Effects of arterial ligation and embolization on pulmonary vascular pressure distribution

The effects of embolization on the longitudinal distribution of pulmonary vascular pressures with respect to vascular compliance were determined by the vascular inflow and outflow occlusion technique in isolated blood-perfused pig lungs treated with papaverine to prevent vasomotor responses. Embolization with microspheres having mean diameters of 75, 200, and 550 microns and with barrier beads (2 X 3 X 3.5 mm) significantly increased the pressure gradient across the relatively compliant middle region (delta Pm) without increasing the gradients across the relatively noncompliant regions on the arterial (delta Pa) or venous (delta Pv) ends of the vasculature. In contrast ligation of several lobar arteries caused delta Pa to increase from 0.9 +/- 0.3 to 5.9 +/- 1.1 mmHg but did not change delta Pm or delta Pv. Assuming that delta Pa and delta Pv measured by vascular occlusion result from cessation of flow through resistances, these data suggest that in isolated pig lungs the vessels at the boundary between the arterial and middle regions defined by the occlusion technique are arteries greater than 2-3 mm diam and smaller than lobar arteries.     

Role of venoconstriction in thromboxane-induced pulmonary hypertension and edema in lambs

We evaluated the dose response to a stable thromboxane (Tx) A2 analogue (sTxA2; 0.3-30 micrograms) in the pulmonary circulation and its effect on the distribution of pressure gradients determined by the occlusion technique in isolated nonblood perfused newborn lamb lungs. The total pulmonary pressure gradient (delta Pt) was partitioned into pressure drops across the relatively indistensible arteries and veins (delta Pv) and relatively compliant vessels. We also evaluated the effects of prostacyclin (PGI2) and a Tx receptor antagonist (ONO 3708) on the sTxA2-induced pulmonary responses. Injection of sTxA2 caused a dose-related increase in the pulmonary arterial pressure, with the primary component of the increase in delta Pt (4.1 +/- 0.8 to 13.9 +/- 0.4 Torr) at 30 micrograms derived from the prominent rise in delta Pv (1.8 +/- 0.3 to 9.8 +/- 0.9 Torr). Infusion of PGI2 (0.4 microgram.kg-1.min-1) reduced the response to sTxA2 mainly by attenuating the delta Pv elevation. Infusion of ONO 3708 (100 micrograms.kg-1.min-1) completely abolished the sTxA2-induced pulmonary hypertension. Injection of sTxA2 resulted in pulmonary edema characterized by a significant increase in wet-to-dry lung weight ratio (9.13 +/- 0.35 vs. 7.15 +/- 0.41 in control lungs). The sTxA2-induced pulmonary edema was increased by PGI2 and inhibited by ONO 3708. We conclude that thromboxane-induced pulmonary hypertension is primarily produced by venoconstriction and prostacyclin may worsen the edema induced by thromboxane.     

Flow-volume characteristics in the pulmonary circulation

Isolated ferret and canine lungs were used to validate a method for assessing determinants of vascular volume in the pulmonary circulation. With left atrial pressure (Pla) constant at 5 mmHg, flow (Q) was raised in steps over a physiological range. Changes in vascular volume (delta V) with each increment in Q were determined as the opposite of changes in perfusion system reservoir weight or from the increase in lung weight. At each level of Q, the pulmonary arterial and left atrial cannulas were simultaneously occluded, allowing all vascular pressures to equilibrate at the same static pressure (Ps), which was equal to the compliance-weighted average pressure in the circulation before occlusion. Hypoxia (inspired PO2 25 Torr) in ferret lungs, which causes intense constriction in arterial extra-alveolar vessels, had no effect on the slope of the Ps-Q relationship, interpreted to represent the resistance downstream from compliance (control 0.025 +/- 0.006 mmHg.ml-1.min, hypoxia 0.030 +/- 0.013). The Ps-axis intercept increased from 8.94 +/- 0.50 to 13.43 +/- 1.52 mmHg, indicating a modest increase in the effective back-pressure to flow downstream from compliant regions. The compliance of the circulation, obtained from the slope of the relationship between delta V and Ps, was unaffected by hypoxia (control 0.52 +/- 0.08 ml/mmHg, hypoxia 0.56 +/- 0.08). In contrast, histamine in canine lungs, which causes constriction in veins, caused the slope of the Ps-Q relationship to increase from 0.013 +/- 0.007 to 0.032 +/- 0.006 mmHg.ml-1.min (P less than 0.05) and the compliance to decrease from 3.51 +/- 0.56 to 1.68 +/- 0.37 ml/mmHg (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of increased alveolar surface tension on segmental pulmonary vascular resistance

