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PubMed1985

Opposing hemodynamic effects of substance P on pulmonary vasculature in rabbits.

Substance P is a peptide implicated in the control of a variety of physiological processes. Although substance P-containing neurons impinge on the pulmonary vasculature, the effects of substance P on the pulmonary circulation have not been systematically investigated. Rabbits were anesthetized with methohexital sodium and paralyzed with pancuronium bromide. Injection of substance P (0.002-0.10 microgram/kg) in the vena cava produced dose-dependent pulmonary vasoconstriction and systemic vasodilation. Pulmonary arterial pressure reached a peak within 15-20 s and declined toward base line over 10 min. Aortic pressure fell rapidly, reaching minimum at 5-10 s. At higher doses cardiac output fell transiently, resulting in a 65% fall in pulmonary vascular conductance. If repeat substance P dosages were administered 15 min apart, there was no tachyphylaxis. Pulmonary vasoconstriction was inhibited by the cyclooxygenase blocker meclofenamate (10 mg/kg) and the thromboxane synthase inhibitor Dazmegrel (UK-38,485) (2 mg/kg). In contrast, vasoconstriction was enhanced by atropine (2 mg/kg). In Dazmegrel-treated animals in whom pulmonary vasoconstriction was established by epinephrine infusion, low doses of substance P produced vasodilation. Our findings indicate that substance P produces pulmonary vasoconstriction via prostaglandin (particularly thromboxane) generation and pulmonary vasodilation via activation of cholinergic pathways.

Animals↗

PubMed1986

Regulation of breathing movements in fetal sheep by prostaglandin E2.

In fetal sheep, plasma prostaglandin (PG) E2 concentrations are high, and fetal breathing movements (FBM) occur intermittently, primarily during low-voltage fast electrocortical activity (LVFA). There is evidence suggesting that prostaglandins, specifically PGE2, may regulate FBM. To define the physiological role of PGE2 in regulation of FBM, we infused meclofenamate (0.9 mg X kg-1 X h-1), a prostaglandin synthetase inhibitor, into six fetal sheep to suppress endogenous prostaglandin production. Afterward, PGE2 was added in mean doses of 9, 18, 36, and 90 ng X kg-1 X min-1. Meclofenamate decreased PGE2 concentrations and increased FBM, especially during high-voltage slow electrocortical activity (HVSA). Addition of PGE2 reversed the effects of meclofenamate, increasing PGE2 concentrations and decreasing FBM, especially during HVSA. The response to PGE2 was dose dependent; the overall incidence of FBM and incidences of FBM during HVSA and LVFA were inversely correlated with both the infused PGE2 dose and the mean PGE2 concentration. At higher doses of PGE2, FBM occurred intermittently and only during LVFA; thus PGE2 infusion restored the physiological pattern of FBM. These results indicate that PGE2 regulates FBM by inhibiting FBM during HVSA.

Animals↗

PubMed1986

Thromboxane A2 and prostacyclin do not modulate pulmonary hemodynamics during exercise in sheep.

The purpose of this study was to determine the role of thromboxane and prostacyclin in modulating pulmonary hemodynamics during maximal cardiopulmonary stress in the healthy lung. We studied 11 yearling sheep in paired studies during progressive maximal treadmill exercise with and without meclofenamate (n = 5), ibuprofen (n = 6), or UK38485 (n = 2). We also studied five sheep during hypoxia and hypoxic exercise, and six sheep during prolonged steady-state treadmill exercise for 45-60 min with and without drug treatment. We measured the metabolites of thromboxane A2 (thromboxane B2, TxB2) and prostacyclin (6-ketoprostaglandin F1 alpha, 6-keto-PGF1 alpha) in blood plasma and lung lymph in each protocol. We found that progressive exercise significantly reduced pulmonary vascular resistance but that cyclooxygenase or thromboxane synthesis blockade did not alter the change. Plasma TxB2 rose minimally but significantly during maximal exercise, but 6-keto-PGF1 alpha did not change. During continuous hypoxia, exercise reduced pulmonary vascular resistance nearly to base-line levels, but the degree of reduction was also unchanged by drug treatment. There were also no significant changes in lymph or plasma TxB2 or 6-keto-PGF1 alpha during 45-60 min of continuous moderate exercise. We conclude that neither TxB2 nor prostacyclin modulate pulmonary hemodynamics in the normal lung during maximal exercise, prolonged moderate exercise, or exercise-induced reductions in vascular resistance during hypoxia.

