Lipoxygenase and cyclooxygenase blockade by BW 755C enhances pulmonary hypoxic vasoconstriction

Lipoxygenase products (leukotrienes) have been proposed as the mediators of pulmonary hypoxic vasoconstriction. However, the supporting data are inconclusive because the lipoxygenase and leukotriene receptor blockers that reduce hypoxic vasoconstriction (such as diethylcarbamazine and the FPL's) have confounding effects. We investigated BW 755C, a potent inhibitor of both lipoxygenase and cyclooxygenase, in eight intact anesthetized dogs with acute left lower lobe atelectasis. We examined two manifestations of hypoxic vasoconstriction: shunt fraction, as an inverse indicator of regional constriction in response to local hypoxia, and the pulmonary pressor response to global alveolar hypoxia, as an index of general hypoxic vasoconstriction. During normoxia, shunt fraction, measured using a sulfur hexafluoride infusion, was 32.0 +/- 7.0%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient produced by 10% O2 inhalation, averaged 4.5 +/- 1.8 mmHg. Then, during normoxia, BW 755C was administered. Shunt fraction fell in all eight dogs from the previous mean of 32% to 25.5 +/- 6.1% (t = 6.5, P less than 0.0005). The hypoxic pressor response rose in all dogs, from the previous 4.5 mmHg to 9.0 +/- 3.5 mmHg (t = 4.5, P less than 0.005). BW 755C enhances hypoxic vasoconstriction, an effect consistent with its activity as a cyclooxygenase inhibitor. These data do not support a substantive role for the lipoxygenase pathway in hypoxic vasoconstriction.     

Relation of prostanoids to strength of hypoxic vasoconstriction in dogs with lobar atelectasis

In dogs with acute lobar atelectasis, meclofenamate administration decreases shunt fraction uniformly and moderately without abolishing the wide variation of strength of hypoxic vasoconstriction and resultant variability of shunt fraction (J. Appl. Physiol. 54: 284-289, 1983). To further assess the role of prostanoids, we measured prostanoid metabolites as well as shunt fraction and pressor response to alveolar hypoxia. In six intact anesthetized dogs with acute left lower lobe atelectasis, shunt fraction during normoxia was measured with SF6. Levels of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 in arterial, mixed venous, and left lower lobe venous blood were measured with the double antibody radioimmunoassay technique. Ten percent O2 was administered to assess pressor response. Twenty-one percent O2 was restarted, meclofenamate was administered, and measurements were repeated 30 min later. Atelectasis did not elevate levels of prostanoid metabolites. 6-Keto-PGF1 alpha averaged 88 +/- 65 pg/ml prior to atelectasis and 81 +/- 73 pg/ml after atelectasis (F = 0.7, P = NS). Likewise, thromboxane B2 values were normal. No transpulmonary concentration differences were found. 6-Keto-PGF1 alpha did not correlate with shunt values, which ranged from 14 to 35% (mean 21%). Meclofenamate effectively blocked cyclooxygenase, as demonstrated by decreases in prostanoid metabolite levels. It seems likely that in dogs with acute atelectasis prostacyclin localized in the pulmonary vasculature decreases strength of hypoxic vasoconstriction modestly and uniformly without raising blood levels of prostacyclin metabolite.     

Regional alveolar hypoxia does not affect air embolism-induced pulmonary edema

We studied the effects of regional alveolar hypoxia on permeability pulmonary edema resulting from venous air embolization. Anesthetized dogs had the left upper lobe removed and a double-lumen tube placed so that right lung and left lower lobe (LLL) could be ventilated independently. Air was infused into the femoral vein for 1 h during bilateral ventilation at an inspiratory O2 fraction (FIO2) of 1.0. After cessation of air infusion the LLL was then ventilated with a hypoxic gas mixture (FIO2 = 0.05) in six animals and an FIO2 of 1.0 in six other animals. Lung hydroxyproline content was measured as an index of lung dry weight. LLL bloodless lobar wet weight-to-hydroxyproline ratio was 0.33 +/- 0.06 mg/micrograms in the animals exposed to LLL hypoxia and 0.37 +/- 0.03 mg/micrograms (NS) in the animals that had a LLL FIO2 of 1. Both values were significantly higher than our laboratory normal values of 0.19 +/- 0.01 mg/micrograms. We subsequently found in four more dogs exposed to global alveolar hypoxia before and after air embolism that the air injury itself significantly depressed the hypoxic vasoconstrictor response. We conclude that regional alveolar hypoxia has no effect on pulmonary edema formation due to air embolism. The most likely reason for these findings is that the air embolism injury itself interfered with hypoxic pulmonary vasoconstriction.     

