Left Lung Blood Flow Research Articles

Inhibition of Soluble Epoxide Hydrolase Augments Hypoxic Pulmonary Vasoconstriction and Improves Gas Exchange in Mice

Recent studies report that cytochrome P‐450‐derived epoxyeicosatrienoic acids (EETs) increase pulmonary vascular tone. We hypothesized that inhibiting the metabolism of EETs by inhibition of soluble epoxide hydrolase (sEH) would augment hypoxic pulmonary vasoconstriction (HPV) and improve gas exchange.Mice were anesthetized, intubated, and ventilated at FIO2=1. Animals received an i.v. infusion of the sEH inhibitor, IK‐950, or vehicle 30 minutes prior to assessing HPV. After thoracotomy, pulmonary artery pressure (PAP) and left lung blood flow (QLPA) were measured before and during transient inferior vena cava occlusion. Left lung pulmonary vascular resistance (PVRL) was calculated from the slope of the PAP‐QLPA relationship. The pulmonary vasoconstrictor response to unilateral left lung hypoxia was estimated by comparing PVRL before and after left main stem bronchial occlusion (LMBO).Infusion of vehicle or IK‐950 did not change baseline hemodynamic parameters. LMBO increased PVRL, without changing PAP in both vehicle‐and IK‐950‐pretreated mice. Increase in PVRL during LMBO was greater in mice pretreated with IK‐950 than in those pretreated with vehicle (Table). PaO2 after LMBO was greater in mice pretreated with IK‐950 than in those pretreated with vehicle.Taken together, these results indicate that IK‐950 acts as a selective pulmonary vasoconstrictor of hypoxic lung regions, enhancing the perfusion of ventilated lung regions.

Cytochrome P‐450 2J epoxygenase gene function in murine hypoxic pulmonary vasoconstriction (HPV)

Recent studies suggest that cytochrome P‐450 (CYP) epoxygenase‐derived epoxyeicosatrienoic acids (EETs) play an important role in the regulation of the pulmonary vascular tone. To assess the role of the CYP2J‐signaling pathway in HPV, we studied CYP2J+/+ and CYP2J−/− mice, as well as CYP2J−/− mice carrying a transgene specifying human CYP2J (CYP2J−/−‐Tg). Mice were anesthetized, intubated, and ventilated at FIO2=1. After thoracotomy, pulmonary artery pressure (PAP) and left lung blood flow (QLPA) were measured before and during transient inferior vena cava occlusion. Left pulmonary vascular resistance (LPVR) was calculated from the slope of the PAP‐QLPA relationship. The pulmonary vasoconstrictor response to unilateral left lung hypoxia was estimated by comparing LPVR before and after left main stem bronchial occlusion (LMBO). LMBO increased LPVR in CYP2J+/+ and CYP2J−/−‐Tg mice but not in CYP2J−/− mice (see Table). PaO2 during LMBO was greater in CYP2J+/+ and CYP2J−/−‐Tg mice than in CYP2J−/− mice. Administration of MS‐PPOH, a selective inhibitor of CYP‐mediated epoxygenation, blocked the ability of LMBO to increase LPVR in CYP2J+/+ mice. Taken together, these results indicate that CYP2J epoxygenase contributes importantly to HPV in mice. (Supported by MGH, Department of Anesthesia, Critical Care and Pain Medicine).

Synchronized independent lung ventilation in palliated congenital heart disease with variable sources of pulmonary blood flow.