The site of change in pulmonary vascular resistance (PVR) after surfactant displacement with the detergent diocytl sodium sulfosuccinate (OT) was studied in the isolated canine left lower lobe preparation. Changes in PVR were assessed using the arterial and venous occlusion technique and the vascular pressure-flow relationship. Changes in alveolar surface tension were confirmed from measurements of pulmonary compliance as well as from measurements of surface tension of extracts from lung homogenates. After surfactant depletion (the perfusion rate constant) the total pressure gradient (delta PT) across the lobe increased from 13.4 +/- 1 to 17.1 +/- 0.8 mmHg. This increase in delta PT was associated with a significant increase in the arterial and venous gradients (3.7 +/- 0.3 to 4.9 +/- 0.4 and 5.7 +/- 0.5 to 9.4 +/- 0.6 mmHg, respectively) and a decrease in middle pressure gradient (4.1 +/- 0.8 to 2.9 +/- 0.6 mmHg). The vascular pressure-flow relationship supported these findings and showed that the mean slope increased by 52% (P less than 0.05), whereas the pressure intercept decreased slightly but not significantly (3.7 +/- 0.7 to 3.2 +/- 0.8 mmHg). These results suggest that the resistance of arteries and veins increases, whereas the resistance of the middle segment decreases after surfactant depletion. These effects were apparently due to surface tension that acts directly on the capillary wall. Direct visualization of subpleural capillaries supported the notion that capillaries become distended and recruited as alveolar surface tension increases. In the normal lung (perfused at constant-flow rate) changes in alveolar pressure (Palv) were transmitted fully to the capillaries as suggested by equal changes in pulmonary arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development of the pulmonary vasculature in newborn lambs: structure-function relationships

Our objectives were 1) to describe the quantitative light microscopy and ultrastructure of newborn lamb lungs and 2) to correlate hemodynamic changes during normoxia and hypoxia with the morphology. By light microscopy, we measured the percent muscle thickness (%MT) and peripheral muscularization of pulmonary arteries and veins from 25 lambs aged less than 24 h, 2-4 days, 2 wk, and 1 mo. At the same ages, lungs were isolated and perfused in situ and, after cyclooxygenase blockade with indomethacin, total, arterial (delta Pa), middle (delta Pm), and venous pressure gradients at inspired O2 fractions of 0.28 (mild hyperoxia) and 0.04 (hypoxia) were determined with inflow-outflow occlusion. During mild hyperoxia, delta Pa and delta Pm fell significantly between 2-4 days and 2 wk, whereas during hypoxia, only delta Pm fell. The %MT of all arteries (less than 50 to greater than 1,000 microns diam) decreased, and peripheral muscularization of less than 100-microns-diam arteries fell between less than 4 days and greater than 2 wk. Our data suggest that 1) the %MT of arteries determines normoxic pulmonary vascular resistance, because only arterial and middle segment resistance fell, 2) peripheral muscularization is a major determinant of hypoxic pulmonary vasoconstriction, because we observed a fall with age in peripheral muscularization of less than 100-micron-diam arteries and in delta Pm with hypoxia, and 3) the arterial limit of the middle segment defined by inflow-outflow occlusion lies in 100- to 1,000-microns-diam arteries.     