Hypoxia augments apnea-induced peripheral vasoconstriction in humans.

Obstructive apnea and voluntary breath holding are associated with transient increases in muscle sympathetic nerve activity (MSNA) and arterial pressure. The contribution of changes in blood flow relative to the contribution of changes in vascular resistance to the apnea-induced transient rise in arterial pressure is unclear. We measured heart rate, mean arterial blood pressure (MAP), MSNA (peroneal microneurography), and femoral artery blood velocity (V(FA), Doppler) in humans during voluntary end-expiratory apnea while they were exposed to room air, hypoxia (10.5% inspiratory fraction of O2), and hyperoxia (100% inspiratory fraction of O2). Changes from baseline of leg blood flow (Q) and vascular resistance (R) were estimated from the following relationships: Q proportional to V(FA), corrected for the heart rate, and R proportional to MAP/Q. During apnea, MSNA rose; this rise in MSNA was followed by a rise in MAP, which peaked a few seconds after resumption of breathing. Responses of MSNA and MAP to apnea were greatest during hypoxia and smallest during hyperoxia (P < 0.05 for both compared with room air breathing). Similarly, apnea was associated with a decrease in Q and an increase in R. The decrease in Q was greatest during hypoxia and smallest during hyperoxia (-25 +/- 3 vs. -6 +/- 4%, P < 0.05), and the increase in R was the greatest during hypoxia and the least during hyperoxia (60 +/- 8 vs. 21 +/- 6%, P < 0.05). Thus voluntary apnea is associated with vasoconstriction, which is in part mediated by the sympathetic nervous system. Because apnea-induced vasoconstriction is most intense during hypoxia and attenuated during hyperoxia, it appears to depend at least in part on stimulation of arterial chemoreceptors.     

Factors affecting perfusion distribution in canine oleic acid pulmonary edema

Factors affecting perfusion distribution in oleic acid pulmonary edema were examined in 28 anesthetized open-chest dogs. Sixteen had unilobar oleic acid edema produced by left lower lobe pulmonary artery infusion of 0.03 ml/kg of oleic acid, and 12 had the same amount of edema produced by left lower lobe endobronchial instillation of hypotonic plasma. Lobar perfusion (determined from flow probes) and lobar shunt (determined from mixed venous and lobar venous blood) were measured at base line, 1.5 h after edema, and 10 min after 10 cmH2O positive end-expiratory pressure (PEEP). Fourteen dogs (8 oleic acid, 6 plasma) received sodium nitroprusside (11.72 +/- 7.10 micrograms X kg-1 X min-1). Total and lobar shunts increased to the same extent in all animals. Lobar perfusion decreased by 49.8 +/- 4.8% without nitroprusside and 34.0 +/- 3.6% with nitroprusside in the oleic acid group, corresponding values being 40.3 +/- 0.8% and 26.4 +/- 1.7% in the hypotonic plasma group. PEEP returned perfusion and shunt to base line. In oleic acid edema, most of the decreased perfusion results from mechanical effects of the edema, a smaller fraction results from other vascular effects of the oleic acid, and approximately 30% is reversible by nitroprusside. PEEP normalizes the perfusion distribution.     

Effect of a local disorder of bronchial patency on the circulation and gas exchange in the lungs

Acute and chronic experiments on dogs have demonstrated the onset of local alveolar hypoxia in disturbed bronchial patency. Alveolar hypoxia caused a rise in the pulmonary vascular resistance. Pulmonary hypertension is predetermined by an increased number of pulmonary zones of hypoxic vasoconstriction due to higher incidence and degree of bronchial obstruction. Despite pulmonary circulation redistribution confirmed by radioactive indicator 99mTc distribution, the perfusion of hypoventilated pulmonary regions is retained leading to venous shunt generation and the reduction of oxygen tension in the arterial animal blood.     

