison of muscular pulmonary arteries in low and high altitude hamsters and rats

Measurements were made of the ratio of medial area to total arterial area in the muscular pulmonary arteries of a fossorial species, the hamster, and a non-fossorial control, the rat. It was found that the medial area was less in hamsters than in rats. In addition, chronic hypoxic exposure resulted in further medial thickening in rats, while the hamster was unaffected. The hamster has previously been shown to have a blunted hypoxic pulmonary pressor response, and the present data indicate that this relative unresponsiveness is associated with less pulmonary vascular smooth muscle. In addition, the insensitivity to hypoxia of the pulmonary vasculature and a lack of vascular luminal narrowing may tend to minimize increases in pulmonary vascular resistance during chronic hypoxia in the hamster, and thus be beneficial adaptations for a burrowing species.

The role of histamine in acute hypoxic pulmonary hypertension in dogs.

The role of histamine in acute hypoxic pulmonary hypertension was studied in dogs, and the correlation between the effect of histamine and the characteristics of hypoxic pulmonary response was examined. Acute hypoxic pulmonary vasoconstrictive response was not blocked by H1-receptor antagonist, but was potentiated by H2-receptor antagonist. Combined H1- and H2-receptor blockade failed to modify the hypoxic pulmonary vasoconstriction. It seems that H1-receptor antagonist could abolish the potentiating effect of H2-receptor antagonist. Exogenous histamine dilated lung vessels when pulmonary vascular tone was increased. This is in contrast to its vasoconstrictive effect when pulmonary vascular tone was normal. The vasodilating effect of histamine was blocked by H2-receptor antagonist. It is deduced that histamine probably plays the role of a modulator in hypoxic pulmonary vascular response. The dominant effect of H2-receptor caused by increasing pulmonary vascular tone might be implicated in the modulating effect. Infusion of histamine not only suppressed the pulmonary response to hypoxia, but also attenuated the progressive increase in pulmonary vascular resistance in repeated hypoxia. The reduction of the modulating effect of histamine probably contributes to the progressive increase in pulmonary vascular response to repeated hypoxia.

Site and sensitivity for stimulation of hypoxic pulmonary vasoconstriction.

Rat lungs were perfused in an in vitro circuit with separate control of alveolar and pulmonary arterial O2 tension. With perfusion flow constant, the hypoxic pulmonary vasoconstrictor (HPV) response was measured as changes of perfusion pressure. HPV was a function of both alveolar O2 tension (PvO2) and was described by a double sigmoid response surface. Where RA-v is this pressure response expressed as a percent of the maximum, the linearized form of the response surface is given by log [RA-v/(100-RA-v)] = 3.93 - 1.029 (log PvO2) - 1.623 (log PAO2). From this relationship it was concluded that 1) HPV is determined by PAO2 and PvO2; 2) the fundamental stimulus-response relationship is a sigmoid with a 50% response when both PAO2 and PvO2 are 30.3 Torr; 3) PAO2 has a greater effect than PvO2 due in part to the geometry of the vascular wall but principally due to O2 exchange between alveolar gas and blood in small pulmonary arteries; 4) there is not a localized sensor for HPV (the response is accounted for by each smooth muscle cell in the pulmonary arterial wall responding to the O2 tension in its vicinity); and 5) the characteristics of the response suggest that the cell sensor resembles a cytochrome.

Ritodrine inhibition of hypoxic pulmonary vasoconstriction

The effect of ritodrine hydrochloride on hypoxic pulmonary vasoconstriction (HPV), the normal control mechanism for shunting blood flow away from nonventilated areas of the lung, was studied in nonpregnant dogs equipped with central monitors and electromagnetic flow probes. The systemic infusion of ritodrine at a dose of 4 μg/kg/min resulted in a 66.4% ± 4.6% decrease in the HPV response, whether administered before or after the induction of isolated lobar hypoxia. These findings have significant implications for the patient who develops pulmonary edema during ritodrine therapy, in which inability to bypass nonventilated areas of the lung would serve to aggravate further the ventilation/perfusion inequalities that already exist.

Intermittent hypoxia increases lobar hypoxic pulmonary vasoconstriction.

The author tested the hypothesis that in a canine lobar hypoxic pulmonary vasoconstriction (HPV) model, the passage of time alone would eliminate a previously observed association between increasing lobar HPV and repeated intermittent hypoxia of the lung lobe. The HPV model included electromagnetic measurement of the fraction of the cardiac output perfusing the left lower lobe (QLLL/Qt) and ventilation of the left lower lobe (LLL) independent of, but still synchronous with, the rest of the lung. Following surgical preparation of the model, the LLL and the rest of the lung were ventilated with 100% O2 and no further manipulations or procedures were performed for 120-150 min. The LLL then was made intermittently hypoxic four times by ventilation with 95% N2 and 5% CO2 and the LLL HPV response was quantified as the per cent decrease in QLLL/Qt. The LLL was kept either normoxic or hypoxic until the QLLL/Qt ratio was stable for several minutes. The first three LLL hypoxic exposures caused a significant progressive increase in LLL HPV response (from 37.8 to 54.7 to 61.3%) while the second LLL HPV response required significantly less time (16.6 min) to reach a stable decreased QLLL/Qt value compared with the first LLL HPV response (26.4 min). Animals with the smallest initial LLL HPV response increased their HPV response the most, and animals with the largest initial LLL HPV response increased their HPV response the least with repeated LLL hypoxic exposures. The conclusion that intermittent hypoxia increases HPV has important implications for the conduct of HPV experiments and the interpretation of blood-gas changes during one-lung ventilation for thoracic surgery.