6-Ketoprostaglandin F1 alpha↗

PubMed1986

Mechanism of peptidoleukotriene-induced increases in pulmonary transvascular fluid filtration.

We examined the effects of leukotrienes C4 (LTC4) and D4 (LTD4) (1 microgram) on the pulmonary vascular filtration coefficient, a measure of vessel wall conductivity to water, and the alterations in pulmonary vascular resistance (PVR) in isolated-perfused guinea pig lungs. We also assessed whether LTC4 and LTD4 increased the permeability to albumin in cultured monolayers of pulmonary artery endothelial cells. In Ringer-perfused and blood-perfused lungs, LTC4 resulted in increases in pulmonary arterial pressure (Ppa) and the pulmonary capillary pressure (Pcap) measured as the equilibration pressure after simultaneous pulmonary arterial and venous occlusions. Pulmonary venous resistance (Rv) increased to a greater extent than arterial resistance (Ra) in both Ringer-perfused and blood-perused lungs challenged with LTC4. The greater increase in PVR in blood-perfused lungs corresponded with a greater elevation of lung effluent thromboxane B2 (TxB2) concentration. The LTC4-stimulated increase in PVR was prevented by pretreatment with meclofenamate (10(-4) M). LTD4 also induced rapid increases in Ppa and Pcap in both Ringer-perfused and blood-perfused lungs; however, Ppa decreased before stabilizing at a pressure higher than base line. The increases in Rv with LTD4 were greater than Ra. The LTD4-stimulated increases in Ra and Rv also paralleled the elevation in TxB2 concentration. As with LTC4, the increases in Ppa, Pcap, PVR, and TxB2 concentration were greater in blood-perfused than in Ringer-perfused lungs. Pretreatment with meclofenamate reduced the magnitude of the initial increase in Ppa, but did not prevent the response.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1986

Platelet-activating factor increases lung vascular permeability to protein.

We studied the effects of platelet-activating factor (PAF) on pulmonary hemodynamics and microvascular permeability in unanesthetized sheep prepared with lung-lymph fistulas. Since cyclooxygenase metabolites have been implicated in mediating these responses, we also examined the role of the cyclooxygenase pathway. PAF infusion (4 micrograms X kg-1 X h-1 for 3 h) produced a rapid, transient rise in pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), plasma thromboxane B2 concentration (TxB2), and pulmonary lymph flow (Qlym). The lymph-to-plasma protein concentration ratio (L/P) did not change from base line. Pretreatment with the cyclooxygenase inhibitor, sodium meclofenamate, prevented the generation of TxB2 and the hemodynamic changes but did not prevent the increase in Qlym. The estimated protein reflection coefficient decreased from a control value of 0.66 +/- 0.04 to 0.43 +/- 0.06 after PAF infusion. We also studied the effects of PAF on endothelial permeability in vitro by measuring the flux of 125I-albumin across cultured bovine pulmonary artery endothelial cells (EC) grown to confluency on a gelatinized micropore filter and mounted within a modified Boyden chemotaxis chamber. PAF (10(-8) to 10(-4) M) had no direct effect on EC albumin permeability, suggesting that the increase in permeability in sheep was not the direct lytic effect of PAF. In conclusion, PAF produces pulmonary vasoconstriction mediated by cyclooxygenase metabolites. PAF also increases pulmonary vascular permeability to protein that is independent of cyclooxygenase products and is not the result of a direct effect of PAF on the endothelium.

