The ETA receptor antagonist, BMS-182874, reduces acute hypoxic pulmonary hypertension in pigs in vivo

OBJECTIVE: Elevated levels of the potent vasoactive peptide endothelin (ET), have been found in pathophysiological conditions associated with pulmonary hypertension. In this study, we have investigated the effects of the ETA receptor antagonist, BMS-182874, on hypoxic pulmonary hypertension in pigs. METHODS: Pigs were subjected to acute, intermittent 15-min periods of hypoxia (FiO2 0.1). Following a first hypoxia establishing hypoxic baseline values, vehicle or BMS-182874 (10 or 30 mg/kg) was administered i.v. before a second hypoxic period. In separate groups of animals, the effects of the nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NNA) in combination with BMS-182874 (10 mg) during repeated hypoxia were investigated. The ET-1-blocking properties of BMS-182874 were studied in vivo by infusion of ET-1 during normoxia and in vitro using isolated porcine pulmonary arteries. RESULTS: The hypoxia-evoked increase in mean pulmonary artery pressure was reduced by administration of BMS-182874 (10 mg/kg i.v.; from 42 +/- 8 to 34 +/- 4 mmHg, P < 0.05 and 30 mg/kg i.v.; from 38 +/- 4 to 30 +/- 5 mmHg, P < 0.05). In addition, BMS-182874 at 30 mg/kg reduced the pulmonary vascular resistance during hypoxia (from 7.4 +/- 1.5 to 5.3 +/- 1.1 mmHg.min.l-1 P < 0.05). The hemodynamic response to repeated hypoxia was reproducible in control animals and unaffected by the cyclo-oxygenase inhibitor diclophenac (3 mg/kg). Infusion of L-NNA alone resulted in an augmented pulmonary vasoconstriction during hypoxia; pulmonary arterial pressure from 35 +/- 6 to 43 +/- 9 mmHg; P < 0.05 and vascular resistance from 7.2 +/- 1.1 to 9.9 +/- 1.8 mmHg.min.l-1; P < 0.05. L-NNA in combination with BMS-182874 (10 mg/kg) resulted in a hypoxic pulmonary vasoconstriction of similar magnitude as hypoxic baseline. In addition, BMS-182874 reduced the hemodynamic response to ET-1 in normoxic pigs and competitively antagonized the vasoconstrictor effect of ET-1 in isolated porcine pulmonary arteries. CONCLUSIONS: The non-peptide, selective ETA receptor antagonist, BMS-182874, reduces hypoxic pulmonary vasoconstriction in pigs. The reduction in pulmonary vascular response to hypoxia following BMS-182874 is at least partly independent of nitric oxide.     

Functional and structural adaptation of the yak pulmonary circulation to residence at high altitude

The high-altitude (HA) native yak (Bos grunniens) has successfully adapted to chronic hypoxia (CH) despite being in the same genus as domestic cows, which are known for their great hypoxic pulmonary vasoconstrictor responses (HPVRs), muscular pulmonary arteries, and development of severe pulmonary hypertension on exposure to CH. To determine possible mechanisms by which the pulmonary circulation may adapt to CH, yak pulmonary vascular reactivity to both vasoconstrictor and vasodilator stimuli and yak pulmonary artery structure were assessed. Hypoxia caused a small but significant HPVR, and norepinephrine infusion caused a greater rise in pulmonary arterial pressure (Ppa) than did hypoxia. Acetylcholine, an endothelium-dependent vasodilator, had no effect on Ppa but lowered pulmonary resistance (Rp) by causing an increase in cardiac output. Sodium nitroprusside, an endothelium-independent vasodilator, decreased both Ppa and Rp significantly. Yak small pulmonary arteries had a 4.1 +/- 0.1% medial thickness, with vessels < or = 100 microns devoid of smooth muscle. Yak pulmonary artery endothelial cells were much longer, wider, and rounder in appearance than those of domestic cows. Thus the yak has successfully adapted to HA conditions by maintaining both a blunted HPVR and thin-walled pulmonary vessels. Differences in both endothelial cell morphology and response to acetylcholine between the yak and those reported in the domestic cow suggest the adaptation to HA may include changes not only in the amount of pulmonary vascular smooth muscle but in endothelial cell function and structure as well.     