Pulmonary vasoconstriction in a canine model of neurogenic pulmonary edema

The intracisternal administration of veratrine to the chloralose-anesthetized dog produces pulmonary hypertension (PH) and neurogenic pulmonary edema (NPE). To determine whether pulmonary vasoconstriction, mediated by a circulating agent, contributes to the PH, the left lower lung lobe (LLL) perfusion of seven splenectomized (to keep hematocrit and blood viscosity constant) dogs was isolated so the LLL could be perfused at constant flow and outflow pressure with blood pumped from the pulmonary artery. The LLL was denervated by removing it from the dog. Veratrine (40-160 micrograms/kg) increased LLL arterial pressure by 39.2% and produced large increases in plasma catecholamine concentrations. The double-occlusion technique indicated that 74% of the increase in the LLL arteriovenous pressure gradient was due to an increase in venous tone. This pattern of vasoconstriction was similar to that previously observed during the infusion of exogenous catecholamines and suggested that catecholamines mediated the LLL response. The more severe degree of PH observed in the intact animal in NPE, however, suggests that passive rather than active changes in pulmonary hemodynamics are predominantly responsible for the development of PH in this disorder.     

Mechanisms by which dopamine alters blood flow distribution during lobar collapse in dogs

Dopamine increases blood flow to a hypoxic left lower lobe in dogs. To elucidate possible mechanisms, left lower lobe collapse was induced in anesthetized dogs, and lobar (QLLL) and total (QT) pulmonary blood flow was measured by electromagnetic flow probes. Dopamine infusion increased mean pulmonary arterial pressure (Ppa), QT, and QLLL. However, the increase in QLLL was double that produced by a similar increase in Ppa without increase in QT (inflation of a Swan-Ganz balloon in right pulmonary artery) or by a similar increase in QT with smaller increase in Ppa (opening of arteriovenous fistulas). QLLL/QT was not changed by opening arteriovenous fistulas, but was increased by Swan-Ganz balloon inflation, and by infusion of dopamine. It is concluded that the increase in QLLL/QT produced by dopamine was due to a decrease in hypoxic vasoconstriction in the lobe secondary to an increase in mixed venous PO2 and to vasoconstriction in the oxygenated lung.     

Does indomethacin affect shunt and its response to PEEP in oleic acid pulmonary edema?

We assessed hemodynamics, lobar perfusion, and shunts at base line 1.5 h after unilobar oleic acid edema, 15 min after indomethacin (10 mg/kg iv), and 15 min after positive end-expiratory pressure (PEEP) (10 cm) in 10 dogs. In 10 additional dogs (control) the same measurements were made but no indomethacin was administered. Shunts of the edematous lobe were: 10.6 +/- 6.3, 54.1 +/- 22.8, 30.8 +/- 16.6, and 12.4 +/- 6.3% for dogs administered indomethacin and 10.9 +/- 4.2, 53.8 +/- 13.1, 72.3 +/- 14.6, and 11.5 +/- 4.1% for the controls. Perfusions (% cardiac output) to the edematous lobe were 27.6 +/- 3.6, 14.6 +/- 2.0, 9.9 +/- 1.5, and 27.9 +/- 2.9% in the dogs administered indomethacin and 27.3 +/- 3.1, 14.0 +/- 1.7, 13.2 +/- 1.3, and 26.9 +/- 2.8% in controls. The decrease in lobar perfusion was similar before indomethacin with a further decrease in lobar perfusion and an increase in lobar vascular resistance 15 min after indomethacin. The increase in vascular resistance of the edematous lobe was three times that of nonedematous lobes after indomethacin (149.6 +/- 76% vs. 58.0 +/- 43%). Indomethacin, therefore, decreases shunt possibly by enhancing alveolar hypoxic vasoconstriction and does not block the improvement in shunt with PEEP.     

Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1.

Hypoxia-inducible factor (HIF)-1 is stabilized by hypoxia and iron chelation. We hypothesized that HIF-1 might be involved in pulmonary vascular regulation and that infusion of desferrioxamine over 8 h would consequently mimic hypoxia and elevate pulmonary vascular resistance. In study A, we characterized the pulmonary vascular response to 4 h of isocapnic hypoxia; in study B, we measured the pulmonary vascular response to 8 h of desferrioxamine infusion. For study A, 11 volunteers undertook two protocols: 1) 4 h of isocapnic hypoxia (end-tidal PO(2) = 50 Torr), followed by 2 h of recovery with isocapnic euoxia (end-tidal PO(2) = 100 Torr), and 2) 6 h of air breathing (control). For study B, nine volunteers undertook two protocols while breathing air: 1) continuous infusion of desferrioxamine (4 g/70 kg) over 8 h and 2) continuous infusion of saline over 8 h (control). In both studies, pulmonary vascular resistance was assessed at 0.5- to 1-h intervals by Doppler echocardiography via the maximum pressure gradient during systole across the tricuspid valve. Results show a progressive rise in pressure gradient over the first 3-4 h with both isocapnic hypoxia (P < 0.001) and desferrioxamine infusion (P < 0.005) to increases of ~16 and 4 Torr, respectively. These results support a role for HIF-regulated gene activation in human hypoxic pulmonary vasoconstriction.     

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.     

Acute and chronic hypoxic pulmonary hypertension in guinea pigs

To determine whether the strength of acute hypoxic vasoconstriction predicts the magnitude of chronic hypoxic pulmonary hypertension, we performed serial studies on guinea pigs. Unanesthetized, chronically catheterized guinea pigs increased mean pulmonary arterial pressure (PAP) from 11 +/- 0.5 to 13 +/- 0.7 Torr in acute hypoxia (10% O2 for 65 min). The response was maximal at 5 min, remained stable for 1 h, and was reversible on return to room air. Cardiac index did not change with acute hypoxia or recovery. Guinea pigs exposed to chronic hypoxia increased PAP, measured in room air 1 h after removal from the hypoxic chamber, to 18 +/- 1 Torr by 5 days with little further increase in PAP to 20 +/- 1 Torr after 21 days. Cardiac index fell from 273 +/- 12 to 206 +/- 7 ml.kg-1.min-1 (P less than 0.05) after 21 days of hypoxia. Medial thickness of pulmonary arteries adjacent to terminal bronchioles and alveolar ducts increased significantly by 10 days. The magnitude of the pulmonary vasoconstriction to acute hypoxia persisted and was unabated during the development and apparent stabilization of chronic hypoxic pulmonary hypertension, suggesting that if vasoconstriction is the stimulus for remodeling, then the importance of the stimulus lessens with duration of hypoxia. In individual animals followed serially, we found no correlation between the magnitude of the acute vasoconstrictor response before chronic hypoxia and the severity of chronic pulmonary hypertension that subsequently developed either because the initial response was small and variable or because vasoconstriction may not be the sole stimulus for vascular remodeling in the guinea pig.     