Animals↗

PubMed1987

Effects of prostaglandins on fetal breathing do not involve peripheral chemoreceptors.

In sheep, prostaglandin (PG) E2 inhibits fetal breathing movements and meclofenamate, a PG synthetase inhibitor, causes a marked stimulation of fetal breathing movements; the site of action of these agents is not known. To determine whether these effects are mediated through the peripheral chemoreceptors, we studied 13 fetal sheep at gestational ages of 127 to 138 days. Seven fetuses had bilateral section of the carotid sinus and vagus nerves (denervated); six had sham operations. Beginning at least 6 days after the operation, we infused PGE2 (0.6 microgram X kg-1 X min-1) into five denervated and five sham-operated fetuses and meclofenamate (0.4 mg X kg-1 X h-1) into six denervated and four sham-operated fetuses. Infusions averaged 20 h in duration. During preinfusion control periods, the incidence of fetal breathing movements (% of time) was lower in denervated than in sham-operated fetuses (18.9% vs. 31.5%; P less than 0.005). In both groups, the incidence of fetal breathing movements was decreased by PGE2 and was increased by meclofenamate; when expressed as absolute values, the magnitude of the changes with both agents was greater in sham-operated fetuses than denervated fetuses. However, the effects were similar in both groups when the changes were expressed as a percent of the respective control values. The incidence of fetal breathing movements (% of control) was decreased by PGE2 to 25.4% in denervated and to 28.2% in sham-operated fetuses and was increased by meclofenamate to 297.3% in denervated and to 304.0% in sham-operated fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Effects of cyclooxygenase inhibition on pulmonary vascular responses to serotonin.

The vasopressor response to graded bolus doses (50-500 micrograms) of serotonin (5-hydroxytryptamine; 5-HT) was examined in the isolated canine lower left lung lobe (LLL) perfused at constant flow with autogenous blood before and after cyclooxygenase inhibition (COI). Lobar vascular resistance (LVR) was partitioned into pre- (Ra) and postcapillary (Rv) segments by venous occlusion with lobar blood volume changes monitored gravimetrically. Before COI, 5-HT produced transient, dose-dependent increases in pulmonary arterial pressure (Ppa) of 43.8 +/- 4.8-123.0 +/- 8.5% (n = 22) and simultaneous decreases in lobar blood volume (5.5 +/- 0.5-8.2 +/- 0.6 g/100 g LLL) with nearly proportionate increases in Ra and Rv at each 5-HT dose. After the initial challenge to 5-HT, LLL's were treated either with saline (n = 7) or one of three chemically distinct cyclooxygenase inhibitors. COI with 40 microM indomethacin (n = 6) or 45 microM meclofenamate (n = 6) increased resting LVR by 36.0 +/- 8.3% (P less than 0.01; n = 12) and decreased the Ra/Rv from 1.9 +/- 0.3 to 1.1 +/- 0.2 (P less than 0.01), whereas 1 mM aspirin (n = 3) caused a fourfold increase in resting LVR without affecting Ra/Rv. After indomethacin or meclofenamate treatment, the vasopressor response to graded doses of 5-HT was markedly potentiated as Ppa increased by 71.6 +/- 7.6-207.0 +/- 24.6%. COI did not potentiate the lobar vasopressor response to graded doses (10-100 micrograms) of norepinephrine (NE, n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Effects of meclofenamate on breathing movements in fetal sheep before delivery.

There is evidence that prostaglandins (PG), specifically PGE2, participate in the regulation of fetal breathing movements (FBM). During late gestation, when FBM occur intermittently and primarily during low-voltage electrocortical activity, the concentration of PGE2 in fetal plasma ([PGE2]) is high. During the days before delivery [PGE2] increases and FBM decrease. To determine whether the increase in [PGE2] is responsible for the concurrent decrease in FBM, we infused the prostaglandin synthase inhibitor, meclofenamate (0.7 mg.kg-1.h-1), into eight fetal sheep continuously for 5-13 days before delivery; five control fetuses received a continuous infusion of the solvent for 5-11 days before delivery. Compared with control infusion, meclofenamate caused a significant decrease in [PGE 2] until the day of delivery and a significant increase in FBM [overall and during high-voltage electrocortical activity (HVA)] until 2 days before delivery. Although there were significant correlations between [PGE2] and FBM (overall and during HVA), both groups showed similar decreases in FBM during the 2 days before delivery. We conclude that the decrease in FBM before delivery is not dependent on the concurrent increase in [PGE2].