Pulmonary vasodilation with structurally altered pulmonary vessels and pulmonary hypertension

To evaluate pulmonary vasodilation in a structurally altered pulmonary vascular bed, we gave endothelium-dependent (acetylcholine) and endothelium-independent [sodium nitroprusside, prostaglandin I2 (PGI2)] vasodilators in vivo and to isolated lobar pulmonary arteries from neonatal calves with severe pulmonary hypertension. Acetylcholine, administered by pulmonary artery infusion, decreased pulmonary arterial pressure from 120 +/- 7 to 71 +/- 6 mmHg and total pulmonary resistance from 29.4 +/- 2.6 to 10.4 +/- 0.9 mmHg.l-1.min without changing systemic arterial pressure (90 +/- 5 mmHg). Although both sodium nitroprusside and PGI2 lowered pulmonary arterial pressure to 86 +/- 4 and 96 +/- 4 mmHg, respectively, they also decreased systemic arterial pressure to 65 +/- 4 and 74 +/- 3 mmHg, respectively. Neither sodium nitroprusside nor PGI2 was as effective as acetylcholine at lowering total pulmonary resistance (18.0 +/- 3.6 and 19.1 +/- 2.2 mmHg.l-1.min, respectively). Right-to-left cardiac shunt through the foramen ovale was decreased by acetylcholine from 1.6 +/- 0.4 to 0.1 +/- 0.2 l/min but was not changed by sodium nitroprusside or PGI2. Isolated lobar pulmonary arteries from pulmonary hypertensive calves did not relax in response to acetylcholine, whereas isolated pulmonary arteries from age-matched control calves did relax in response to acetylcholine. Control and pulmonary hypertensive lobar pulmonary arteries relaxed equally well in response to sodium nitroprusside. We concluded that acetylcholine vasodilation was impaired in vitro in isolated lobar pulmonary arteries but was enhanced in vivo in resistance pulmonary arteries in neonatal calves with pulmonary hypertension.     

Mechanism of stimulation of pulmonary prostacyclin synthesis at birth

In order to investigate the mechanism behind ventilation-induced pulmonary prostacyclin production at birth, chloralose anesthetized, exteriorized, fetal lambs were ventilated with a gas mixture that did not change blood gases (fetal gas) and unventilated fetal lungs were perfused with blood containing increased O2 and decreased CO2. Ventilation with fetal gas (3%O2, 5%CO2) increased net pulmonary prostacyclin (as 6-keto-PGF1 alpha) production from -5.1 +/- 4.4 to +12.6 +/- 7.6 ng/kg X min. When ventilation was stopped, net pulmonary prostacyclin production returned to nondetectable levels. Ventilation with gas mixtures which increased pulmonary venous PO2 and decreased PCO2 also stimulated pulmonary prostacyclin production, but did not have greater effects than did ventilation with fetal gas. In order to determine if increasing PO2 or decreasing PCO2 could stimulate pulmonary prostacyclin production independently from ventilation, unventilated fetal lamb lungs were perfused with blood that had PO2 and PCO2 similar to fetal blood, blood with elevated O2, and blood that had PO2 and PCO2 values similar to arterial blood of newborn animals. Neither increased O2 nor decreased CO2 in the blood perfusing the lungs stimulated pulmonary prostacyclin synthesis. We conclude that the mechanism responsible for the stimulation of pulmonary prostacyclin production with the onset of ventilation at birth is tissue stress during establishment of gaseous ventilation and rhythmic ventilation.     

Occlusion pressures vs. micropipette pressures in the pulmonary circulation

Because of the discrepancies between the arterial and venous occlusion technique and the micropuncture technique in estimating pulmonary capillary pressure gradient, we compared measurements made with the two techniques in the same preparations (isolated left lower lobe of dog lung). In addition, we also obtained direct and reliable measurements of pressures in 0.9-mm arteries and veins using a retrograde catheterization technique, as well as a microvascular pressure made with the double-occlusion technique. The following conclusions were made from dog lobes perfused with autologous blood at normal flow rate of 500-600 ml/min and pressure gradient of 12 mmHg. 1) The double-occlusion technique measures pressure in the capillaries, 2) a small pressure gradient (0.5 mmHg) exists between 30- to 50-micron arteries and veins, 3) a large pressure gradient occurs in arteries and veins greater than 0.9 mm, 4) the arterial and venous occlusion techniques measure pressures in vessels that are less than 900 microns diam but greater than 50 microns, very likely close to 100 microns, 5) serotonin constricts arteries (larger and smaller than 0.9 mm) whereas histamine constricts veins (larger and smaller than 0.9 mm). Thus three different techniques (small retrograde catheter, arterial and venous occlusion, and micropuncture) show consistent results, confirming the presence of significant resistance in large arteries and veins with minimal resistance in the microcirculation.     