Long-term effects of prenatal indomethacin administration on the pulmonary circulation in rats

Mechanical properties of the adult pulmonary vasculature are affected by perinatal experience of hypoxic pulmonary hypertension. In the present study, we followed the long-term effects of perinatal pulmonary hypertension induced by means other than hypoxia in rats. Daily injections of indomethacin (1 mg.kg-1 body weight (BW)) were given to the parturient rats. Their newborn pups had significantly increased number of muscularized peripheral pulmonary vessels. Pulmonary hypertension, however, did not persist to adulthood (mean pulmonary arterial pressure (Ppa) was 17.2 +/- 1.3 torr in the experimental group and 16.4 +/- 0.8 torr in controls). Pulmonary hypertension induced in adult rats by exposure to chronic hypoxia or by acute hypoxic challenges was similar in indomethacin-treated and control rats. Normoxic perfusion pressure/flow (P/Q) plots in isolated lungs were less steep in indomethacin-treated than in control rats. Acute hypoxia increased the slope of P/Q plots in indomethacin treated rats but not in controls. The described changes in the pulmonary vasculature induced by indomethacin are similar to those found previously in adult rats born in hypoxia. We conclude that perinatal pulmonary hypertension permanently modifies the pulmonary vasculature.     

Hemodynamic effects of acute hypoxia and minute amounts of endotoxin in awake swine

Hemodynamic measurements and arterial blood gases were determined from awake swine (n = 8) during acute hypoxia (12% O2, balance N2 for 5 minutes) and following injection of Escherichia coli endotoxin (4 microgram/kg of body weight) into the pulmonary artery. Comparison of baseline data with these treatments indicated: (1) swine exhibited a marked pulmonary pressor response to acute hypoxia (deltaBPpul = 9 to 12 mm of Hg): (2) injection of minute amounts of endotoxin led to a marked increase of pulmonary arterial blood pressure 10 to 20 minutes following the injection (deltaBPpul = 15 mm of Hg); and (3) the pulmonary pressor response to a 2nd exposure of acute hypoxia was unaffected by the intervening endotoxin injection.     

Minoxidil reduces pulmonary vascular resistance in dogs and cattle

Minoxidil has a direct dilator effect on the systemic arterial smooth muscle. It is potentially an important drug in the treatment of systemic hypertension, especially when combined with beta blockade, which is used to control the associated tachycardia and increase in cardiac output. However, recent observations have suggested that minoxidil might cause pulmonary hypertension. Consequently, we examined the acute effect of monoxidil and propranolol, separately and in combination, on the pulmonary vasculature of the anesthetized dog and the awake calf during normoxia and hypoxia. In both species minoxidil reduced pulmonary vascular resistance. In the dogs this appeared to be the result of a direct action on the pulmonary vascular smooth muscle and in the cattle it was secondary to beta-receptor stimulation. Propranolol alone in the cattle increased the pulmonary pressor response to hypoxia. While we have not examined the possibility that chronic administration of minoxidil might cause pulmonary hypertension by some other mechanism, our acute studies suggest that it reduces, rather than increases, pulmonary vascular resistance. Furthermore, there seems to be a species difference in the mode of its action in dogs and cattle.     

Pyridoxalated hemoglobin polyoxyethylene conjugate does not restore hypoxic pulmonary vasoconstriction in ovine sepsis