OBJECTIVE: Presentation of two patient studies demonstrating the use of synchronized independent lung ventilation in the management of acute respiratory failure in patients with complex palliated congenital heart disease and variable sources of pulmonary blood flow. DESIGN: Clinical course of two patients. SETTING: Cardiac intensive care unit in a tertiary care, university-affiliated pediatric teaching hospital. PATIENTS: Patient 1 was a 22-yr-old woman with a single ventricle and right lung blood flow supplied by a classic Glenn shunt and left lung blood flow through a systemic-to-pulmonary artery shunt. Patient 2 was a 12-yr-old boy with tetralogy of Fallot and complete common atrioventricular canal defect with right lung blood flow supplied by a classic Glenn shunt and left lung blood flow supplied by the right ventricle. Both patients presented with acute, left-sided lung disease and hypoxemia. INTERVENTIONS: We used selective bronchial intubation via a double-lumen tracheal tube with a bronchial extension for synchronized independent lung ventilation to permit high-pressure ventilation of the abnormal left lung low-pressure ventilation of the normal right lung supplied by a Glenn shunt. Inhaled nitric oxide was administered to both patients and continued in one when improved oxygenation was observed. MEASUREMENTS AND MAIN RESULTS: Serial arterial blood gas measurements, mechanical indices of pulmonary function, and chest radiographs were closely followed. Synchronized independent lung ventilation contributed to improvements in systemic arterial blood oxygenation and alveolar ventilation allowing resumption of conventional ventilation in both patients. No adverse effects related to bronchial tube placement or maintenance occurred. CONCLUSION: Independent lung ventilation is an effective means of isolating the two lungs for differential ventilation, as well as the selective delivery of inhaled medications. In patients with unilateral lung disease and a Glenn shunt supplying the unaffected lung, selective lung ventilation allows aggressive treatment of the abnormal lung while optimizing flow through the Glenn shunt to maximize effective pulmonary blood flow, systemic oxygenation, and hemodynamics.

Inhaled nitric oxide during partial liquid ventilation shifts pulmonary blood flow to the non-dependent lung regions.

To elucidate the change in pulmonary blood flow brought about by nitric oxide (NO) inhalation during partial liquid ventilation (PLV). Prospective, controlled study. A research laboratory at a university medical center. Fourteen Japanese white rabbits (3.2 +/- 0.05 kg body weight). Animals were mechanically ventilated in the right decubitus position. Following saline lung lavage, PLV was started with perflubron (15 ml/kg). In the NO group (n = 7), PLV was supplemented by a 30-min challenge of NO inhalation (10 ppm) from 30 min after the initiation of PLV. In the control group (n = 7), PLV was continued for 60 min. For the pulmonary blood flow analysis, colored microspheres were administered from the right atrium at 30 min (T(PLV1)) and 60 min (T(PLV2)) after the initiation of PLV. The percentage of the left lung blood flow in the total pulmonary blood flow (%Q(L)/Q(T)) was significantly increased by NO inhalation in the NO group (p = 0.0164), while that in the control group was significantly decreased during the same period (p = 0.0107). PaO2 in the NO group was significantly increased by NO inhalation (p = 0.0153), but not in the control group (p = 0.7911). Inhaled NO during PLV shifted the pulmonary blood flow to the non-dependent region and improved pulmonary gas exchange. This result suggested that inhaled NO took effect predominantly in the non-dependent region during PLV.

Inhaled carbon monoxide does not cause pulmonary vasodilation in the late-gestation fetal lamb.