Effect of hypoxia on erythrocyte deformability in different species

The contribution of erythrocyte deformability to the pulmonary vascular resistance during hypoxia in different animal species has not been examined. We hypothesized that the increase in pulmonary vascular resistance during hypoxia was partially due to erythrocytes (RBC's) becoming less deformable during hypoxia, and therefore their transit in the capillaries becomes restricted. To test this, we measured an index of deformability of RBC's from six animal species (dog, pig, cat, rabbit, hamster, rat) during normoxic and hypoxic condition, and compared the changes in deformability with the pulmonary hypoxic pressor response (HPR) which has been reported in the same species. Deformability was indexed as the resistance that a Hemafil polycarbonate membrane (Nucleopore filter, 4.7 micron pores) offers to a 10% suspension of RBC's. The RBC suspension was either normoxic (PO2 = 150 torr) or hypoxic (PO2 = 50 torr). We found that hypoxia decreased RBC deformability; the largest decrease occurred in rat RBC's, a small but significant decrease was observed in the RBC's of cats, rabbits and hamsters, but no change was detected in RBC's of dogs or pigs. In general, such changes in deformability do not correlate well with the HPR in intact or in isolated lungs, for example the pig, had the largest HPR but the smallest change in RBC deformability. In some species, however, there was a positive correlation between RBC deformability and HPR, for example rats, rabbits and cats are usually better responders than dogs and hamsters, similarly the deformability of RBC's in rats, rabbits and cats were also more influenced by hypoxia than RBC's from dogs. The limiting factors in this relationship are the artificial conditions which were used to measure deformability and HPR, both may be different than in the intact conditions. Nevertheless the present data show that erythrocytes of some species can become less flexible during hypoxia, and hence may impede the transit in the capillaries. Therefore we propose that the hypoxic pressor response in the pulmonary vasculature may be partly due to smooth muscle contraction (vasoconstriction) and partly due to a decrease in erythrocyte deformability (capillary obstruction). Both components are likely to be species dependent.     

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.     

Regional hypoxic pulmonary vasoconstriction in prone pigs.

Hypoxic pulmonary vasoconstriction (HPV) is known to affect regional pulmonary blood flow distribution. It is unknown whether lungs with well-matched ventilation (V)/perfusion (Q) have regional differences in the HPV response. Five prone pigs were anesthetized and mechanically ventilated (positive end-expiratory pressure = 2 cmH2O). Two hypoxic preconditions [inspired oxygen fraction (FI(O2)) = 0.13] were completed to stabilize the animal's hypoxic response. Regional pulmonary blood Q and V distribution was determined at various FI(O2) (0.21, 0.15, 0.13, 0.11, 0.09) using the fluorescent microsphere technique. Q and V in the lungs were quantified within 2-cm3 lung pieces. Pieces were grouped, or clustered, based on the changes in blood flow when subjected to increasing hypoxia. Unique patterns of Q response to hypoxia were seen within and across animals. The three main patterns (clusters) showed little initial difference in V/Q matching at room air where the mean V/Q range was 0.92-1.06. The clusters were spatially located in cranial, central, and caudal portions of the lung. With decreasing FI(O2), blood flow shifted from the cranial to caudal regions. We determined that pulmonary blood flow changes, caused by HPV, produced distinct response patterns that were seen in similar regions across our prone porcine model.     

Strength of pulmonary vascular response to regional alveolar hypoxia.

Regional alveolar hypoxia in the lung induces regional pulmonary vasoconstriction which diverts blood flow from the hypoxic area. However, the predominant determinant of the distribution of perfusion in the normal erect lung is gravity so that more perfusion occurs at the base than at the apex. To determine the strength of the regional alveolar hypoxic response in diverting flow with or against the gravity gradient a divided tracheal cannula was placed in anesthetized dogs and unilateral alveolar hypoxia created by venilating one lung with nitrogen while ventilating the other lung with oxygen to preserve normal systemic oxygentation. Scintigrams of the distribution of perfusion obtained with intravenous 13-N and the MGH positron camera revealed a 34 and 32 per cent decrease in perfusion to the hypoxic lung in the supine and erect positions and a 26 per cent decrease in the decubitus position with the hypoxic lung dependent (P equal to 0.94 from supine shift), indicating nearly equal vasoconstriction with shift of perfusion away from the hypoxic lung in all positions. Analysis of regional shifts in perfusion revealed an equal vasoconstrictor response from apex to base in the supine position but a greater response in the lower lung zones in the erect position where perfusion was also greatest.     