OBJECTIVES: Hypoxic pulmonary vasoconstriction, a protective mechanism, minimizes perfusion of underventilated lung areas to reduce ventilation-perfusion mismatching. We studied the effects of sepsis on hypoxic pulmonary vasoconstriction and attempted to determine whether hypoxic pulmonary vasoconstriction is influenced by pyridoxalated hemoglobin polyoxyethylene conjugate, a nitric oxide scavenger. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational intensive care unit at a university medical center. SUBJECTS: Nineteen female merino sheep, divided into three groups: group 1, controls (n = 5); group 2, sheep with sepsis (n = 6); and group 3, septic sheep treated with pyridoxalated hemoglobin polyoxyethylene conjugate (n = 8). INTERVENTIONS: All sheep were instrumented for chronic study. An ultrasonic flow probe was placed around the left pulmonary artery. After a 5-day recovery, a tracheostomy was performed and a double-lumen endotracheal tube was placed. Animals in groups 2 and 3 received a 48-hr infusion of live Pseudomonas aeruginosa (6 x 10(4) colony-forming units/kg/hr). After 24 hrs, sheep in group 3 received pyridoxalated hemoglobin polyoxyethylene conjugate (20 mg/kg/hr) for 16 hrs; sheep in groups 1 and 2 received only the vehicle. Hypoxic pulmonary vasoconstriction was repeatedly tested by unilateral hypoxia of the left lung with 100% nitrogen. Hypoxic pulmonary vasoconstriction was assessed as the change in left pulmonary blood flow. MEASUREMENTS AND MAIN RESULTS: In the animals in group 1, left pulmonary blood flow decreased by 62 +/- 8 (SEM)% during left lung hypoxia and remained stable during repeated hypoxic challenges throughout the study period. After 24 hrs of sepsis, left pulmonary blood flow decreased from 56 +/- 10% to 26 +/- 2% (group 2) and from 50 +/- 8% to 23 +/- 6% (group 3). In the sheep in group 2, there was no adaptation over time. Pulmonary shunt fraction increased. Pyridoxalated hemoglobin polyoxyethylene conjugate had no effect on hypoxic pulmonary vasoconstriction or pulmonary shunt. The animals receiving the bacterial infusion developed a hyperdynamic circulatory state with hypotension, decreased systemic vascular resistance, and increased cardiac output. Pyridoxalated hemoglobin polyoxyethylene conjugate increased mean arterial pressure and systemic vascular resistance but did not influence cardiac index. Pulmonary arterial pressure was increased during sepsis and increased even further after pyridoxalated hemoglobin polyoxyethylene conjugate administration. Oxygenation and oxygen delivery and uptake were not affected by pyridoxalated hemoglobin polyoxyethylene conjugate. CONCLUSIONS: Hypoxic pulmonary vasoconstriction is blunted during sepsis and there is no adaptation over time. It is not influenced by pyridoxalated hemoglobin polyoxyethylene conjugate. Pyridoxalated hemoglobin polyoxyethylene conjugate reversed hypotension and, with the exception of an increase in pulmonary arterial pressure, had no adverse effects on hemodynamics or oxygenation.     

Capillary oxygen transport during severe hypoxia: role of hemoglobin oxygen affinity

The efficacy of an increased hemoglobin oxygen affinity [decreased oxygen half-saturation pressure of hemoglobin (P50)] on capillary oxygen transport was evaluated in the hamster retractor muscle under conditions of a severely limited oxygen supply resulting from the combined effects of a 40% reduction in systemic hematocrit and hypoxic ventilation (inspired oxygen fraction 0.1). Two groups of hamsters were utilized: one with a normal oxygen affinity (untreated; P50 = 26.1 +/- 2.4 Torr) and one with an increased oxygen affinity (treated; P50 = 15.7 +/- 1.4 Torr) induced by the chronic short-term administration of sodium cyanate. Using in vivo video microscopy and image analysis techniques, we determined oxygen saturation and associated hemodynamics at both ends of the capillary network. During hypoxic ventilation, the decrease in oxygen saturation across the network was 3.6% for untreated animals compared with 9.9% for treated animals. During hypoxia, estimated end-capillary PO2 was significantly higher in the untreated animals. These data indicate that, at the capillary level, a decreased P50 is advantageous for tissue oxygenation when oxygen supply is severely compromised, because normal oxygen losses in capillaries are maintained in treated but not in untreated animals. The data are consistent with the presence of a diffusion limitation for oxygen during severe hypoxia in animals with a normal hemoglobin oxygen affinity.     

Hypoxia impairs vasodilation in the lung

Alveolar hypoxia causes pulmonary vasoconstriction; we investigated whether hypoxia could also impair pulmonary vasodilation. We found in the isolated perfused rat lung a delay in vasodilation following agonist-induced vasoconstriction. The delay was not due to erythrocyte or plasma factors, or to alterations in base-line lung perfusion pressure. Pretreating lungs with arachidonic acid abolished hypoxic vasoconstriction, but did not influence the hypoxia-induced impairment of vasodilation after angiotensin II, bradykinin, or serotonin pressor responses. Progressive slowing of vasodilation followed angiotensin II-induced constriction as the lung oxygen tension fell progressively below 60 Torr. KCl, which is not metabolized by the lung, caused vasoconstriction; the subsequent vasodilation time was delayed during hypoxia. However, catecholamine depletion in the lungs abolished this hypoxic vasodilation delay after KCl-induced vasoconstriction. In lungs from high altitude rats, the hypoxia-induced vasodilation impairment after an angiotensin II pressor response was markedly less than it was in lungs from low altitude rats. We conclude from these studies that (a) hypoxia impairs vasodilation of rat lung vessels following constriction induced by angiotensin II, serotonin, bradykinin, or KCl, (b) hypoxia slows vasodilation following KCl-induced vasoconstriction probably by altering lung handling of norepinephrine, (c) the effect of hypoxia on vasodilation is not dependent on its constricting effect on lung vessels, (d) high altitude acclimation moderates the effect of acute hypoxia on vasodilation, and (e) the hypoxic impairment of vasodilation is possibly the result of an altered rate of dissociation of agonists from their membrane receptors on the vascular smooth muscle.     