As observed with nitric oxide (NO), carbon monoxide (CO) binds and may activate soluble guanylate cyclase and increase cGMP levels in smooth muscle cells in vitro. Because inhaled NO (I(NO)) causes potent and sustained pulmonary vasodilation, we hypothesized that inhaled CO (I(CO)) may have similar effects on the perinatal lung. To determine whether I(CO) can lower pulmonary vascular resistance (PVR) during the perinatal period, we studied the effects of I(CO) on late-gestation fetal lambs. Catheters were placed in the main pulmonary artery, left pulmonary artery (LPA), aorta, and left atrium to measure pressure. An ultrasonic flow transducer was placed on the LPA to measure blood flow to the left lung. After baseline measurements, fetal lambs were mechanically ventilated with a hypoxic gas mixture (inspired O(2) fraction < 0.10) to maintain a constant fetal arterial PO(2). After 60 min (baseline), the lambs were treated with I(CO) [5-2,500 parts/million (ppm)]. Comparisons were made with I(NO) (5 and 20 ppm) and combined I(NO) (5 ppm) and I(CO) (100 and 2,500 ppm). We found that I(CO) did not alter left lung blood flow or PVR at any of the study doses. In contrast, low-dose I(NO) decreased PVR by 47% (P < 0.005). The combination of I(NO) and I(CO) did not enhance the vasodilator response to I(NO). To determine whether endogenous CO contributes to vascular tone in the fetal lung, zinc protoporphyrin IX, an inhibitor of heme oxygenase, was infused into the LPA in three lambs. Zinc protoporphyrin IX had no effect on baseline PVR, aortic pressure, or the pressure gradient across the ductus arteriosus. We conclude that I(CO) does not cause vasodilation in the near-term ovine transitional circulation, and endogenous CO does not contribute significantly to baseline pulmonary vascular tone or ductus arteriosus tone in the late-gestation ovine fetus.

Prolonged Estradiol Infusion Causes a Marked and Sustained Increase in Pulmonary Blood Flow in Fetal Lambs • 1717

Estradiol (E2), a steroid hormone which causes vasodilation of many adult tissues, is present in high levels in the fetus and surges just prior to delivery. However, whether E2 contributes to the marked increase in pulmonary blood flow (PBF) which characterizes the normal transitional circulation at birth is not known. Because the surge in E2 immediately preceeds the fall in pulmonary vascular resistance (PVR), we hypothesized that E2 modulates the increase in PBF at birth. To study whether E2 causes pulmonary vasodilation in fetal lambs, we treated chronically prepared lambs with intrapulmonary infusions of E2 or vehicle (V) and measured their hemodynamic responses. Fetal surgery was performed at 128 d (term=147 d) and catheters were placed in the aorta, main pulmonary artery, and left atrium for pressure measurements and the left pulmonary artery (LPA) for local infusions of E2. An ultrasonic flow transducer was placed around the left pulmonary artery to measure blood flow. Aortic and pulmonary artery pressure (PAP), left atrial pressure (LAP), and left pulmonary blood flow (Qp) were measured daily. PVR in the left lung was calculated by (PAP-LAP)/Qp. After recovery from surgery, E2 (250 ng/hr; n=9) or vehicle (0.025% ethanol; n=4) was infused continuously into the LPA for 8 days or until PBF increased. E2 treatment increased left lung blood flow(195±44 vs. 55±12 ml/min, E2 vs. V, p<0.05) and decreased left lung PVR (0.31±0.07 vs. 0.93±0.20 mmHg/ml/min, E2 vs. V, p<0.05). The response of individual animals varied markedly and treated females responded earlier than did males (change in left lung PVR at 48 hours,-44±16 vs. 15±10%, female vs. male, p<0.05). In a second set of extremely premature animals (n=4), fetal surgery was performed at 114 d and E2 infusions started 3 d after surgery. 2 of these 4 animals responded, with PBF increasing from 53 and 73 to 186 and 173 ml/min, respectively. We conclude that continuous infusion of E2 causes marked and sustained pulmonary vasodilation in near-term fetal lambs, and that this effect can also be demonstrated in very premature fetal lambs. Because E2 causes acute nitric oxide (NO) release and endothelial nitric oxide synthase upregulation in isolated pulmonary artery endothelial cells from fetal lambs, we speculate that E2 mediates its vasoactive effects through endogenous NO release.

