Continuous, low dose of hydralazine, reduces acute hypoxic pulmonary hypertension without a corresponding fall in systemic arterial pressure

Administration of hydralazine in patients with pulmonary hypertension has been reported to cause excessive systemic vasodilatation, limiting its clinical utility (N Engl J Med 1982; 306: 1326). We studied the effects of hydralazine on hypoxic pulmonary vasoconstriction (HPV) in chronically instrumented sheep and evaluated whether different methods of intravenous administration could prevent severe systemic hypotension. Mean left atrial, pulmonary and systemic arterial pressures (Pla, Ppa and Psa mmHg), cardiac output (CO, l/min, electromagnetic flowmeter) and heart rate were measured continuously. Systemic (SVR) and pulmonary vascular resistances (PVR) were calculated by Psa/CO and (Ppa-Pla)/CO, respectively. Following a 30 min baseline period, we initiated hypoxia with mixture of 10% oxygen in nitrogen. After 20 min of hypoxia we then performed the following two experiments: Group A-Hydralazine (10 micrograms/kg/min) was infused continuously for a further 20 min of hypoxia (n = 6); Group B-Hydralazine (400 micrograms/kg) was administered as a single bolus, followed by an additional 20 min of hypoxia (n = 6). In both Groups A and B, hypoxia produced a prominent pulmonary hypertensive response. Continuous infusion of hydralazine (Group A) significantly decreased the hypoxic values of Ppa and PVR from 25.1 +/- 1.1 to 21.7 +/- 1.6 mmHg (p less than 0.01) and from 4.82 +/- 0.50 to 4.17 +/- 0.40 mmHg/l/min (p less than 0.05), respectively. In Group B, hydralazine as a bolus also significantly decreased HPV, with Ppa dropping from 20.9 +/- 0.9 to 18.3 +/- 1.5 mmHg (p less than 0.05) and PVR falling from 4.98 +/- 0.55 to 4.34 +/- 0.53 mmHg/l/min (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Sildenafil and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets

Devising therapies that might prevent the onset or progression of pulmonary hypertension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. Another objective was to determine whether sildenafil causes pulmonary vasodilation without systemic vasodilation in piglets with chronic pulmonary hypertension. Piglets were raised in room air (control, n = 5) or 10-11% O(2) (hypoxic, n = 17) for 3 days. Some piglets (n = 4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n = 6) or placebo (n = 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic hypoxia-induced pulmonary hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. However, a single oral dose of sildenafil caused pulmonary vasodilation, without systemic vasodilation, in piglets with chronic hypoxia-induced pulmonary hypertension, which may have therapeutic implications.     

Effects of alveolar hypoxia on lung fluid and protein transport in unanesthetized sheep.

To determine whether hypoxia directly affects pulmonary microvascular filtration of fluid or permeability to plasma proteins, we measured steady state lung lymph flow and protein transport in eight unanesthetized sheep breathing 10% O2 in N2 for 4 hours. We also studied three sheep breathing the same gas mixture for 48 hours. We surgically prepared the sheep to isolate and collect lung lymph and to measure average pulmonary arterial (Ppa) and left atrial (Pla) pressures. We placed a balloon catheter in the left atrium to elevate Pla. After recovery, the sheep breathed air through a tracheostomy for 2-4 hours, followed by 4 or 48 hours of hypoxia. In 13 4-hour studies, the average arterial PO2 fell from 97 to 38 torr; Ppa rose from 20 to 33 cm H2O; and lung lymph flow and lymph protein flow were unchanged. We also found that during 48-hour hypoxia, with a sustained elevation in Ppa and a decline in Pla, lymph flow and protein flow did not increase. In four sheep, we also raised Pla for 4 hours, followed by 4 hours of hypoxia with elevated Pla. Again, despite the added stress of elevated Pla, we found that lymph flow and lymph protein flow remained constant during hypoxia. We conclude that severe alveolar hypoxia, for 4 or 48 hours, alone or with increased pulmonary microvascular pressure, produced no change in lung fluid filtration or protein permeability, a finding supported by normal postmortem histology and extravascular lung water content.     

