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.     

Effect of cyclic guanosine monophosphate on hypoxic and angiotensin-II-induced pulmonary vasoconstriction

We examined, in isolated blood perfused rat lungs, the effect of the cell permeable 8-bromo derivative of cGMP on pulmonary vasoconstriction induced by either alveolar hypoxia or angiotensin II. 8-Bromo cGMP dose-dependently reduced both hypoxia-(IC₅₀=2.2 × 10^?5 M) and angiotensin-II-induced pulmonary vasoconstriction (IC₅₀=5.0 × 10^?5 M). This effect of 8-bromo cGMP on pulmonary vasoconstriction was not affected by cyclooxygenase blockade. M & B 22948 (0.1 mM), an inhibitor of cGMP-phosphodiesterase, reduced synergistically with 8-bromo cGMP the hypoxiaor angiotensin-II-induced vasoconstriction. The cGMP-phosphodiesterase inhibitor M & B 22948, by itself, selectively reduced hypoxia-induced vasoconstriction, suggesting a modulating effect of endogenous cGMP during hypoxic vasoconstriction.     

Effect of cyclic guanosine monophosphate on hypoxic and angiotensin-II-induced pulmonary vasoconstriction

We examined, in isolated blood perfused rat lungs, the effect of the cell permeable 8-bromo derivative of cGMP on pulmonary vasoconstriction induced by either alveolar hypoxia or angiotensin II. 8-Bromo cGMP dose-dependently reduced both hypoxia-(IC50 = 2.2 X 10(-5) M) and angiotensin-II-induced pulmonary vasoconstriction (IC50 = 5.0 X 10(-5) M). This effect of 8-bromo cGMP on pulmonary vasoconstriction was not affected by cyclooxygenase blockade. M & B 22948 (0.1 mM), an inhibitor of cGMP-phosphodiesterase, reduced synergistically with 8-bromo cGMP the hypoxia or angiotensin-II-induced vasoconstriction. The cGMP-phosphodiesterase inhibitor M & B 22948, by itself, selectively reduced hypoxia-induced vasoconstriction, suggesting a modulating effect of endogenous cGMP during hypoxic vasoconstriction.     

Effect of cigarette smoke extract on hypoxic pulmonary vasoconstriction]

Using an intravital microscopic-video recording TV system, we observed change in microvascular internal diameter (ID) of surface lung and mean pulmonary arterial pressure (Ppa) in Wistar rats (n = 60) in vivo during hypoxic ventilation (Fi02 = 0.1, 3 min) before and after intravenous administration of cigarette smoke extract (CSE). Our results showed that: (1) ID of pulmonary arterioles venules significantly decreased during acute alveolar hypoxia (P less than 0.001 vs control). After pretreatment of animal with administration of CSE intravenously, much more remarkable pulmonary vasoconstriction was induced by hypoxia than before CSE injection. (2) During hypoxia Ppa increased by 13.53 percent before administration of CSE (less than 0.001 vs control), and by 30.57 percent after CSE (P less than 0.001 VS control and before CSE), respectively. The data suggested that CSE can strengthen pulmonary vasoconstriction and hypertension induced by acute alveolar hypoxia.     

Effect of potassium channel openers on hypoxic pulmonary vasoconstriction]