Sustained pulmonary vasodilation after inhaled nitric oxide for hypoxic pulmonary hypertension in swine

It has been shown that pulmonary vasodilation is sustained after discontinuation of inhaled nitric oxide (INO) during moderate hypoxic pulmonary hypertension (HPH) in swine. The present investigations demonstrated how INO dose, hypoxia duration, and endogenous NO production influence this important phenomenon. Fifteen adolescent Yorkshire swine were randomly assigned to three groups (n = 5 each) and underwent the following phasic experimental protocol: (I) Baseline ventilation (FIO2 = .3); (II) Initiating HPH (FIO2 = .16 to .18, PaO2 = 45 to 55 mm Hg); (III) INO at 10 ppm; (IV) Posttreatment observation; (V) INO of 80 ppm; and (VI) Posttreatment observation. Phase II (pretreatment hypoxia) lasted 30 minutes in group A (short hypoxia) and 120 minutes in group B (long hypoxia). N-nitro-L-arginine methyl ester (NAME) was used to inhibit nitric oxide synthase (NOS) throughout the experiment in group C (short hypoxia + NAME). Hemodynamics and blood gases were monitored by systemic and pulmonary artery catheters placed by femoral cutdown. Analysis of variance with post-hoc adjustment was used to compare groups at each phase, and the paired t test was used for comparisons within a group. With respect to baseline mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR), there were no significant differences among the three groups. MPAP and PVR were significantly higher in group C than in group A during phase II, (MPAP, 76% +/- 8% v 33% +/- 2%; PVR, 197% +/- 19% v 78% +/- 10%; P < .05). There were no significant differences in MPAP or PVR during phases III through VI. When MPAP was expressed as percent dilation, 80 ppm caused significantly more dilation than did 10 ppm in all three groups. Groups A and C had significantly higher sustained pulmonary artery dilation after 80 ppm than after 10 ppm (A, 82% +/- 31% v 17% +/- 11%; C, 68% +/- 10% v 42% +/- 12%; both P < .05), but group B did not (43% +/- 15% v 30% +/- 9%; P = .25). High dose results in stronger vasodilation than low dose during and after INO for moderate HPH of short duration. Long hypoxia blunts this high-dose advantage. Endogenous NO inhibition augments HPH but does not decrease pulmonary vasodilation during or after INO.     

Response of upper airway and chest wall muscles to selective brain stem hypoxia in the newborn

In animals with intact peripheral chemosensory afferents, hypoxia differentially affects upper airway (UA) and chest wall muscles. To determine the contribution of brain stem (BS) hypoxia to the response of UA and chest wall muscles during early life, we perfused the BS through a vertebral artery intermittently with blood from an extracorporeal circuit in nine newborn piglets (age 1-5 days). BS perfusions were performed with hypoxemic blood (arterial PO2 32 +/- 6 to 38 +/- 8 Torr) with different levels of BS PCO2 (28 +/- 2, 37 +/- 4, and 56 +/- 5 Torr) while systemic normocapnic hyperoxia was maintained (arterial PCO2 36 +/- 3 to 40 +/- 6 Torr, arterial PO2 345 +/- 73 to 392 +/- 37 Torr). Electromyograms (EMGs) of alae nasi (AN), external intercostal (EI), and diaphragm (DIA) were recorded. Normocapnic hypoxia of the BS induced a sustained increase in AN EMG (P < 0.01, analysis of variance) and depression of EI and DIA EMGs without a transient increase. These contrasting responses were also observed during hypocapnic and hypercapnic hypoxia of the BS and were not affected by inputs from the peripheral chemoreceptors or rostral cerebral structures that were not exposed to hypoxia. We conclude that, despite eliciting the known central respiratory depression, BS hypoxia causes an increase in the respiratory drive to an UA airway muscle. Thus, BS hypoxia elicits a selective rather than a generalized respiratory muscle depression. The respiratory muscles with high energy expenditure (DIA and EI) are depressed while UA muscles are stimulated or disinhibited. This response is independent of the level of BS arterial PCO2.     