Pulmonary Vascular Effects of Selective cGMP-Specific (Type V) Phosphodiesterase Inhibitors in the Ovine Fetus. ♦ 314

The nitric oxide (NO) - cGMP cascade modulates perinatal pulmonary vascular tone. cGMP-specific (type V) phosphodiesterase (PDE5) hydrolyzes cGMP, limiting vasodilation and maintaining high pulmonary vascular resistance (PVR) in the fetus. Two new drugs, E4021 (Eisai) and DMPPO (Glaxo-Welcome), have been developed which cause potent and selective inhibition of PDE5 activity. To test the hypothesis that PDE5 activity contributes to high PVR in the fetal lung, we studied the hemodynamic effects of these novel PDE5 antagonists in 11 chronically-prepared, late gestation fetal lambs (mean gestational age, 132 days; 147 days, term). At surgery, we placed catheters in the main pulmonary artery (PAP), aorta (AoP), left atrium (LAP) and amniotic cavity to measure pressure. A catheter was placed in the left pulmonary artery (LPA) to infuse drug directly into the left lung. An ultrasonic flow transducer was placed on the LPA to measure left lung blood flow. After at least 48 hours recovery from surgery, E4021 (doses: 0.04 - 4 mg) were infused over 10 minutes into the LPA. Hemodynamic measurements were recorded at baseline and at 10 minute intervals for 60 minutes. E4021 caused dose-related pulmonary vasodilation, decreasing PVR from baseline by 30% (0.04 mg) to 58% (4 mg; p 1 mg. Equimolar infusions of DMPPO caused a similar fall in PVR(61%). To determine the importance of endogenous NO in stimulation of cGMP production, E4021 (1 mg) was infused before and after treatment with nitro-L-arginine (L-NA), a selective inhibitor of NO synthase. L-NA completely blocked E4021 -induced pulmonary vasodilation. We conclude that E4021 and DMPPO cause potent pulmonary vasodilation in the ovine fetus. These findings support the hypothesis that PDE5 plays a critical role in regulation of pulmonary vascular tone in the developing lung. We speculate that PDE5 inhibitors may provide a new therapy for pulmonary hypertension.

Plasma copper and iron changes in sheep after left lung inhalation injury: effect of the thromboxane antagonist BM 13.177 (Solutroban).

A significant decline in plasma concentrations of copper and iron were observed in sheep exposed to preferential smoke inhalation of the left lung. The decline was evident 30 minutes after smoke inhalation, and the levels of both trace metals persisted at quite low levels for up to the 18-hour time interval after injury. From that time a gradual recover for copper but not for iron levels was observed so that by 24 hours the levels of copper were in the same range of those at baseline. Copper and iron levels showed an inverse correlation to airway peak and plateau pressures and left lung vascular resistance index and a direct correlation to left lung blood flow. Administration of BM 13.177 (Solutroban), a thromboxane antagonist, before exposure to smoke inhalation protected the sheep from the decline of copper and iron levels in plasma. In these animals airway peak and plateau pressure, left lung vascular resistance, and blood flow were also unmodified. Lipid peroxidation of the lung tissue by oxygen free radicals were lower than in those animals that did not receive BM 13.177. There was likewise a tendency of a decreased wet-to-dry weight ratios in the animals treated with BM 13.177. BM 13.177 treatment in an inhalation injury model might partly protect lung damage and parallels unchanged plasma copper and iron levels. The plasma copper and iron may therefore be an indicator of acute lung damage.