Animals↗

PubMed1988

Pulmonary hemodynamics at birth: effect of acute cyclooxygenase inhibition in lambs.

The effect of acute cyclooxygenase (CYO) inhibition on the cardiopulmonary adjustments at birth was examined in chronically instrumented, unanesthetized, term lambs before, during, and after cesarean section (spontaneous respiration). One of three infusions was started 20 min before birth: saline control (C, n = 6), indomethacin (I, n = 6), or meclofenamate (M, n = 3). The stable metabolite of prostacyclin, plasma 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha, aorta), was measured by radioimmunoassay as an index of CYO activity. Indomethacin blocked the rise of 6-keto-PGF1 alpha observed in control lambs after birth and indomethacin-treated lambs exhibited an attenuation of the postnatal decrease in mean pulmonary arterial pressure. Pulmonary arterial pressure (Ppa) was 53 +/- 2 and 47 +/- 2 Torr (mean +/- SE) at 15 min and 40 +/- 3 and 34 +/- 2 Torr at 120 min in I and C groups, respectively. There were no serial or group differences in cardiac output and cardiac right to left shunt (indicator dilution) from 15 to 120 min after birth. Arterial PO2 (PaO2) was not different between groups: 37 +/- 4 Torr at 15 min and 47 +/- 5 min at 120 min after birth (control lambs). The results for I and M were similar for all measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1988

Histamine tachyphylaxis in canine airways despite prostaglandin synthesis inhibition.

Tachyphylaxis to aerosolized histamine was studied in dogs anesthetized with thiamylal after pretreatment with prostaglandin synthesis inhibitors. Three consecutive histamine dose-response curves were obtained in nine dogs pretreated with 5 mg/kg indomethacin; two of these nine were also pretreated with 10 mg/kg indomethacin. Seven of the nine dogs were pretreated with 4 mg/kg sodium meclofenamate; four of these seven were also pretreated with 12 mg/kg. All dogs had tachyphylaxis at high concentrations of histamine regardless of inhibitor used. Pretreatment with indomethacin while the dogs were under alpha-chloralose-urethan anesthesia gave similar results. Histamine tachyphylaxis was also studied both in the presence and in the absence of indomethacin in tracheal smooth muscle strips obtained from seven additional dogs. A decrease in the median effective dose to histamine was observed in the indomethacin-treated strips, but tachyphylaxis to histamine remained. We conclude that prostaglandin synthesis inhibition does not reverse histamine tachyphylaxis either in vivo or in vitro. Thus the mechanism of histamine tachyphylaxis remains unexplained.

Airway Resistance↗

PubMed1989

Cyclooxygenase blockers inhibit ethanol-induced pulmonary vasoconstriction in lambs.