Left atrial pressure can be accurately transmitted to the pulmonary artery despite zone 1 conditions

Pulmonary arterial occlusion pressure is not thought to reflect left atrial pressure (Pla) when alveolar pressure (PA) exceeds pulmonary venous pressure because alveolar capillaries collapse and the required continuous fluid column between the pulmonary artery and left atrium is interrupted. However, arterial-to-venous flow can occur when PA exceeds both the pulmonary arterial pressure (Ppa) and pulmonary venous pressure (i.e., in Zone 1 conditions), indicating the existence of a continuous patent vascular channel. Accordingly, Ppa should reflect Pla under these conditions. To investigate this connection cannulas were placed in the pulmonary arteries and left atria of eight excised rabbit lungs. Ppa and Pla were set 5 cm H2O above PA, which ranged from 0 to 25 cm H2O. Pla was then reduced in 2 to 4 cm H2O decrements while recording Ppa when arterial-to-venous flow ceased. At all PAs greater than 0 cm H2O, Pla was accurately reflected by the Ppa when both were exceeded by PA. The greater the PA, the lower the Ppa could track Pla below PA. Pla can be accurately measured by a pulmonary arterial catheter under Zone 1 conditions.     

The effects of agents that bind to cytochrome P-450 on hypoxic pulmonary vasoconstriction

The relationship between pulmonary arterial pressure (Ppa) and blood (Q) was determined during normoxia and hypoxia in ventilated pig lungs perfused in situ with the animal's own blood. Hypoxia shifted the Ppa-Q relationship to the right and decreased its slope, indicating pulmonary vasoconstriction. Carbon monoxide (11.5% in the inspired gas) and metyrapone ditartrate (10 mg/min into the perfusate) caused vasodilation when oxygenation was normal and reduced the vasoconstriction caused by hypoxia. Since the only pharmacological property CO and metyrapone are thought to have in common at the concentrations employed is the ability to bind to the heme iron of cytochrome P-450, these results are consistent with the hypothesis that desaturation of this cytochrome leads to pulmonary vasoconstriction. Prostaglandin F2alpha, infused into the pulmonary artery at 0.01 mg/min, when oxygenation was normal, had effects on the Ppa-Q relationship similar to those of hypoxia. The F2alpha response was also reduced by CO and metyrapone, suggesting either that P-450 was involved in the F2alpha response or that CO and metyrapone were toxic to pulmonary vascular smooth muscle. Proadifen hydrochloride (1 mg/min), which is thought to bind to the protein moiety of P-450 also reduced the hypoxic response, but was a vasoconstrictor during normoxia and did not affect the F2alpha response.     

Vasodilatory effect of aerosol histamine during pulmonary vasoconstriction in unanesthetized sheep

The effects of aerosol histamine on pulmonary vascular resistance during pulmonary vasoconstriction were studied in 12 unanesthetized sheep. Sheep were chronically instrumented with Silastic catheters in the pulmonary artery and left atrium, thermodilution Swan-Ganz catheter in the main pulmonary artery for measurement of cardiac output, and tracheostomy for delivery of hypoxic gas and/or aerosol histamine. Seven minutes of isocapnic hypoxia (Fl_O2 = 0.12) caused pulmonary artery pressure (P_PA) to increase from 17.2 ± 0.4 to 27.0 ± 1.0 cm H₂O (X¯ ± SEM, P < 0.05) and pulmonary vascular resistance (PVR) to increase from 3.94 ± 0.33 to 4.71 ± 0.38 cm H₂O · L^?1. min (P < 0.05). When sheep breathed a combination of aerosol histamine (5 mg/ml) and 12% O₂, P_PA rose only to 21.3 ± 1.11 cm H₂O and PVR decreased to 3.51 ± 0.31 cm H₂O · L^?1. min. This was a significantly (P < 0.05) smaller response compared to hypoxia alone. Aerosol histamine alone had no significant effect on P_PA or PVR. Meclofenamate did not restore the histamine-induced loss of hypoxic vasoconstriction. Aerosol histamine significantly blunted the pulmonary vasoconstriction caused by intravenous serotonin (8 μg/kg/min) and intravenous prostaglandin H₂-analog (0.74 μg/kg/min). It was concluded that in the awake sheep aerosol histamine acted as a pulmonary vasodilator only in the presence of pulmonary vasoconstriction. Pediatr Pulmonol 1987; 3:94–100 .     