Pulmonary blood pressure and flow during atelectasis in the dog.

The purpose of the study was to measure the time course, direction, and magnitude of the hypoxic pulmonary vasoconstriction (HPV) response to atelectasis. Six dogs were anesthetized with pentobarbital. With the chest open, each lung was ventilated separately. Pulmonary blood flow was measured with electromagnetic flow probes. Pulmonary arterial, left atrial, and systemic arterial pressures were measured via indwelling catheters. The right lung was ventilated continuously with 100% O2, while the left lung was either ventilated with 100% O2 (control phase), unventilated (4 hours of atelectasis), or ventilated with a gas mixture containing 4% O2, 3% CO2, and 93% N2 (hypoxia phase). Left lung atelectasis resulted in a reduction of the per cent lung blood flow from 43 +/- 4% (mean +/- SE) to 25 +/- 7% at 15 min and to 12 +/- 1% at 60 min which persisted for the remaining four-hour period. The per cent left lung blood flow was significantly lower (8 +/- 1%) and the PaO2 significantly higher (356 +/- 38 mmHg) during the maximal response to atelectasis as compared to 15 min of hypoxic ventilation (23 +/- 5%; 211 +/- 21 mmHg). With atelectasis or hypoxic ventilation, pulmonary perfusion pressure was increased significantly from the control value of 7.9 +/- 0.8 mmHg to approximately 11 mmHg. The present study demonstrated that in the open chest model without systemic hypoxemia, the response to acute atelectasis is a regional increase in pulmonary vascular resistance which develops quickly (15 min) and is maximal by 60 min and is maintained thereafter. As a result, there is a sustained diversion of blood flow away from the atelectatic lung and a generalized increase of pulmonary perfusion pressure.

Variability of Hypoxic Pulmonary Vasoconstriction in Sheep

In a minority of conscious sheep, the hypoxic pulmonary vasoconstrictor response is blunted ("nonresponders"). The purpose of this investigation was to determine if this blunted response is related to an increased activity of H2-histamine receptors, beta-adrenergic receptors, or the generation of inhibitory prostaglandins. We measured pulmonary arterial pressure, pulmonary arterial wedge pressure, and pulmonary blood flow for the calculation of pulmonary vascular resistance (PVR) in 5 "nonresponders" and 5 sheep with a typical hypoxic pulmonary vasoconstrictor response ("responders") while breathing room air and 13% O2 (balance, N2). Arterial oxygen tension (PaO2) was also determined as a measure of the severity of hypoxia. During hypoxia, mean PVR increased by 6% (p = NS) in the "nonresponders" (PaO2, 49 +/- 4 mmHg), and by 70% (p less than 0.01) in the "responders" (mean PaO2, 46 +/- 4 mmHg). Metiamide (H2-blocker) and propranolol (beta-adrenergic blocker) pretreatments did not restore the hypoxic pulmonary vascular response in the "nonresponders," whereas pretreatment with indomethacin (prostaglandin synthetase inhibitor) caused mean PVR to increase by 48% (p less than 0.01) during hypoxia, indicating a partial restoration of hypoxic pulmonary vasoconstriction. In the "responders," the hypoxic pulmonary vascular response was not potentiated by indomethacin pretreatment (68% increase in mean PVR). We conclude that some sheep exhibit a blunted hypoxic pulmonary vasoconstrictor response caused by enhanced production of inhibitory prostaglandins.

Aminophylline does not inhibit canine hypoxic pulmonary vasoconstriction.

We studied the effect of intravenously administered aminophylline on hypoxic pulmonary vasoconstriction (HPV). The HPV model consisted of 8 pentobarbital anesthetized dogs, weighing 17 to 25 kg, in whom selective hypoxia (95% N2 and 5% CO2) of the left lower lobe (LLL) caused decreases in the electromagnetically measured fraction of the cardiac output perfusing the LLL (expressed as percent decrease QLLL/Qt). Initial and final control (no drug) LLL HPV responses were performed before and 2 h after the aminophylline test HPV responses, and the aminophylline test HPV responses were performed when the drug had been administered before the induction of LLL hypoxia (Group I, n = 4) and after the establishment of LLL hypoxia (Group II, n = 4). In both Groups I and II, our aminophylline dosage schedules, which consisted of intravenously administered boluses of 6 and 3 mg/kg followed by constant infusions of 1 mg/kg/h, resulted in serum theophylline levels that ranged from 12.0 to 15.1 micrograms/ml. The average control LLL HPV response for Groups I and II were, respectively, 72.5 +/- 4.7 and 60.2 +/- 2.8%. In both groups of dogs the magnitude of the LLL HPV responses after the administration of both the 6 and 3 mg/kg dosages of aminophylline were not significantly different when compared with either the initial or final LLL HPV responses or with each other. We conclude that aminophylline does not inhibit acute in vivo lobar HPV in dogs. If these results can be extrapolated to humans, then the effect of aminophylline on arterial oxygenation should simply be explained on the basis of changes in respiratory mechanics rather than some sort of summation of deleterious vasodilator and efficacious bronchodilator effects.