UNILATERAL SMOKE INHALATION INCREASES PULMONARY BLOOD FLOW TO THE INJURED LUNG

Smoke inhalation (SI) affects the homogeneity of lung perfusion possibly by increasing alveolar surface tension. Anesthetized dogs (n = 8) were ventilated with a tracheal divider and a dual ventilator. One lung (left or right) was exposed to 5 minutes of SI while the other remained on room air. Total pulmonary blood flow (cardiac output) was measured by thermal dilution and left lung blood flow was measured with an ultrasonic flow probe. Since SI is associated with elevation of alveolar surface tension (AST), we studied a second group of dogs (n = 6) in which AST was increased in one lung with aerosolized dioctyl sodium sulfosuccinate (OT). The OT elevates AST without otherwise damaging the lung. Unilateral SI resulted in systemic hypoxemia (Pao2 fell from 91 +/- 6 to 55 +/- 4 mm Hg) and increased venous admixture (9 +/- 2% to 29 +/- 4%) both of which remained different from baseline values (p < 0.05) for 2 hours. Blood flow to the smoke exposed lung increased gradually and became significantly larger than that to the contralateral normal lung 2 hours following inhalation (smoke lung = 64% +/- 6% and normal lung = 36% +/- 6% of total blood flow). Following smoke exposure, pulmonary vascular resistance (PVR) increased with time in the unexposed normal lung (baseline = 8.7 +/- 1.4; 2 hours post smoke = 22.6 +/- 7.9 mm Hg/L/min, p < 0.05); PVR did not change in the smoke injured lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary hemodynamics and tissue damage after one lung infusion of Pseudomonas aeruginosa in sheep.

The relative roles of hematogenous mediators and direct bacterial toxicity due to phagocytosis by pulmonary intravascular macrophages were determined by selective bacterial infusion into the left pulmonary artery and comparison of right and left lungs at 24 h. Chronically instrumented sheep received 15-min pulmonary arterial infusions of live Pseudomonas aeruginosa (0.35-2.9 x 10(9), n = 6) or saline (n = 5). The saline group demonstrated stable cardiopulmonary function over time. Left lung blood flow, measured by Doppler flow probe, decreased 15 min into the bacterial infusion, with a concomitant sevenfold increase in left lung pulmonary vascular resistance index. The right lung pulmonary vascular resistance index doubled at 1 h, in association with increased plasma thromboxane B2 levels. An increase in cardiac index and decrease in systemic vascular resistance occurred at 12 h. The wet-to-dry weight ratio of the Pseudomonas-infused left lung was increased compared with that of the sham-infused lung. The tissue count of neutrophils in the lungs was doubled in both sides, but neutrophils on the left were more degranulated. The left lung tissue damage was caused by direct bacterial toxicity, including activation of phagocytic cells. Hematogenous mediators induced pulmonary and systemic hemodynamic changes and right lung neutrophil sequestration, but they did not damage the noninfused lung.

Antibody against neutrophil adhesion improves reperfusion and limits alveolar infiltrate following unilateral pulmonary artery occlusion

Relief of unilateral pulmonary arterial occlusion results in bilateral lung injury and results in only partial restoration of pulmonary blood flow distal to the site of occlusion. We hypothesized that the “no reflow” phenomenon was in part due to neutrophil adherence and aggregation in the pulmonary vasculature. The study was carried out in two phases. First, we studied the effect of neutrophil depletion on left lung blood flow following 24 hr of left pulmonary artery occlusion. Hydroxyurea was used to deplete circulating neutrophils to 77 ± 18/mm 3 (means ± sem) ( n = 6) as compared to 708 ± 165/mm 3 in control rabbits ( n = 8). In both groups left lung blood flow immediately following reperfusion was markedly reduced at 6.4 ± 2.2% of cardiac output in control rabbits and 7.3 ± 2.3 in treated rabbits. However, at 4 hr, neutrophil-depleted animals had significantly greater flow (18.7 ± 3.6 vs 8.4 ± 2.3% for control rabbits, P < 0.05). In both groups, flow remained substantially below the normal rabbit left lung blood flow of 39.8 ± 2.2%. To test whether the improved reflow was due to decreased numbers of neutrophils limiting aggregation, or whether active neutrophil adherence played a role, we tested the effect of a monoclonal antibody that interferes with neutrophil adhesiveness (MoAb 60.3) on reflow and on neutrophil emigration into the alveoli. We found that MoAb 60.3 did not affect initial reflow. However, at 24 hr, flow in treated rabbits was virtually normal (38.8 ± 1.5+%) but remained markedly diminished in untreated animals at 25.5 ± 3.9%. MoAb 60.3 also markedly diminished neutrophil emigration into the alveoli following reperfusion. We conclude that neutrophils play a significant role in preventing reflow following lung ischemia and that inhibition of neutrophil adhesiveness reverses this phenomenon and decreases the inflammatory response in the alveolus.