Superior ophthalmic vein at computed tomography

Simultaneous hemodynamic, ventilatory, and blood gas studies were performed in 16 men with congestive heart failure before and during infusion of sodium nitroferricyanide (nitroprusside). The cardiac index increased from 2.00+/-0.16 L/min/sq m (SE) to 2.38+/-0.14 L/min/sq m, and the total pulmonary and systemic peripheral resistances fell from 928+/-123 to 494+/-57 dynes sec cm-5 and from 2,208+/-210 to 1,558+/-121 dynes sec cm-5, respectively. Both systemic and pulmonary arterial decreased during infusion of sodium nitroferricyanide, and the mixed venous oxygen pressure increased. There was no change in total or alveolar ventilation, arterial carbon dioxide tension, pH, or base excess; however, the mean arterial oxygen pressure (PaO2) decreased from 74+/-3 mm Hg to 68+/-3 mm Hg and the venous admixture effect increased from 8+/-1% to 13+/-2%. We conclude that the decrease in PaO2 during infusion of sodium nitroferricyanide resulted from a worsening of the ventilation-perfusion relationships due to increased perfusion of underventilated pulmonary units.     

Influence of applied tension and nitric oxide on responses to endothelins in rat pulmonary resistance arteries: effect of chronic hypoxia

1. The effect of basal tension (transmural tensions 235 +/- 29 mg wt (low tension: equivalent to approximately 16 mmHg) and 305 +/- 34 mg wt (high tension: equivalent to 35 mmHg)) on rat pulmonary resistance artery responses to endothelin-1 (ET-1) and the selective ET(B)-receptor agonist sarafotoxin S6c (S6c) were studied. The effects of nitric oxide synthase inhibition with N(omega)-nitro-L-arginine methylester (L-NAME, 100 microM) on ET receptor-induced responses, as well as vasodilator responses to acetylcholine (ACh) and S6c, were also investigated. Changes with development of pulmonary hypertension, induced by two weeks of chronic hypoxia, were determined. 2. Control rat preparations showed greatest sensitivity for ET-1 when put under low tension (pEC50: 8.1 +/- 0.1) compared with at the higher tension (pEC50: 7.7 +/- 0.1) and there were significant increases in maximum contractile responses to S6c (approximately 80%) and noradrenaline (approximately 60%) when put under high tension. 3. In control pulmonary resistance arteries, both ET-1 and S6c produced potent vasoconstrictor responses. S6c was 12 fold more potent than ET-1 in vessels set at low tension (S6c pEC50: 9.2 +/- 0.1) and 200 fold more potent than ET-1 when the vessels were set at high tension (S6c pEC50: 9.0 +/- 0.1). Chronic hypoxia did not change the potencies of ET-1 and S6c but did significantly increase the maximum contractile response to ET-1 by 60% (at low tension) and 130% (at high tension). 4. In control rat vessels, L-NAME itself caused small increases in vascular tone (5-8 mg wt tension) in 33-56% of vessels. In the chronic hypoxic rats, in vessels set at high tension, L-NAME-induced tone was evident in 88% of vessels and had increased to 26.9 +/- 6.6 mg wt tension. Vasodilatation to sodium nitroprusside, in non-preconstricted vessels, was small in control rat vessels (2-6 mg wt tension) but increased significantly to 22.5 +/- 8.0 mg wt tension in chronic hypoxic vessels set at the higher tensions. Together, these results indicate an increase in endogenous tone in the vessels from the chronic hypoxic rats which is normally attenuated by nitric oxide production. 5. L-NAME increased the sensitivity to S6c 10 fold (low tension) and 6 fold (high tension) only in chronic hypoxic rat pulmonary resistance arteries. It had no effect on responses to ET-1 in any vessel studied. 6. Vasodilatation of pre-contracted vessels by ACh was markedly greater in the pulmonary resistance arteries from the chronic hypoxic rats (pIC50: 7.12 +/- 0.19, maximum: 72.1 +/- 0.2.0%) compared to their age-matched controls (pIC50: 5.77 +/- 0.15, maximum: 28.2 +/- 2.0%). There was also a 2.5 fold increase in maximum vasodilatation induced by ACh. 7. These results demonstrate that control rat preparations showed greatest sensitivity for ET-1 when set at the lower tension, equivalent to the pressure expected in vivo (approximately 16 mmHg). Pulmonary hypertension due to chronic hypoxia potentiated the maximum response to ET-1. Pulmonary resistance arteries from control animals exhibited little endogenous tone, but exposure to chronic hypoxia increased endogenous inherent tone which is normally attenuated by nitric oxide. Endogenous nitric oxide production may increase in pulmonary resistance arteries from chronic hypoxic rats and attenuate contractile responses to ET(B2) receptor stimulation. Relaxation to ACh was increased in pulmonary resistance arteries from chronic hypoxic rats.     