The ATP-sensitive potassium channel (K+ATP) has been suggested as an important mechanism for the reactivity of vascular smooth muscle. We investigated the effects of K+ channel openers (lemakalim, pinacidil) on hypoxic pulmonary vasoconstriction (HPV) and angiotensin II (Ag II) induced vasoconstriction in isolated rat lungs (Sprague-Dawley rats: 300-450 g). Ventilation with hypoxic gas (2% O2, 5% CO2) was performed for 6 min after the injection of Ag II (0.1 microgram). Isolated lungs were perfused under constant flow (0.04 ml/g/min) using 20 ml of blood from donor rat. The perfusion pressure was used as the pulmonary artery pressure. Lemakalim or pinacidil was pre-administered through the reservoir. Pretreatment with pinacidil (10(-4) M) or lemakalim (10(-5) M) inhibited the pressor response to hypoxia, but did not inhibit the response to angiotensin II. Although the effect of lemakalim on HPV was reversed by administration of glibenclamide (10(-5) M) or tolbutamide (10(-3) M), the effect of pinacidil on HPV was not influenced by either drug. These results suggest that 1) K+ channel openers (lemakalim and pinacidil) inhibit the pressor response to hypoxia, and 2) lemakalim seems to act through K+ATP, whereas pinacidil may have other mechanisms of inhibition of vascular smooth muscle contraction. K+ATP may play an important role in the regulation of pulmonary vascular reactivity to hypoxia.     

Lung cyclic nucleotides in exercise-trained rats attenuate hypoxic pulmonary vasoconstriction

We examined the effects of exercise training on pulmonary arterial blood pressure (Ppa) and on adenosine 3,5-cyclic monophosphate (cAMP) and guanosine 3,5-cyclic monophosphate (GMP) concentrations in lung tissue at rest and during exercise under hypoxic conditions in catheter-implanted rats. Male Wistar rats were divided into an exercise-trained group (ET, n = 32) and nonexercised control group (control, n = 32). ET rats exercised 40 min/day 6 days/week for 6 weeks, at an altitude of 610 m on a treadmill. The mean Ppa levels of the ET were significantly lower than those of controls at rest and during exercise at 610- and 2500-m altitudes. The exercise-induced mean Ppa increase in the ET was less than that in controls at both 610- and 2500-m altitudes. Resting lung cAMP increased more in the ET than in controls at both 610- and 2500-m altitudes. In ET, cGMP was significantly greater at the 2500-m altitude than at the 610-m altitude at rest and just after exercise. Hypoxic exercise in ET was accompanied by a preferential increase in cGMP but not in cAMP. These results suggest that the intracellular augmentation of cAMP and cGMP in ET plays an important role in attenuating hypoxic pulmonary vasoconstriction (HPV) and exercise-induced increases in Ppa.Offprint requests to: Osamu Kashimura     

Effects of vasodilators on hypoxic pulmonary vasoconstriction in normal man

A reduction of arterial PO2 is generally observed when vasodilators are given to patients with cardiac or pulmonary disease. This has been attributed to a release of preexisting hypoxic pulmonary vasoconstriction (HPV). We investigated the effects of hemodynamics and blood gases of IV nitroglycerin, IV nitroprusside and sublingual nifedipine, at dosages currently used in clinical practice, in 23 healthy volunteers at normoxic conditions (fraction of inspired O2, FIO2 0.21) and at acute inspiratory hypoxia (FIO2 0.125 during 10 min). Breathing FIO2 0.125 elicited pulmonary vasoconstriction in all the subjects. At FIO2 0.21, nitroglycerin reduced preload, nifedipine reduced afterload, nitroprusside had balanced effects, but none of the drugs induced pulmonary vasodilation and only nitroglycerin deteriorated arterial oxygenation. At FIO2 0.125, nitroglycerin did not at all affect the pulmonary pressor response, while both nitroprusside and nifedipine decreased it. An inhibition of HPV was obtained with certainty in only one subject who received nitroprusside. In all the subjects in whom HPV was partially inhibited by vasodilator administration, the alveolar-arterial PO2 gradients remained significantly lowered, suggesting that the pulmonary vascular tone adaptation to alveolar hypoxia still was effective in improving ventilation/perfusion relationships. The role of impaired HPV in the reduction of arterial PO2 in patients under vasodilator therapy may have to be reevaluated.     