Dibutyryl cyclic AMP inhibits acute hypoxic pulmonary vasoconstriction in conscious sheep

We examined the effects of cell-permeable dibutyryl cyclic AMP (DBcAMP) on acute hypoxic pulmonary vasoconstriction (HPV) in conscious sheep. Mean left and right atrial, pulmonary, and systemic pressures (Pla, Pra, Ppa, and Psa, mm Hg), cardiac output (CO, L/min), and heart rate were measured continuously. Systemic (SVR) and pulmonary vascular resistances (PVR) were calculated by (Psa-Pra)/CO and (Ppa-Pla)/CO, respectively. Five groups of experiments were performed using the same sheep (n = 6). After a 30-min baseline period, sheep inhaled a hypoxic gas mixture (O2:N2 = 1:9) for 40 min. Pretreatment with DBcAMP (200 micrograms/kg/min) inhibited HPV (Ppa, 12.0 +/- 2.3 to 20.0 +/- 2.3 versus 13.2 +/- 2.5 to 14.3 +/- 1.4 mm Hg, p less than 0.01; PVR, 2.61 +/- 0.81 to 4.15 +/- 1.14 versus 2.30 +/- 0.87 to 2.52 +/- 0.59 mm Hg/L/min, p less than 0.01). DBcAMP treatment (200 micrograms/kg/min) after induction of HPV also significantly attenuated hypoxic pulmonary response (Ppa, 19.0 +/- 1.7 to 14.2 +/- 2.3 mm Hg, p less than 0.01; PVR, 3.92 +/- 0.39 to 2.34 +/- 0.34 mm Hg/L/min, p less than 0.01) without significant decreases in Psa and SVR. Pretreatment with DBcAMP (200 micrograms/kg/min) did not significantly alter pulmonary pressor responses to bolus injections of prostaglandin F2 alpha (PGF2 alpha) (10 micrograms/kg) and norepinephrine (4 micrograms/kg). These results may suggest that intracellular augmentation of cyclic AMP plays a crucial role in modulating HPV.     

Effects of prostacyclin (PGI2) on hypoxic pulmonary vasoconstriction in the conscious adult sheep

The effects of prostacyclin (PGI2) on alveolar hypoxic pulmonary vasoconstriction were investigated in the conscious adult sheep. In our model, hypoxia also produced increases in pulmonary arterial pressure (PPA) and pulmonary vascular resistance (PVR), indicating pulmonary vasoconstriction. PGI2 was injected rapidly as a 0.5 microgram/kg bolus via the right atrium in five sheep during normoxia and hypoxia. During normoxia, PGI2 increased PPA and cardiac output, and decreased systemic arterial pressure (PSA), systemic vascular resistance (SVR) and PVR. Left atrial pressure did not change. During hypoxia following PGI2 administration, PPA decreased, CO increased, and PVR decreased, suggesting dilator action on the pulmonary resistance vessels. As the same time PSA and SVR decreased, suggesting dilator action on the systemic resistance vessels. However, the degree of the decline in PVR caused by PGI2 was much greater during hypoxia than during normoxia. The decreases in PSA and SVR induced by PGI2 were not significant between hypoxia and normoxia. These findings confirm that PGI2 decreases pulmonary and systemic vascular resistances in normoxic and hypoxic sheep. Moreover, during hypoxia, associated with the increased PPA and PVR, the administration of PGI2 appears to be particularly effective in "normalizing" these parameters.     