Low-Dose Almitrine Bismesylate Enhances Hypoxic Pulmonary Vasoconstriction in Closed-Chest Dogs

The effect of almitrine bismesylate on the hypoxic pulmonary vasoconstrictor response was studied in six closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2; the left lung was ventilated either with 100% O2 ("hyperoxia") or with an hypoxic gas mixture ("hypoxia": end-tidal oxygen tension = 60.3 +/- 0.6 mm Hg). On two consecutive days, each dog received either almitrine (Vectarion, Servier Lab) or malic acid. Consecutive almitrine doses of 0.003, 0.03, 0.3, and 3.0 micrograms.kg-1.min-1, or the equivalent volumes of malic acid without almitrine, were administered intravenously as a constant peripheral infusion for 15 min. Percent blood flow to each lung was calculated based on a variation of the traditional shunt equation. The change in percent left lung blood flow (delta %QL-VA) increased significantly between the hypoxia-no drug and the hypoxia-almitrine (3.0 micrograms.kg-1.min-1) phase. No significant changes occurred during the other almitrine doses or the respective malic acid control phases. The change in arterial oxygen tension (delta PaO2) also increased significantly between the hypoxia-no drug and the hypoxia-almitrine (3.0 micrograms.kg-1.min-1) phase. No significant changes occurred during the other almitrine doses or the respective malic acid control phases. It is concluded that in dogs low-dose almitrine enhances hypoxic pulmonary vasoconstriction and that this enhancement is dose-related.

Effect of positive end-expiratory pressure on hypoxic pulmonary vasoconstriction in the dog

We studied the effects of uni- and bilateral positive end-expiratory pressure (PEEP) on pulmonary artery pressure-flow (Ppa/Q) relationships during unilateral hypoxia in anesthetized dogs. A bronchial divider was inserted, the right lung was ventilated with 100% O2, and the left lung was ventilated with either 100% O2 (hyperoxia) or a hypoxic gas mixture (hypoxia). Left lung blood flow (QL) and aortic flow (QT) were measured by electromagnetic flow probes. Simultaneous Ppa/Q relations for both lungs, with Q on the ordinate, were obtained by altering QT via an arteriovenous fistula and an inferior vena cava occluder. Ppa/Q slopes (delta Q/delta Ppa) and extrapolated zero-flow Ppa intercepts (Pzf) were obtained by linear regression analysis. Bilateral PEEP increased Pzf for both lungs (P less than 0.01) but did not alter delta Q/delta Ppa of either lung. Unilateral PEEP decreased ipsilateral blood flow (P less than 0.001) and increased Pzf for the ipsilateral lung (P less than 0.05). Left lung PEEP did not affect the slope of the left lung Ppa/Q relationship (delta QL/delta Ppa). Hypoxic ventilation of the left lung decreased QL (P less than 0.001), increased Pzf (P less than 0.05), and decreased delta QL/delta Ppa (P less than 0.001). Neither uni- nor bilateral PEEP altered this flow diversion away from the left lung or the reduction in delta QL/delta Ppa with left lung hypoxia. We conclude that PEEP and alveolar hypoxia increase pulmonary vascular resistance at different loci, such that their effects are additive. A net increase in 10 cmH2O of PEEP does not inhibit the pulmonary vascular response to regional alveolar hypoxia.

Mechanical factors do not influence blood flow distribution in atelectasis.