Effect of aerosol heparin on the development of hypoxic pulmonary hypertension in the guinea pig

Chronic hypoxia produces pulmonary artery hypertension through vasoconstriction and structural remodeling of the pulmonary vascular bed. The present study was designed to test the effect of heparin administered via aerosol on the development of hypoxic pulmonary hypertension. Anesthetized, intubated, and mechanically ventilated guinea pigs received an aerosol of either 2 ml normal saline (hypoxic control, HC) or 4,500 units of heparin diluted in 2 ml normal saline via an ultrasonic nebulizer (hypoxic heparin, HH). After 24 h of recovery, the animals were placed in a hypoxic chamber (10% O2) for 10 days. Animals kept in room air served as normoxic controls (NC). Hypoxia increased mean pulmonary artery pressure from 11 +/- 1 (SEM) mm Hg in NC to 24 +/- 1 mm Hg in HC (p < 0.05). Pulmonary artery pressure was significantly lower in HH-treated animals (20 +/- 1 mm Hg, p < 0.05 versus HC) as was the total pulmonary vascular resistance (0.15 +/- 0.01 in HH versus 0.20 +/- 0.01 mm Hg/ml/min in HC, p < 0.05). There was no difference in cardiac output (146 +/- 12 in HH versus 126 +/- 7 ml/min in HC), hematocrit (57 +/- 2 in HH versus 56 +/- 2% in HC), partial thromboplastin time (30 +/- 2 in HH versus 32 +/- 3 s in HC), prothrombin time (46 +/- 1 in HH versus 48 +/- 4 s in HC) or room air arterial blood gas values after 10 days of hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Trypsin-like enzymes during fertilization in the shrimp Rhynchocinetes typus

OBJECTIVE: To determine factors affecting postoperative pulmonary circulation in patients with major systemic-to-pulmonary collateral arteries. METHODS: A total of 48 patients underwent biventricular repair subsequent to unifocalization at ages in the range 1-34 years. The preparative procedures consisted of ligation of the collateral arteries in 6, plasty to the pulmonary arteries using no artificial materials in 12 and extensive reconstruction using heterologous pericardial tubes in 30. The number of the pulmonary vascular segments unifocalized was 9-18 (16 +/- 3). The amount of flow draining via residual minute systemic-to-pulmonary collaterals measured at the time of repair was 4-58% (24 +/- 16%) of the total perfusion by the cardiopulmonary bypass machine. RESULTS: This value was 40 +/- 16% in 5 patients dying in the short term after repair. The number of segments was nine or ten after unifocalization in 2 of these. Another 4 patients died in the longer term, 3 of these with CATCH 22 syndrome dying because of pulmonary hypertension. Postoperative catheterization demonstrated mean pulmonary arterial pressures in the range 8-40 (21 +/- 9) mmHg and pulmonary resistance in the range 1.7-10 (5.0 +/- 2.1) units/m2. Pulmonary resistance was correlated statistically to age at repair (r = 0.77), the number of pulmonary vascular segments (r = -0.41) and to percent collateral flow (r = 0.48). The use of a heterologous pericardial tube for unifocalization was also related probably to higher pulmonary resistance. CONCLUSION: It is essential to accomplish effective unifocalizations followed by earlier definitive repair so as to establish better pulmonary circulation.     

Bronchoarterial ratio on thin section CT: comparison between high altitude and sea level

PURPOSE: Our goal was to measure normal bronchial to accompanying pulmonary arterial diameter ratios and normal bronchial wall thickness on thin section CT at high altitude and at sea level. METHOD: Seventeen normal, healthy, nonsmoking subjects living at 1,600 m altitude and 16 living at sea level underwent thin section CT (1.5 to 2.0 mm collimation). All images were photographed at window levels of -450 and -700 HU and window width of 1,500-1,600 HU. Internal diameters of the segmental and subsegmental bronchi were measured and compared with the diameter of the adjacent pulmonary artery. Bronchial wall thickness of each bronchus was measured. Only bronchi and arteries seen in cross section and within 1 mm from each other were included in the analysis. RESULTS: Four hundred sixty-seven bronchi (215 at high altitude, 252 at sea level) were assessed. At window level of -450 HU, the bronchoarterial ratio was 0.76 +/- 0.14 (mean +/- SD) at altitude and 0.62 +/- 0.13 at sea level (p < 0.001). Bronchial wall thickness measured 0.92 +/- 0.09 mm (mean +/- SD) at altitude and 1.12 +/- 0.19 mm at sea level (p < 0.001). At window level of -700 HU, there was an artifactual decrease in the bronchoarterial diameter ratios and an increase in bronchial wall thickness. CONCLUSION: Bronchoarterial ratio increases and bronchial wall thickness decreases with altitude. These findings are presumably related to hypoxic bronchodilatation and vasoconstriction.     