The effect of dextran solution on pulmonary plasma-lymph barrier in awake sheep

We investigated the effect of dextran solution on lung lymph flow in awake sheep with chronic lung lymph fistulas. Ten percent of dextran (molecular weight 40,000) solution or normal saline were infused at 1000 ml/h for 2 h through left atrial catheter. We measured pulmonary arterial pressure (Ppa), left atrial pressure (Pla), aortic pressure (Psa), cardiac output (CO), oncotic pressures of both plasma (IImv) and lung lymph (IIpmv), lung lymph flow rate (Qlym), and lymph-to-plasma ratio of total protein (L/P). Infusion of dextran solution caused significant increases in Ppa, Pla and CO and decrease in plasma-lung lymph oncotic pressure gradient (IImv-IIpmv), without changes in L/P. Infusion of normal saline caused significant increases in Ppa and Pla and no changes in IImv-IIpmv and CO, and slight decrease in L/P. The calculated filtration coefficients increased by 2.2 fold after dextran infusion and 1.7 fold after normal saline infusion. Moreover, an apparent increase in protein transport across microvessels as evidenced by the normal L/P despite increases in hydrostatic pressure occurred after dextran solution infusion. These results suggest that dextran solution may increase permeability of microvascular wall, as well as effective net pressure gradient across microvessels, both of which result in a large net fluid filtration from microvessels to perimicrovascular compartment.     

Pulmonary vascular resistance in dogs and minipigs—effects of hypoxia and inhaled nitric oxide

The pig has been reported to present with a stronger hypoxic pulmonary vasoconstriction than many other species, including the dog, but it is not known whether this is associated with a different longitudinal partitioning of pulmonary vascular resistance (PVR). We investigated the relationships between cardiac output (Q̇) and mean pulmonary artery pressure (Ppa) minus occluded Ppa (Ppao), and effective pulmonary capillary pressure (Pc′) minus Ppao, in seven minipigs and in seven dogs in hyperoxia (FI_O2 0.4) and hypoxia (FI_O2 0.1), first without, then with the inhalation of 80 ppm nitric oxide (NO) to inhibit any reversible component of PVR. Pc′ was estimated from the Ppa decay curve following pulmonary artery balloon occlusion. In hyperoxia, minipigs compared to dogs had (Ppa−Ppao)/Q̇ and (Pc′−Ppao)/Q̇ plots shifted to higher pressures. Hypoxia at each level of Q̇ increased Ppa−Ppao in minipigs more than in dogs, and Pc′−Ppao in minipigs only. Inhaled NO reversed hypoxia-induced changes in (Ppa−Ppao)/Q̇ and (Pc′−Ppao)/Q̇ plots. We conclude that the minipig, compared to the dog, presents with higher PVR and reactivity including vessels downstream to the site of Pc′ as determined by the arterial occlusion technique.     

Cellular mechanisms that control pulmonary vascular tone during hypoxia and normoxia. Possible role of Ca2+ATPases.

We investigated cellular mechanisms that may be involved in controlling cytosol calcium and pulmonary artery pressure during hypoxia and normoxia in isolated blood-perfused ferret lungs. Alveolar hypoxia in ferret lungs causes an active increase in pulmonary vascular resistance. Hypoxic pulmonary vasoconstriction directly correlates with extracellular calcium ([Ca2+]o), and the absence of [Ca2+]o in the perfusate markedly attenuates the hypoxemia-induced pulmonary vasoconstriction. Alveolar hypoxia does not potentiate the production of thromboxane B2 (TxB2) or 6-keto-PGF1 alpha. Vanadate, a widely used inhibitor of Ca2+ATPases, increases pulmonary arterial pressure (Ppa) in the presence or absence of [Ca2+]o and without affecting the production of TxB2 or 6-keto-PGF1 alpha. Vanadate and ouabain, an inhibitor of Na+/K+ATPase, produce synergistic increases in Ppa. Amiloride, an inhibitor of Na+/Ca2+ exchange, reverses the increase in Ppa caused by ouabain, but not the increase caused by vanadate. The additional effect produced by ouabain on Ppa after near maximal vanadate effect and the ability of amiloride to reverse the pulmonary vasoconstriction caused by ouabain, but not vanadate, suggests that vanadate does not inhibit Na+/K+ATPase in ferret lungs. In addition, cyclic GMP (cGMP), which has been reported to increase the activity of Ca2+ATPases in vascular smooth muscle, was able to reverse and prevent the effect of vanadate on Ppa, but not the effect of ouabain. Inhibition of Ca2+ATPases with vanadate in ferret lungs increases pulmonary vascular resistance during both normoxia and hypoxia. The Ca2+ entry mediated by alveolar hypoxia appears to overpower the ability of Ca2+ATPases and other membrane Ca2+ transport proteins to translocate [Ca2+]i.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intratracheal administration of pulmonary vasodilator agents.