The contribution of mechanical factors to the vascular resistance of the atelectatic lung has been studied in vivo in the anesthetized open-chest dog. When the left lung was ventilated with an hypoxic gas mixture (while the right lung was ventilated with 100% O2), left lung blood flow decreased from 0.99 +/- 0.11 1.min-1 to 0.40 +/- 0.08 1.min-1 due to hypoxic pulmonary vasoconstriction (hypoxic stimulus PSO2 = 36.1 +/- 0.8 mmHg). When the left lung was made atelectatic, blood flow decreased to 0.65 +/- 0.11 1.min-1, consistent with a weaker hypoxic stimulus (PSO2 = 54.0 +/- 3.2 mmHg). With the addition of sodium nitroprusside infused intravenously, left lung blood flow increased to 1.05 +/- 0.14 1.min-1 during atelectasis, and to 0.61 +/- 0.09 1.min-1 during hypoxic ventilation, while flow remained at 0.94 +/- 0.18 1.min-1 during hyperoxic ventilation. When the results were plotted on pressure-flow diagrams, the hyperoxic, hypoxic, and atelectatic lung points fell on the same pressure-flow line in the presence of nitroprusside. It is concluded that hypoxic pulmonary vasoconstriction is the major (but not necessarily only) determinant of increased vascular resistance in the atelectatic lung, and that passive mechanical factors do not measurably affect blood flow distribution during open-chest atelectasis.

Pulmonary vascular resistance after cessation of positive end-expiratory pressure.

This report describes the pulmonary vascular response of infant lamb lung to abrupt cessation of positive end-expiratory pressure (PEEP) during volume-regulated continuous positive-pressure breathing (CPPB). In an intact, endobronchially ventilated preparation, the increase in left lung blood flow (QL) after abrupt cessation of 11 Torr left lung PEEP was found to be gradual, although peak airway pressure (Pmax) fell promptly from 36 to 14 Torr; 49% of the increase in QL occurred greater than 10 s after cessation of PEEP. Recruitment of zone I vasculature that had been created by balloon occlusion of the left pulmonary artery was found to occur promptly after balloon deflation. Isolated neonatal lamb lungs, perfused at constant flow rate, showed similar persistent elevation of pulmonary vascular resistance after cessation of 15 Torr PEEP, although Pmax fell abruptly from 39 to 12 Torr. This hysteresis was eliminated by calcium channel blockade with verapamil, and the magnitude of the change in pulmonary arterial pressure after either application or cessation of PEEP was reduced (25 and 26%, respectively). These observations suggest that, during CPPB, lung stretch alters neonatal pulmonary vascular tone or, by causing calcium channel-dependent lung volume hysteresis, modulates pulmonary vascular resistance. This interaction exaggerates the effect of airway pressure changes on pulmonary vascular resistance during mechanical ventilation.

Intravenous PGF2 alpha infusion does not enhance hypoxic pulmonary vasoconstriction during canine one-lung hypoxia.

The effect of prostaglandin F2 alpha (PGF2 alpha) on the hypoxic pulmonary vasoconstrictor (HPV) response was studied in 12 closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2, while the left lung was either ventilated with 100% O2 ("hyperoxia") or ventilated with an hypoxic gas mixture ("hypoxia:" end-tidal PO2 approximately equal to 50.0 +/- 0.1 mmHg). Cardiac output (CO) was altered from a "normal" value of 2.89 +/- 0.26 1.min-1 to a "high" value of 3.55 +/- 0.26 1.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 performed in the absence of, and in the presence of, PGF2 alpha administered as a constant peripheral intravenous infusion of 1.0 microgram.kg-1.min-1. During left lung hypoxia, mean pulmonary artery pressure (PAP) increased significantly when compared to hyperoxia. With PGF2 alpha administration, mean PAP increased significantly during both hyperoxia and hypoxia. The presence or absence of PGF2 alpha had no effect on cardiac output or PaO2 during hypoxia. 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 45 +/- 1%. When the left lung was exposed to hypoxia, the %QL-VCO2 decreased significantly to 29 +/- 3%. However, with the administration of PGF2 alpha, the %QL-VCO2 during left lung hypoxia did not change significantly 26 +/- 3%.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Micropuncture measurement of lung microvascular pressure profile in 3- to 4-week-old rabbits.