Mechanisms of hypoxic pulmonary vasoconstriction

During the last 4 decades hypoxic vasoconstriction has been acknowledged as an important pulmonary control mechanism that via matching ventilation and perfusion regulates one of the important physiologic parameters--PaO2. Whether the hypoxic vasoconstriction occurs directly in a localized vascular site with distinct biochemistry or whether it is mediated by a local hormone has not been resolved. Progress has been made because of the introduction of micropuncture techniques that allow direct pressure measurements in small segments of the lung vascular tree. Measurements of the force of contraction and membrane potential (118) and manipulation of the environment of pulmonary microvessels are the most recent progress in the elucidation of the mechanism of hypoxic vasoconstriction. Elements of energy, oxygen, and lipid metabolism appear to contribute to the biochemistry of this elusive response.     

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.     

Naloxone: effects on hypoxic pulmonary vasoconstriction

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

Chemoreceptor stimulation interferes with regional hypoxic pulmonary vasoconstriction

Hypoxemia interferes with the diversion of blood flow away from hypoxic regions of the lung, possibly through activation of the arterial chemoreceptor reflex. The purpose of this study was to determine if selective stimulation of carotid chemoreceptors reduces the diversion of flow (hypoxic vasoconstriction) when normal systemic oxygen levels are present. Chloralose anesthetized dogs were paralyzed and each lung was separately ventilated via a dual-lumen endobronchial tube. Left pulmonary artery (QL) and main pulmonary artery (QT) blood flows were measured with electromagnetic flow probes. Chemoreceptors were stimulated by perfusion of the carotid sinuses with hypoxic, hypercapnic blood. QL/QT averaged 46 +/- 4, 29 +/- 2, and 36 +/- 4% during bilateral O2 ventilation (control), left lung N2 ventilation, and left lung N2 plus chemoreceptor stimulation in dogs treated with the cyclo-oxygenase inhibitor meclofenamate. After vagotomy, QL/QT averaged 45 +/- 4, 27 +/- 3, and 28 +/- 2% during the same conditions. QL/QT decreased significantly from control (P less than 0.05) during left lung N2 alone but did not decrease during left lung N2 plus chemoreceptor stimulation in dogs with intact vagi. In contrast, QL/QT decreased significantly both before and during chemoreceptor stimulation in vagotomized dogs. The same responses were observed in dogs not treated with meclofenamate. These results indicate that selective stimulation of arterial chemoreceptors can interfere with regional hypoxic vasoconstriction and suggest that the vagus nerves may mediate this effect.     

Effects of S-nitrosation of hemoglobin on hypoxic pulmonary vasoconstriction and nitric oxide flux

Free hemoglobin (Hb) augments hypoxic pulmonary vasoconstriction (HPV), ostensibly by scavenging nitric oxide (NO). However, recent evidence suggests that Hb that is S-nitrosated may act as an NO donor and vasodilator. We studied the effects of oxyHb, Hb that is chemically modified to prevent heme binding or oxidation of NO (cyanometHb), and Hb that is S-nitrosated (SNO-Hb and SNO-cyanometHb) on HPV, expired NO (eNO), and perfusate S-nitrosothiol (SNO) concentration in isolated, perfused rabbit lungs. Perfusate containing either 4 microM oxyHb or SNO-Hb increased normoxic pulmonary artery pressure (Ppa), augmented HPV dramatically, and resulted in an 80% fall in eNO in comparison to perfusion with buffer, whereas 4 microM cyanometHb or SNO-cynanometHb had no effect on these variables. Excess glutathione (GSH) added to perfusate containing SNO-Hb resulted in a 20 to 40% fall in the perfusate SNO concentration, with a concomitant increase in metHb content, without affecting Ppa, HPV, or eNO. In conclusion, free Hb augments HPV by scavenging NO, an effect that is not prevented by S-nitrosation. NO released from SNO-Hb in the presence of GSH does not produce measurable vascular effects in the lung or changes in eNO because of immediate oxidation and metHb formation.     

CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca²⁺ mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca²⁺ mobilization. Ca²⁺ mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase- and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P_2/4). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P_2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction.In regional hypoventilation of the lung, hypoxic pulmonary vasoconstriction (HPV) protects against systemic hypoxemia by redistributing blood flow from poorly to better ventilated areas of the lung, thereby minimizing ventilation-perfusion (V_A/Q) mismatch (1). In chronic hypoxemia-associated lung disease, however, HPV contributes to pulmonary hypertension (PH), characterized by increased resistance and progressive remodeling of the pulmonary arteries, eventually leading to right ventricular hypertrophy and, ultimately, right heart failure.In the lung, hypoxia is initially sensed at the alveolocapillary level (2). The signal is then propagated retrogradely via gap junctions to upstream arterioles, where it is transmitted to adjacent pulmonary arterial smooth muscle cells (PASMCs) for initiation of HPV (2). Contraction of PASMCs is ultimately triggered by RhoA/rho kinase (RhoK)-mediated Ca²⁺ sensitization and concomitant cytosolic Ca²⁺ increase (1), for which transient receptor potential canonical 6 (TRPC6) plays a predominant role (3). TRPC6 is a nonselective cation channel (4) that is highly expressed in PASMCs (3) and colocalizes with caveolin-1 (5). Upon hypoxia, TRPC6 translocates to caveolin- and sphingolipid-rich lipid rafts (6), where it is activated by diacylglycerol (DAG) via phospholipase C (PLC) (4, 7). However, the signaling pathways that translocate TRPC6 to caveolae and activate PLC and RhoA in response to hypoxia remain obscure. Here, we provide evidence for a previously unrecognized role of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) in HPV and mechanistically link this finding to a newly identified, dual role of sphingolipids in both the activation of PLC and RhoA and the translocation of TRPC6.Gene mutations in CFTR cause CF, an autosomal recessive genetic disorder leading to viscous mucus secretion and recurring lung infections. CF is typically associated with profound pulmonary V_A/Q mismatches (8) and intrapulmonary shunts (9), which led us to hypothesize that HPV may be impaired in this condition. Indeed, arterial hypoxemia in CF patients can be accounted for by V_A/Q inequalities and shunts, yet not by impaired O₂ diffusion (10). Intriguingly, HPV is also abrogated in pneumonia (11) or sepsis (12) caused by Pseudomonas aeruginosa, which phenocopy CF disease via secretion of the virulence factor CFTR inhibitory factor (Cif) (13). Robert et al. reported the expression of CFTR in PASMCs and demonstrated its involvement in the modulation of pulmonary arterial tone (14). In the systemic circulation, CFTR-F508del, the most common mutation underlying human CF disease, has recently been associated with diminished Ca²⁺ release in vascular smooth muscle cells, decreased aortic tone, and responsiveness (15). Of specific relevance for HPV, CFTR was recently shown to directly interact with TRPC6, thus regulating TRPC6-dependent Ca²⁺ influx (16). Based on these considerations, we postulated that CFTR may play a crucial, yet so far unrecognized, role in hypoxia-induced Ca²⁺ mobilization underlying PASMC contraction and HPV.Interestingly, CFTR is considered to regulate homeostasis and lipid raft concentrations of sphingolipids (17, 18), which have recently become implicated in HPV in that HPV is blocked by inhibition of neutral sphingomyelinase (nSMase), which releases ceramide from sphingomyelin (19). nSMase is activated upon oxidative stress (20), possibly via arachidonic acid liberation by phospholipase A₂ (21), which all have been linked to HPV (1). In addition, ceramide accumulates in PASMCs upon hypoxia (22), mediates caveolar TRPC6 translocation in lung endothelial cells (23), and contributes to constriction of pulmonary artery rings (19, 24). Although ceramide may thus potentially act as a direct mediator of HPV, it may also serve as substrate for the formation of other, bioactive sphingolipids, most notably sphingosine-1-phosphate (S1P). S1P is generated by conversion of ceramide to sphingosine and its subsequent phosphorylation by sphingosine kinase (SphK) (25), which is known to be up-regulated upon hypoxia (26). In the lung, SphK1 is the predominant SphK isoform (27) and has been shown to modulate pulmonary vascular responsiveness and remodeling (28). S1P acts intracellularly as a second messenger or extracellularly via activation of five G protein-coupled receptors (GPCRs) termed S1P_1–5 (25), of which S1P₂ (29) and S1P₄ (30) mediate pulmonary vasoconstriction. Because S1P₂ (29, 31) and S1P₄ (32) receptor engagement activates PLC and RhoK, and S1P is a known activator of TRPC5 (33), we hypothesized that S1P may trigger both central pathways of HPV, DAG formation and consecutive TRPC6-induced Ca²⁺ mobilization, as well as RhoK-mediated Ca²⁺ sensitization (1). A potential role of S1P in HPV is particularly intriguing in consideration of its potential tie to CFTR, in that CFTR is one of only two transporters shown to translocate S1P across biological membranes (17). In the present study, we hence probed for the functional role of CFTR and its mechanistic link to sphingolipid signaling in HPV.     