We compared intravenous and intratracheal administration of histamine (0.4 and 1.6 micrograms/kg, respectively) and nitroglycerin (5.0 and 20.0 micrograms/kg, respectively) in seven hypoxemic 2 week old lambs, during right lung only perfusion, to see if intratracheal administration could limit their vasodilator action to the pulmonary vessels. The hemodynamic variables: pulmonary artery pressure (Ppa), left atrial pressure (Pla), pulmonary blood flow per kilogram (Q/kg), and aortic pressure (Pao) were measured at baseline and in each experimental state, then pulmonary vascular resistance (PVR) and systemic vascular input resistance (SVR) were determined. We found that intravenous histamine showed some pulmonary vasodilator selectivity in that it caused a 19% decrease of Ppa from baseline (P less than 0.002), a 23% decrease of PVR from baseline (P less than 0.002), and an 8% decrease of SVR from baseline (P less than 0.05). Intratracheal histamine produced smaller effects, decreasing Ppa by 11% from baseline (P less than 0.02), and PVR by 14% from baseline (P less than 0.02), while SVR was unaffected. Intravenous nitroglycerin decreased cardiac output by 16% from baseline (P less than 0.02), and also decreased SVR by 8% while producing a small increase in PVR. Intratracheal nitroglycerin caused a similar 17% (P less than 0.01) decrease in cardiac output, and again an increased PVR but a decreased SVR. This study confirms that histamine has some intrinsic pulmonary vasodilator selectivity. Furthermore, the data suggest that intratracheal administration may accentuate pulmonary selectivity by lessening systemic effects. Nitroglycerin, on the other hand, had untoward hemodynamic effects in the presence of hypoxia.     

Stimulus-response curves for hypoxic pulmonary vasoconstriction in piglets.

OBJECTIVE: The aim was to characterise stimulus-response curves for hypoxic pulmonary vasoconstriction and to observe the effects of drugs reputed to enhance it: aspirin (a cyclo-oxygenase inhibitor), and doxapram (a peripheral chemoreceptor agonist). METHODS: Mean pulmonary artery pressure (Ppa) versus fraction of inspired O2 (FIO2) relationships were studied in 18 intact anaesthetised piglets, before and after the intravenous administration, in random order, of either physiological saline, 1 g aspirin, or 20 mg.kg-1 doxapram. Cardiac output (Q) was kept constant, to avoid passive Q dependent changes in Ppa. RESULTS: A progressive decrease in FIO2 from 100% to 12% was associated with an average increase in Ppa from 19 to 38 mm Hg (p < 0.001). When FIO2 was further decreased to 8%, Ppa decreased to 32 mm Hg (p < 0.01). This stimulus-response curve was unaffected by saline, but displaced in a non-PO2-dependent manner to higher Ppa by doxapram and by aspirin. CONCLUSIONS: The pulmonary vascular response to inspiratory hypoxia in intact anaesthetised piglets is biphasic, with a maximum at an FIO2 of 12%. Neither aspirin nor doxapram affect the shape of this stimulus-response curve, and in particular do not prevent low FIO2 associated inhibition of hypoxic pulmonary vasoconstriction.     