We have reported the longitudinal distribution of vascular resistance in the three segments (arteries, microvessels, and veins) of the pulmonary circulation of adult rabbits (J Appl Physiol 60:539-545, 1986). To determine the longitudinal distribution of vascular resistance in lungs of younger animals, we measured microvascular pressures in the subpleural microcirculation in nine isolated blood perfused lungs of 3- to 4-wk-old rabbits. We used micropipettes and the servonull pressure measuring system to directly measure pressures in 20-50 microns diameter subpleural arterioles and venules. We also measured pulmonary arterioles and venules. We also measured pulmonary arterial and left atrial pressures and lung blood flow. To determine the influence of vascular tone on segmental vascular resistance, in four lungs we measured microvascular pressures both before and after paralyzing the vasculature with papaverine. We found that 51% of the total pressure drop in the pulmonary circulation was in arteries, 24.5% in microvessels, and 24.5% in veins. Vascular tone contributed minimally to baseline arterial resistance. The greater arterial and venous resistance in lungs of 3- to 4-wk-old rabbits as compared to that in adult rabbits is probably due to differences in vessel geometry.

Microvascular pressures measured by micropipettes in isolated edematous rabbit lungs.

To study the mechanical effects of lung edema on the pulmonary circulation, we determined the longitudinal distribution of vascular resistance in the arteries, veins, and microvessels, and the distribution of blood flow in isolated blood-perfused rabbit lungs with varying degrees of edema. Active vasomotor changes were eliminated by adding papaverine to the perfusate. In three groups of lungs with either minimal [group I, mean wet-to-dry weight ratio (W/D) = 5.3 +/- 0.6 (SD), n = 7], moderate (group II, W/D = 8.5 +/- 1.2, n = 10), or severe (group III, W/D = 9.9 +/- 1.6, n = 5) edema, we measured by direct micropuncture the pressure in subpleural arterioles and venules (20-60 micron diam) and in the interstitium surrounding these vessels. We also measured pulmonary arterial and left atrial pressures and lung blood flow, and in four additional experiments we used radio-labeled microspheres to determine the distribution of blood flow during mild and severe pulmonary edema. In lungs with little or no edema (group I) we found that 33% of total vascular pressure drop was in arteries, 60% was in microvessels, and 7% was in veins. Moderate edema (group II) had no effect on total vascular resistance or on the vascular pressure profile, but severe edema (group III) did increase vascular resistance without changing the longitudinal distribution of vascular resistance in the subpleural microcirculation. Perivascular interstitial pressure relative to pleural pressure increased from 1 cmH2O in group I to 2 in group II to 4 in group III lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxic pulmonary vasoconstriction is not potentiated by repeated intermittent hypoxia in closed chest dogs.

Hypoxic pulmonary vasoconstrictor (HPV) responses were measured with repeated intermittent hypoxic challenges in eight non-traumatized closed chest dogs anesthetized with pentobarbital. The right lung was ventilated continuously with 100% O2 while the left lung was either ventilated with 100% O2 (control) or ventilated with a gas mixture containing 3-4% O2 (hypoxia). Mean per cent left lung blood flow for all four normoxic periods was 43.1 +/- 1.5% (mean +/- SE) of the total blood flow by the SF6 excretion method and 40.8 +/- 1.1% by the differential CO2 excretion method, corrected for the Haldane effect. With hypoxic ventilation, flow diversion from the hypoxic lung was maximal with the first exposure and did not change subsequently with a total of four alternating exposures to normoxia and hypoxia. Flow diversion during hypoxia was approximately 50.5 +/- 2.4% by the SF6 method and 50.3 +/- 3.5% by the VCO2 method. This result contrasts with the increasing flow diversion response with intermittant hypoxic exposure that has been reported in animals exposed first to thoracotomy and surgical dissection. It is concluded that in the absence of surgical trauma the initial response to hypoxia is maximal and is not potentiated by repeated hypoxic stimulation.