We investigated the mechanism of ethanol-induced pulmonary vasoconstriction in lambs, by a pharmacological approach. We chronically instrumented 28 lambs to determine whether phentolamine (alpha-block), propranolol (beta-block), promethazine and cimetidine (H1- and H2-block), high-dose indomethacin, or low- and high-dose meclofenamate (cyclooxygenase block) altered the vasoconstriction. Ethanol alone increased pulmonary vascular resistance from 0.14 to 0.49 Torr.ml-1.kg-1.min (U). Only indomethacin (7-8 mg/kg po) and high-dose meclofenamate (7-8 mg/kg iv) abolished the pulmonary vascular response to ethanol infusion. Pulmonary vascular resistance was 0.14 U after ethanol plus indomethacin and was 0.2 U after ethanol plus high-dose meclofenamate (P = NS vs. base line). Low-dose meclofenamate (2 mg/kg) attenuated the vasoconstrictor response. Systemic vascular resistance increased moderately after ethanol and had a similar pattern of inhibition by cyclooxygenase blockade. Cardiac output and heart rate decreased nearly significantly after ethanol (P less than 0.06), a tendency that was also ablated by cyclooxygenase inhibition. Thus the acute cardiocirculatory response to ethanol involves an intact prostaglandin synthase system in lambs. To our knowledge, these data are the first documentation that cyclooxygenase enzyme blockade can eliminate the acute cardiac and vascular effects of ethanol in a whole-animal system.

Adrenergic alpha-Antagonists↗

PubMed1989

Influence of tone on responses to acetylcholine in the rabbit pulmonary vascular bed.

Pulmonary vascular responses to acetylcholine were compared under resting and high tone conditions of the intact-chest rabbit. Under resting tone conditions, intralobar injections of acetylcholine increased lobar arterial pressure in a dose-related manner. The pressor responses to acetylcholine under resting conditions were blocked by meclofenamate, indomethacin, atropine, and pirenzepine. When lobar vascular resistance was raised to a high steady level, low doses of acetylcholine decreased lobar arterial pressure, whereas higher doses elicited a biphasic response with the pressor component predominating at the highest dose studied. Under high tone conditions, only the pressor component of the response was blocked by meclofenamate or indomethacin, whereas pressor and depressor responses were blocked by atropine or the 600-micrograms/kg iv dose of pirenzepine. Pressor responses to acetylcholine under resting and high tone conditions were blocked by pirenzepine (50 micrograms/kg iv), whereas gallamine had no effect on responses to acetylcholine. The 50-micrograms/kg iv dose of pirenzepine had no effect on depressor responses or the depressor component of the response to acetylcholine. The present data support the concept that acetylcholine has significant cyclooxygenase-dependent pressor activity in the rabbit pulmonary vascular bed and suggest that this response is mediated by a muscarinic M1-type receptor. These data also show that, under high tone conditions, a vasodilator response or a vasodilator component of a biphasic response is unmasked. This response is not dependent on the release of cyclooxygenase products and is mediated by a muscarinic receptor that is neither of the M1- nor the M2-type.

Acetylcholine↗

PubMed1989

Control of shunt pathway perfusion in diffuse granulomatous lung disease.

To assess the roles of cyclooxygenase inhibition and alveolar hypoxia in controlling the distribution of pulmonary perfusion in granulomatous lung injury, we studied 15 dogs (anesthetized and ventilated) 4 wk after intravenous injection of complete Freund's adjuvant (0.5-0.75 ml/kg). Base-line hemodynamic and blood gas observations were obtained at fractional O2 concentration (FIO2) 0.21 and 0.10. Observations at each FIO2 were repeated 30 min after infusion of meclofenemate (2 mg/kg; n = 10) or saline (n = 5). Resistance to pulmonary blood flow was assessed using the difference between pulmonary arterial diastolic and left atrial pressures (PDG). Distribution of blood flow between normal and diseased regions of the lung was evaluated with measurement of inert gas shunt flow. Before infusion, there were no significant differences between the two groups at either FIO2. At FIO2 0.10 PDG rose from 3 +/- 1 to 7 +/- 3 mmHg in the saline group and from 3 +/- 1 to 8 +/- 3 mmHg in the meclofenemate group, although the shunt flow increased from 8.7 +/- 7.7 to 12.2 +/- 9.2% and from 10.7 +/- 11.0 to 17.6 +/- 18.3 in the two groups, respectively. Saline induced no significant changes at either FIO2. After meclofenemate, PDG at FIO2 0.21 rose to 7 +/- 4 mmHg (P less than 0.015) while shunt flow fell to 5.2 +/- 6.2% (P less than 0.0125), whereas at FIO2 0.10 PDG rose to 15 +/- 5 mmHg (P less than 0.001) while shunt flow rose only to 14.3 +/- 16.4% (P = NS). We propose that perivascular inflammation enhanced perfusion of abnormal lung by elaborating vasodilator prostanoids. By inhibiting prostanoid biosynthesis, meclofenemate selectively increased resistance in diseased lung at FIO2 0.21 and lowered shunt flow. The persistent rise in shunt during hypoxia after meclofenemate suggests that factors other than prostanoids may account for the apparent attenuation of hypoxic vasoconstriction in diseased lung.