Absence of parasympathetic control of pulmonary vascular pressure-flow plots in hyperoxic and hypoxic dogs

Hypoxic stimulation of the peripheral chemoreceptors has been reported to inhibit hypoxic pulmonary vasoconstriction (HPV). This has been explained by a reflex vagal (Chapleau et al., 1988) or sympathetic (Naeije et al., 1989) pulmonary vasodilation. We therefore investigated the effects of bilateral cervical vagotomy and of muscarinic block (atropine sulfate 0.1 mg.kg-1 i.v.) on multipoint pulmonary arterial pressure (Ppa)-cardiac index (Q) plots in 16 sodium pentobarbital-anesthetized dogs ventilated alternately in hyperoxia (fraction of inspired O2, FIO2, 0.4) and in hypoxia (FIO2 0.1). Over the range of Q studied, 2 to 5 L.min-1.m-2, hypoxia increased Ppa and did not change pulmonary capillary wedge pressure (Ppw). After bilateral cervical vagotomy or after atropine, Ppa and Ppw at all levels of Q were not modified either during hyperoxia or during hypoxia. These results show that the parasympathetic system does not affect the global hypoxia-induced pulmonary vasopressor response and thus suggest that the depressor effect of chemoreceptor stimulation on HPV is not vagally mediated.     

Endogenous endothelins and nitric oxide in hypoxic pulmonary vasoconstriction.

The effects of endothelin receptor blockade on the pulmonary circulation have been reported variably, possibly in relation to a more or less important associated release of endogenous nitric oxide (NO). The aim of this study was to test whether endothelin antagonism would inhibit hypoxic pulmonary vasoconstriction, and if it would not, then would it do so after NO synthase inhibition. Hypoxic pulmonary vasoconstriction (HPV) was evaluated in anesthetised dogs by the increase in the mean pulmonary artery pressure (Ppa) minus occluded Ppa (Ppao) gradient in response to hypoxia (inspiratory oxygen fraction of 0.1) at constant pulmonary blood flow. Bosentan, an endothelin A and B receptor antagonist, did not affect baseline Ppa, Ppao or systemic arterial pressure (Psa) and did not alter HPV (n=8). The NO synthase inhibitor N(G)-nitro-L-arginine (L-NA) did not affect baseline Ppa and Ppao, but increased Psa and enhanced HPV (n=12). The addition of bosentan in these dogs did not affect baseline Ppa or Ppao, but decreased Psa and inhibited HPV. Exhaled NO was decreased by L-NA and by bosentan and abolished by L-NA+bosentan (n=9). The authors conclude that endogenous nitric oxide is released by, and opposes the vasoconstricting effects of, endothelins in vivo, reducing systemic blood pressure and limiting hypoxic pulmonary vasoconstriction.     

Effects of angiotensin converting enzyme inhibitor and calcium channel blocker on normoxic and hypoxic pulmonary vascular tone in unanesthetized sheep

We evaluated the effects of captopril and nifedipine on normoxic and hypoxic pulmonary vascular tone in unanesthetized sheep. Infusion of captopril (10 micrograms/kg/min) in normoxia revealed a tendency to increase the mean pulmonary arterial pressure (Ppa) and the pulmonary vascular resistance (PVR) following the systemic vasodilation. A statistically significant increase was reached by 20 minutes. Hypoxia of 10% oxygen in nitrogen produced a prominent pulmonary hypertensive response. Captopril significantly decreased the hypoxic values of Ppa and PVR from 20.3 +/- 1.3 to 17.1 +/- 1.1 mmHg (p less than 0.01) and from 4.31 +/- 0.45 to 3.49 +/- 0.45 mmHg/L/min (p less than 0.01), respectively. Infusion of nifedipine (10 micrograms/kg/min) in normoxia caused an increase in Ppa from 15.5 +/- 0.9 to 18.9 +/- 1.0 mmHg (p less than 0.01), but not in PVR. This elevation in Ppa was considered to be derived from the significant increase in the cardiac output. Nifedipine significantly decreased the hypoxic values of Ppa and PVR from 21.3 +/- 1.5 to 19.3 +/- 1.5 mmHg (p less than 0.05) and from 3.88 +/- 0.30 to 27.3 +/- 0.13 mmHg/L/min (p less than 0.01), respectively. Captopril and nifedipine produced systemic hypotensive responses during both normoxic and hypoxic ventilation. It is concluded that both captopril and nifedipine are potent pulmonary vasodilating drugs in animal subjects with a hypoxic condition and that they might be useful in the clinical vasodilator therapy of hypoxic pulmonary hypertension in man.     