Blood lactate and acid-base balance in graded neonatal hypoxia: evidence for oxygen-restricted metabolism

This study examines the neonatal response to graded hypoxia and determines the arterial PO2 (PaO2) threshold for oxygen-restricted metabolism as confirmed by the development of lactic acidosis and altered oxygen handling. Anesthetized, intubated, and ventilated 3-day-old pigs (n = 56) were randomly assigned to one of five predetermined acute (120 min) graded hypoxia groups: normoxia (PaO2 = 80 Torr) or mild (60 Torr), moderate (40 Torr), moderately severe (30 Torr), or severe (20 Torr) hypoxia. In moderate hypoxia, lactate and acid-base homeostasis were unaltered due to a significant increase in oxygen extraction (P < 0.05) that was sufficient to maintain the arteriovenous oxygen content difference (oxygen uptake). In moderately severe hypoxia, increased arterial lactate and decreased HCO3- and base excess were evidence of anaerobic metabolism, yet pH was unaltered, indicating adequate buffering. In this group, despite the increase in oxygen extraction, oxygen uptake was reduced, indicating the onset of oxygen-restricted metabolism. The severe hypoxia group had significantly increased lactate (21.7 +/- 3.9 mmol/l), decreased pH (7.01 +/- 0.07) and base excess (-21.5 +/- 3.0 mmol/l), and depletion of HCO3- (9.7 +/- 1.6 mmol/l) (P < 0.0001). Here, increases in oxygen extraction were severely limited by availability, resulting in significantly reduced oxygen uptake, anaerobic metabolism, and profound lactic acidosis.     

Carbon monoxide inhibits hypoxic pulmonary vasoconstriction in rats by a cGMP-independent mechanism

Hypoxia activates erythropoietin-producing cells, chemoreceptor cells of the carotid body and pulmonary artery smooth muscle cells (PSMC) with a comparable arterial PO2 threshold of some 70 mmHg. The inhibition by CO of the hypoxic responses in the two former cell types has led to the proposal that a haemoprotein is involved in the detection of the PO2 levels. Here, we report the effect of CO on the hypoxic pulmonary vasoconstriction (HPV). Pulmonary arterial pressure (PAP) was measured in an in situ, blood-perfused lung preparation. PAP in normoxia (20% O2, 5% CO2) was 15.2+/-1.8 mmHg, and hypoxia (2% O2, 5% CO2) produced a DeltaPAP of 6.3+/-0.4 mmHg. Addition of 8% or 15% CO to the hypoxic gas mixture reduced the DeltaPAP by 88.3+/-2.7% and 78.2+/-6.1% respectively. The same levels of CO did not affect normoxic PAP nor reduced the DeltaPAP produced by angiotensin II. The effect of CO was studied after inhibition of the NO-cyclic guanosine monophosphate (cGMP) cascade with N-methyl-l-arginine (5.10(-5) M) or methylene blue (1.4.10(-4) M). It was found that both inhibitors more than doubled the hypoxic DeltaPAP without altering the effectiveness of CO to inhibit the HPV. In in vitro experiments we verified the inhibition of guanylate cyclase by measuring the levels of cGMP in segments of the pulmonary artery. Cyclic GMP levels were 1.4+/-0.2 (normoxia), 2.5+/-0.3 (hypoxia) and 3.3+/-0.5 pmole/mg tissue (hypoxia plus 8% CO); sodium nitroprusside increased normoxic cGMP levels about fourfold. Methylene blue reduced cGMP levels to less than 10% in all cases, and abolished the differences among normoxic, hypoxic and hypoxic plus CO groups. It is concluded that CO inhibits HPV by a NO-cGMP independent mechanism and it is proposed that a haemoprotein could be involved in O2-sensing in PSMC.     