Animals↗

PubMed1990

Cyclooxygenase inhibitors increase canine tracheal muscle response to parasympathetic stimuli in situ.

To determine whether cyclooxygenase inhibitors alter parasympathetic control of airway smooth muscle in situ, we pretreated anesthetized dogs with intravenous indomethacin, meclofenamate, or normal saline and measured the isometric contraction of tracheal muscle in response to electrical stimulation of the vagus nerves. Indomethacin and meclofenamate increase the response of airway smooth muscle to parasympathetic stimulation. In subsequent experiments to determine the site of action of cyclooxygenase inhibitors, we found that indomethacin does not alter the response of tracheal muscle to intra-arterial acetylcholine (a muscarinic agonist) but does augment the response to intra-arterial dimethylpiperaziniumiodide (a nicotinic agonist). Moreover, the response to parasympathetic stimulation after pretreatment with a combination of indomethacin and BW755C (a combined cyclooxygenase-lipoxygenase inhibitor) does not differ significantly from the response after indomethacin or meclofenamate alone. We conclude that cyclooxygenase inhibitors increase the sensitivity of the contractile response of tracheal smooth muscle to parasympathetic stimulation, that they exert their effect on the postganglionic parasympathetic neuron, and that their effect is prejunctional. The effect appears secondary to a decrease in cyclooxygenase products rather than to an increase in lipoxygenase products. These findings suggest that endogenous cyclooxygenase products may modulate parasympathetic control of airway smooth muscle in vivo. They may relate to the mechanisms that underlie airway hyperresponsiveness, by which mediators of inflammation modulate airway responsiveness and by which nonsteroidal anti-inflammatory drugs induce severe bronchoconstrictor responses in some persons who have asthma.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1990

Systemic vascular reactivity during high-altitude pregnancy.

There is an increased incidence of preeclampsia at high compared with low altitude. Increased vasoreactivity, possibly due to a deficiency of vasodilator prostaglandins, is thought to contribute to the etiology of preeclampsia. We sought to determine whether high-altitude exposure increased systemic vascular reactivity during pregnancy. We measured systemic vascular reactivity and contractile sensitivity of isolated aortic rings from pregnant and nonpregnant guinea pigs kept for 6 wk at either simulated high altitude (3,900 m) or low altitude (1,600 m). We found that pregnancy at high compared with low altitude increased baseline systemic vascular resistance (SVR) but not the SVR response to angiotensin II in awake unstressed guinea pigs. Contractile sensitivity to norepinephrine was also increased in aortic rings isolated from high-altitude compared with low-altitude pregnant animals. Meclofenamate, a prostaglandin synthesis inhibitor, did not equalize vasoreactivity in the high- and low-altitude pregnant guinea pigs or in their isolated aortic rings. We concluded that pregnancy at high compared with low altitude increased base-line SVR and aortic contractile sensitivity but that mechanisms other than decreased vasodilator prostaglandin production were responsible.

Altitude↗

PubMed1991

Time-varying pulmonary arterial compliance.