Enhancement of hypoxic pulmonary vasoconstriction by almitrine in the dog

In order to test the hypothesis of enhancement of hypoxic pulmonary vasoconstriction by Almitrine, 12 anesthetized and paralyzed dogs with normal lungs were studied under controlled ventilation. They were ventilated in random sequence with air, 12% O2, and 100% O2, and almitrine (0.1 mg/kg body weight) was infused over 30 min during each O2 mixture. The multiple inert gas elimination technique was used to detect alterations in ventilation-perfusion (VA/Q) mismatching before and during the interventions and to measure cardiac output (QT). Arterial, mixed venous and expired gases, inert gas concentrations, and hemodynamic measurements were made while the dogs were breathing the different O2 mixtures before infusing the drug, near the end of 30 min of infusion and 30 min after infusion had ended. There were no significant changes in pH, PaO2, PaCO2, QT, oxygen uptake, oxygen delivery index, systemic vascular resistance, mean systemic arterial pressure, heart rate, stroke volume index, or VA/Q distribution during the experiment. Significant increases in: (a) pulmonary artery pressure (PA), (b) the pressure difference between PA and pulmonary capillary wedge pressure (PCw), and (c) pulmonary vascular resistance (PVR) occurred when the drug was infused during 12% O2 and air, but not during 100% O2. The PVR increased 59.7% with almitrine infusion during 12% O2 and 38.4% during air breathing (p less than or equal to 0.01), but there was no significant change during 100% O2. Vascular responses were not dependent on the order in which the different O2 mixtures were administered. These data strongly suggest that almitrine enhances hypoxic vasoconstriction in the lung, and this effect may explain reported improvement in PaO2 in hypoxic patients given the drug.     

Prolonged lobar hypoxia in vivo enhances the responsivity of isolated pulmonary veins to hypoxia.

The hypoxic response of pulmonary vessels isolated from eight sheep whose right apical lobes (RAL) had inspired 100% N2 for 20 h was studied. The RAL of these conscious sheep inspired hypoxic gas and the remainder of the lung inspired air. During hypoxia, RAL perfusion was 33 +/- 3% of its air value, carotid arterial PO2 averaged 86 +/- 3 mm Hg and pulmonary perfusion pressure was not significantly different from the initial control period when the RAL inspired air. At the end of the hypoxic exposure, the sheep were killed, and pulmonary artery and vein rings (0.5 to 2 mm inner diameter) were isolated from both the RAL and the right cardiac lobe, which served as the control lobe (CL). Arteries from the RAL and CL did not contract in response to 6% O2/6% CO2/88% N2 (hypoxia). In contrast, RAL veins did contract vigorously in response to hypoxia, whereas CL veins did not contract or contracted only minimally. Rubbing of the endothelium or prior incubation of RAL veins with catalase (1,200 units/ml), indomethacin (10(-5) M), or the thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonist, SQ 29,548 (3 X 10(-6) M) each significantly reduced the response to hypoxia. RAL veins were also found to be more reactive than CL veins to the prostaglandin endoperoxide analogue U46619. We conclude that prolonged lobar hypoxia in vivo increases the responsivity of isolated pulmonary veins to hypoxia. These contractions may result from an increase in reactive O2 species, which in turn modify production of, metabolism of, and/or tissue responsivity to TxA2/PGH2.     