Pressure-flow-volume relationships in pulmonary circulation of normal highlanders

Pulmonary vascular pressures and blood flow were measured with and without unilateral pulmonary arterial occlusion (UPAO) at rest and during exercise in 10 normal highlanders at La Paz, Bolivia (altitude, 3,750 m). In 6 other highlanders at rest and during exercise, pulmonary pressures, flow, and blood volume were measured during air breathing (PIO2 congruent to 100 Torr) and 29-30% oxygen (PIO2 congruent to 150 Torr). During air breathing, pulmonary vascular resistance was elevated at rest and did not change with exercise. Pulmonary arterial pressure rose less at rest with UPAO than during exercise without UPAO, and pulmonary vascular resistance was less in the former. Raising PaO2 to normal sea-level values had no effects on the pulmonary circulation at rest but prevented to a large extent the rise in pulmonary arterial pressure during exercise. Hence pulmonary vascular resistance during exercise was lower with oxygen than without. Thus, hypoxic vasoconstriction contributed to the pulmonary hypertension during exercise in normal highlanders. Circumstantial evidence suggests that this is related to the profound mixed venous hypoxemia caused by exercise in a hypoxic environment.     

Pulmonary vascular impedance response to hypoxia in dogs and minipigs: effects of inhaled nitric oxide

The pig has been reported to present with a stronger hypoxic pulmonary vasoconstriction (HPV) than many other species, including dogs. We investigated [pulmonary arterial pressure (Ppa)-pulmonary arterial occluded pressure (Ppao)] vs. pulmonary blood flow (Q) relationships and pulmonary vascular impedance (PVZ) spectra in nine minipigs and nine weight-matched dogs. The animals were anesthetized and ventilated in hyperoxia [inspired O2 fraction 0.4] or hypoxia (inspired O2 fraction 0.12). PVZ was computed from the Fourier series for Ppa and Q. In hyperoxia, the pigs had a higher Ppa (26 +/- 1 vs. 16 +/- 1 mmHg), a higher first-harmonic impedance (Z1), and a more negative low-frequency phase angle but no different characteristic impedance (Zc) compared with the dogs at the same Q. Hypoxia in the dogs increased (Ppa-Ppao) at all levels of Q studied by an average of 2 mmHg but did not affect Z1 or Zc. Hypoxia in the pigs increased (Ppa-Ppao) at all levels of Q by an average of 13 mmHg and increased Z1 and Zc. Inhaled NO (150 ppm) reversed the hypoxia-induced changes in (Ppa-Ppao)/Q plots and PVZ in the dogs and pigs. However, differences in (Ppa-Ppao)/Q plots and PVZ between the dogs and pigs in hyperoxia and hypoxia were not affected by inhaled NO. We conclude 1) that minipigs present with an elevated pulmonary vascular resistance and impedance in hypoxia more than in hyperoxia and 2) that baseline differences in pulmonary hemodynamics between dogs and minipigs are structural rather than functional.     

Effect of hemorrhagic hypotension on cortical oxygen pressure and striatal extracellular dopamine in cat brain

This study investigated the relationships between blood pressure, cortical oxygen pressure, and extracellular striatal dopamine in the brain of adult cats during hemorrhagic hypotension and retransfusion. Oxygen pressure in the blood of the cortex was measured by the oxygen dependent quenching of phosphorescence and extracellular dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) by in vivo microdialysis. Following a 2 h stabilization period after implantation of the microdialysis probe in the striatum, the mean arterial blood pressure (MAP) was decreased in a stepwise manner from 132 +/- 2 Torr (control) to 90 Torr, 70 Torr and 50 Torr, holding the pressure at each level for 15 min. The whole blood was then retransfused and measurements were continued for 90 min. As the MAP was lowered there was a decrease in arterial pH, from a control value of 7.37 +/- 0.05 to 7.26 +/- 0.06. The PaCO2 decreased during bleeding from 32.3 +/- 4.8 Torr to 19.6 +/- 3.6 Torr and returned to 30.9 +/- 3.9 Torr after retransfusion. The PaO2 was 125.9 +/- 15 Torr during control conditions and did not significantly change during bleeding. Cortical oxygen pressure decreased with decrease in MAP, from 50 +/- 2 Torr (control) to 42 +/- 1 Torr, 31 +/- 2 Torr and 22 +/- 2 Torr, respectively. A statistically significant increase in striatal extracellular dopamine, to 2,580 +/- 714% of control was observed when MAP decreased to below 70 Torr and cortical oxygen pressure decreased to below 31 Torr. When the MAP reached 50 Torr, the concentration of extracellular dopamine increased to 18,359 +/- 2,764% of the control value. A statistically significant decrease in DOPAC and HVA were observed during the last step of bleeding. The data show that decreases in systemic blood pressure result in decrease in oxygen pressure in the microvasculature of the cortex, suggesting vascular dilation is not sufficient to result in a full compensation for the decreased MAP. The decrease in cortical oxygen pressure to below 32 Torr is accompanied by a marked increase in extracellular dopamine in the striatum, indicating that even such mild hypoxia can induce significant disturbance in brain metabolism.