We tested the hypothesis that pulmonary arterial compliance (Ca) varies during the ventilatory cycle. Pressure and flow in the main pulmonary artery were measured in open-chest dogs under chloralose anesthesia (n = 12) with a positive-pressure volume-cycled ventilator. Input impedance was calculated from the pressure and flow waves of heart cycles obtained immediately after the start of inspiration (SI) and immediately after the start of expiration (SE). A lumped parameter model was used to calculate Ca from the input impedance spectrum of the main pulmonary artery. Three levels of positive end-expiratory pressure (PEEP) were used before and after meclofenamate (n = 6) or vagotomy (n = 6). Ca was significantly greater at SE than at SI at each level of PEEP. PEEP increased Ca at SE but not at SI. None of these changes was altered by meclofenamate or vagotomy, suggesting that these differences of Ca were due to passive mechanical effects rather than an active neurohumoral mechanisms. We conclude that Ca is time varying during the ventilatory cycle because it is altered by the dynamic increase of lung volume between SI and SE, but not with the quasi-static increase of lung volume induced by raising the level of PEEP. These changes of Ca were unaffected by vagal feedback or inhibition of cyclooxygenase. We suggest that the increased Ca just after the start of expiration may result from dynamic shifts of blood volume from the extra-alveolar to the alveolar vessels.

Animals↗

PubMed1991

Fetal pulmonary vasodilation after exogenous platelet-activating factor.

To determine the fetal pulmonary vascular response to platelet-activating factor (PAF), we studied the hemodynamic effects of the infusion of PAF directly into the left pulmonary artery in 21 chronically catheterized fetal lambs. Left pulmonary arterial blood flow (Q) was measured with electromagnetic flow transducers. Ten-minute infusions of low-dose PAF (10-100 ng/min) produced increases in Q from a baseline of 71 +/- 5 to 207 +/- 20 ml/min (P less than 0.001) without changes in pulmonary arterial pressure. Pulmonary vasodilation with PAF was further confirmed through increases in Q with brief (15-s) infusions and increases in the slope of the pressure-flow relationship as assessed by rapid incremental compressions of the ductus arteriosus during PAF infusion. Infusion of Lyso-PAF had no effect on Q or pulmonary arterial pressure. Treatment with CV-3988, a selective PAF receptor antagonist, but not with meclofenamate, atropine, or diphenhydramine and cimetidine blocked the response to PAF infusion and did not affect baseline tone. Systemic infusion of high-dose PAF (300 ng/min) through the fetal inferior vena cava increased pulmonary arterial pressure (46.5 +/- 1.0 to 54.8 +/- 1.9 mmHg, P less than 0.01) and aorta pressure (44.3 +/- 1.0 to 52.7 +/- 2.2 mmHg, P less than 0.01) while also increasing Q. Neither PAF nor CV-3988 changed the gradient between pulmonary arterial and aorta pressures, suggesting that PAF does not affect ductal tone. We conclude that PAF is a potent fetal pulmonary vasodilator and that the effects are not mediated through cyclooxygenase products or by cholinergic or histaminergic effects.

Animals↗

PubMed1991

Cyclooxygenase inhibitors prevent ethchlorvynol-induced injury in rat and rabbit lungs.

The effect of three chemically dissimilar cyclooxygenase inhibitors on ethchlorvynol-(ECV) induced acute lung injury was studied in isolated buffer-perfused rat and blood-perfused rabbit lungs. ECV caused the microvascular fluid filtration coefficient (Kf) to increase by greater than threefold in the rat lungs and twofold in the rabbit lungs. ECV caused increased pulmonary vascular resistance (PVR) and microvascular pressure measured by the double occlusion technique (Pdo) compared with the vehicle control group in the rat experiments. However, ECV had no effect on PVR or Pdo in the rabbit experiments. Pretreatment with the cyclooxygenase inhibitors indomethacin, ibuprofen, and meclofenamate prevented the increase in microvascular permeability in both the rat and rabbit lung preparations. The cyclooxygenase inhibitors also prevented the ECV-induced PVR and Pdo increases in the rat lungs but had no effect on PVR or Pdo in the rabbit lungs. These results indicate that cyclooxygenase products of arachidonate metabolism mediate the ECV-induced Kf increase in both isolated rat and rabbit lungs.

Animals↗