Effects of selective alpha 1-adrenoceptor blockade in dogs with hypoxic pulmonary vasoconstriction

The acute effects of the selective alpha 1-blocker, E-643 (Bunazosine), on experimental pulmonary hypertension (PH) caused by hypoxic pulmonary vasoconstriction (HPV) in mongrel dogs were examined. Ninety second ventilation with 5% O2 and 95% N2 was used for hypoxic stimulation. The effects of E-643 were evaluated at doses of 1, 5, 10, 20 and 50 micrograms/kg in this order until the systemic arterial mean pressure (SAm) had decreased by 20 mmHg when compared with the control value during room air ventilation. PaO2 and PaCO2 decreased by 64.6 +/- 11.0 Torr and 2.4 +/- 2.5 Torr, respectively, and the pH increased by 0.031 +/- 0.012 during hypoxic ventilation. These blood gas changes affected during hypoxic stimulation were almost the same before E-643 administration. Progression of arterial blood hypoxemia due to E-643 administration during room air ventilation was not observed. SAm decreased by 8.0 +/- 11.9 mmHg after E-643 administration, while left atrial mean pressure (LAm) and cardiac output (CO) did not change significantly. Prior to E-643 administration, mean pulmonary arterial pressure (PAm) and pulmonary vascular resistance (PVR) increased by 6.4 +/- 3.3 mmHg and 6.2 +/- 3.8 HRU, respectively, during the 90 sec hypoxic ventilation period. After E-643 administration, the increases in PAm and PVR were 3.9 +/- 1.7 mmHg and 3.3 +/- 2.3 HRU, respectively. The suppression of increases in PAm and PVR was significant. The conclusion is that E-643, a selective alpha 1-blocker, is effective at restraining HPV in the dog model.     

Inhibition of hypoxic pulmonary vasoconstriction by nifedipine

Nifedipine is a potent slow channel calcium antagonist and systemic vasodilator recently reported to attenuate hypoxic pulmonary vasoconstriction in man. Other systemic vasodilators have also been shown to attenuate hypoxic pulmonary vasoconstriction, but their effects in some species may be mediated by reflex beta-adrenergic discharge. We evaluated the effect of nifedipine on the relation between pulmonary arterial pressure and blood flow during hyperoxia (inspired partial pressure of oxygen [PO₂] 200 mm Hg) and hypoxia (inspired PO₂ 50 mm Hg) in denervated ventilated pig lungs perfused in situ with the animal's own blood. Ten lungs were ventilated with alternating 15 minute periods of hyperoxia and hypoxia. Hypoxia shifted the pulmonary artery pressure (x axis)-blood flow (y axis) relationship to the right and decreased its slope, indicating vasoconstriction. Nifedipine, given as a 0.1, 1, or 10 μg/kg bolus into the pulmonary artery, caused a dose-dependent reduction of hypoxic pulmonary vasoconstriction. It is concluded that nifedipine is a potent pulmonary vasodilator acting locally within the lung and that it might be useful in the therapy of hypoxic pulmonary hypertension from chronic lung disease in man.