Pulmonary vascular responses to surgical chemodenervation and chemical sympathectomy in dogs

We investigated the effects of surgical peripheral chemoreceptor denervation, chemical sympathectomy with 6-hydroxydopamine (6-OHDA), and the peripheral chemoreceptor stimulant almitrine on multipoint pulmonary arterial pressure-cardiac index (PAP/Q) plots in 30 pentobarbital sodium-anesthetized dogs ventilated alternatively in hyperoxia [fraction of inspired O2, (FIO2) = 0.4] and hypoxia (FIO2 = 0.1). A hypoxic pulmonary vasoconstriction (HPV), i.e., a hypoxia-induced increase in PAP over the entire range of Q studied, from 2 to 5 l.min-1.m-2, was elicited in all the animals. Surgical denervation of the carotid and aortic chemoreceptors in a first group of nine dogs increased PAP at the lowest Q of 2 and 3 l.min-1.min-2 in hyperoxia and increased PAP at all levels of Q in hypoxia, so that HPV was enhanced. Chemical sympathectomy in a second group of eight dogs increased PAP at all levels of Q to a comparable extent in hyperoxia and hypoxia so that HPV remained unchanged. Almitrine (8 micrograms.kg-1.min-1 iv) in a third group of eight dogs increased PAP at all levels of Q in hyperoxia but had no effect on PAP/Q plots in hypoxia, so that HPV was inhibited. Almitrine had these same pulmonary vascular effects when administered to the chemodenervated and the sympathectomized dogs. Sham operation and a 2-h delay in a final group of five dogs had no effect on hyperoxic or hypoxic PAP/Q plots. We conclude that in intact dogs 1) the sympathetic nervous system reduces both hyperoxic and hypoxic pulmonary vascular tone, 2) stimulation of the peripheral chemoreceptors inhibits HPV, and 3) almitrine has direct pulmonary vasoconstricting effects in hyperoxia but not hypoxia.     

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)     

Redistribution of blood flow and lung volume between lungs in lateral decubitus postures during unilateral atelectasis and PEEP

The effect of left lung atelectasis on the regional distribution of blood flow (Q), ventilation (V(A)) and gas exchange on the right lung ventilated with 100% O2 was studied in anesthetized dogs in the lateral decubitus posture. Q and V(A) were measured in 1.7 ml lung volume pieces using injected and aerosolized fluorescent microspheres, respectively. Hypoxic pulmonary vasoconstriction (HPV) in the atelectatic lung shifted flow to the ventilated lung. The increased flow in the ventilated lung ensured adequate gas exchange, compensating for the hypoxemia due to shunt contributed by the atelectatic lung. Left lung atelectasis caused a compensatory increase in the ventilated lung FRC that was smaller in the right (RLD) than left (LLD) lateral posture, the effect of lung compression by the atelectatic lung and mediastinal contents in the RLD posture. The O2 deficit measured by (A-a)DO2 increased with left lung atelectasis and was exacerbated in the LLD posture by 10 cm H2O PEEP, a result of increased shunt caused by a shift in Q from the ventilated to the atelectatic lung. The PEEP-induced O2 deficit was eliminated with inversion to the RLD posture.     

Attenuation of pulmonary and systemic vasoconstriction with pentoxifylline and aminophylline

The effects of acute administration of therapeutic doses (1-10 mg/kg) of pentoxifylline and aminophylline on the resistance of the systemic and pulmonary circuits in anaesthetized dogs and pigs were tested. During room air breathing, neither of the two substances caused a significant change in systemic vascular resistance (SVR) or pulmonary vascular resistance (PVR). During hypoxia (10% O2 and nitrogen), however, both substances caused a significant reduction in PVR (p less than 0.05) without affecting SVR. The largest dose of pentoxifylline decreased PVR from 7.8 +/- 2.8 to 4.4 +/- 1.5 in dogs and from 9.9 +/- 1.4 to 5.8 +/- 0.6 mmHg.L-1.min in pigs. Aminophylline was equally effective and selective in lowering PVR but not SVR during hypoxia. When SVR was elevated in dogs by continuous infusion of angiotensin, pentoxifylline lowered SVR from 139 +/- 27 to 83 +/- 20 mmHg.L-1.min (p less than 0.05). The simultaneous small elevation in PVR during angiotensin infusion was also attenuated to base-line value by pentoxifylline injection. These results suggest that xanthines, in therapeutic doses, can have a profound vasodilator effect on either the systemic or on the pulmonary circuit, only wherever the vessels are constricted. The vasodilatory effect of pentoxifylline is viewed as a second beneficial effect besides the benefit derived from its action on erythrocyte deformability.