Physiologic responses to small emboli and hemodynamic effects of changes in deformability of polymorphonuclear leukocytes in isolated rabbit lung.

We hypothesized that polymorphonuclear leukocytes (PMNs) exposed to lipopolysaccharide (LPS) or chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) would alter the pulmonary hemodynamics of buffer-perfused rabbit lung. Pulmonary arterial pressure (Ppa) was measured at baseline, at peak response, and at 30 min after PMN infusion in the perfusate (Ppa x time, PT product). Infusion of peritoneal-harvested PMNs resulted in a transient increase in both pulmonary vascular resistance (PVR) and lung weight. PVR also increased when glutaraldehyde-treated rabbit PMNs (GPMNs) or beads were infused. Upstream PVR (Pao-Pdo) remained high with the infusion of GPMNs and beads and returned to baseline only when PMNs were infused 30 min thereafter. FMLP-exposed PMNs increased the peak Ppa and PT product. Pretreatment with 3-isobutyl-1-methylxanthine (IBMX) blocked this increase in pressure, suggesting the release of vasoconstrictor(s) or a direct effect of FMLP. PMNs exposed to LPS increased peak Ppa and PT product with and without the addition of IBMX. Cytochalasin D treatment of PMNs prevented the increase in PT product, suggesting that actin polymerization of PMNs is involved. The effects of these agents on PMN rigidity were verified by means of 6.5-microm polycarbonate filters. PMN suspension treated with FMLP or LPS increased filter perfusion pressure and PT product. Cytochalasin D prevented these increases. These results suggest that, initially after injection, PMNs behave like small beads embolizing primarily the small arteries in the lung and that they then move distally through the vasculature. Exposure to FMLP or LPS alters PMN deformability and the ability of PMNs to pass through the pulmonary vasculature, resulting in increased pulmonary vascular resistance.     

Inhibition of endogenous nitric oxide during endotoxemia in awake sheep - effects of Nomega-nitro-l-arginine on the distribution of pulmonary vascular resistance and prostanoid products

We examined the effects of endogenous nitric oxide (NO) inhibition on the longitudinal distribution of pulmonary vascular resistance and on arachidonic acid metabolism during endotoxemia in awake sheep. Mean pulmonary artery (Ppa), left atrial (Pla), and systemic artery pressure (Psa) were continuously measured, and cardiac output (CO) was continuously monitored by an implanted ultrasonic flow probe. We advanced a 7-French Swan-Ganz catheter into distal pulmonary artery and measured the pulmonary microwedge pressure (Pmw) with the balloon deflated, allowing calculation of upstream pulmonary vascular resistance (PVRup = [Ppa - Pmw]/CO) and down-stream PVR (PVRdown = [Pmw - Pla]/CO), respectively. In paired studies, endotoxin (1 micro g/kg) was infused over 30 minutes with and without N(omega)-nitro-L-arginine (NLA) treatment. NLA (20 mg/kg) was administered 30 minutes before endotoxin infusion. Endotoxin caused increases in PVRup and PVRdown. Pretreatment with NLA increases PVRup at baseline and enhanced increases in both PVRup and PVRdown during endotoxemia. Plasma level of thromboxane B(2) (TxB(2)) and prostacyclin (6-keto = PGF(1alpha)) significantly increased 1 hour after endotoxin administration (TxB(2), 308.3 +/- 94.8 [SE] to 2163.5 +/- 988.5 pg ml(-1), P <.05; 6-keto=PGF(1alpha), 155.6 +/- 91.4 to 564.9 +/- 131.8 pg ml(-1), P <.05), but the increased levels were similar to those in the NLA-pretreated animals. We conclude that endogenous NO mainly regulates precapillary vascular tone at baseline, and that NO modulated pre- and postcapillary vascular constriction during endotoxemia in sheep. It appears that cyclooxygenase production in response to endotoxin is unaffected by NO and its vascular effects.