Bedside evaluation of the resistance of large and medium pulmonary veins in various lung diseases.

To evaluate the contribution of large and medium pulmonary veins to the total pulmonary vascular resistance in various human lung diseases, we compared in 64 patients the pulmonary arterial proximal wedge pressure (Ppw), obtained when the balloon of a 7F pulmonary artery catheter was inflated with 1.5 ml air, with the distal wedge pressure (Pdw), obtained after the tip of the catheter was advanced until wedged in a small artery without balloon inflation. Ppw, reflecting the pressure in a large pulmonary vein, approximates the left atrial pressure, whereas Pdw reflects the pressure in a smaller pulmonary vein. Pdw was greater than Ppw in all 64 patients. The Pdw-Ppw gradient was 1.1 +/- 0.5 mmHg in nine patients with normal lungs and was significantly higher in 13 patients with chronic congestive heart failure (3.8 +/- 0.8 mmHg, P less than 0.01) and in 22 patients with adult respiratory distress syndrome (3.8 +/- 0.8 mmHg; P less than 0.01), but not in 20 patients with chronic obstructive pulmonary disease (1.8 +/- 0.7 mmHg). The distribution of the pulmonary vascular resistance was clearly different among the four groups. The fraction of the total pulmonary vascular resistance attributable to large and medium pulmonary veins was significantly increased (P less than 0.01) in adult respiratory distress syndrome (27.5 +/- 12%) and cardiac patients (27.5 +/- 9%) compared with patients with chronic obstructive pulmonary disease (13 +/- 5%) and normal lungs (13.5 +/- 6%).(ABSTRACT TRUNCATED AT 250 WORDS)     

ET-1-induced pulmonary vasoconstriction shifts from ET(A)- to ET(B)-receptor-mediated reaction after preconstriction.

Endothelin-1 (ET-1) has been reported to induce pulmonary vasoconstriction via either ET(A) or ET(B) receptors, and vasorelaxation after ET-1 injection has been observed. Our study investigated the effects of ET-1 in isolated rabbit lungs, which were studied at basal tone (part I) and after preconstriction (U-46619; part II). Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. In part I, ET-1 (10(-8) M; n = 6; control) was injected after pretreatment with the ET(A)-receptor antagonist BQ-123 (10(-6) M; n = 6) or the ET(B)-receptor antagonist BQ-788 (10(-6) M; n = 6). The same protocol was carried out in part II after elevation of pulmonary vascular tone. ET-1 induced an immediate PAP increase (DeltaPAP 4.3 +/- 0.4 mmHg at 10 min) that was attenuated by pretreatment with BQ-123 (P < 0.05 at 10 min and P < 0.01 thereafter) and that was more pronounced after BQ-788 (P < 0.01 at 10 min and P < 0.001 thereafter). In part II, ET-1 induced an immediate rise in PAP with a maximum after 5 min (DeltaPAP 6.3 +/- 1.4 mmHg), leveling off at DeltaPAP 3.2 +/- 0.2 mmHg after 15 min. Pretreatment with BQ-123 failed to attenuate the increase. BQ-788 significantly reduced the peak pressure at 5 min (0.75 +/- 0.4 mmHg; P < 0.001) as well as the plateau pressure thereafter (P < 0.01). We conclude that ET-1 administration causes pulmonary vasoconstriction independent of basal vascular tone, and, at normal vascular tone, the vasoconstriction seems to be mediated via ET(A) receptors. BQ-788 treatment resulted in even more pronounced vasoconstriction. After pulmonary preconstriction, ET(A) antagonism exerted no effects on PAP, whereas ET(B) antagonism blocked the PAP increase. Therefore, ET-1-induced pulmonary vasoconstriction is shifted from an ET(A)-related to an ET(B)-mediated mechanism after pulmonary vascular preconstriction.     

Pulmonary hemodynamics in fetal lambs during development at normal and increased oxygen tension.

During the latter third of gestation, the number of resistance vessels in the lungs of the fetal sheep increases by 10-fold even after correction for lung growth. We measured pulmonary arterial pressure and blood flow directly and calculated total pulmonary resistance (pressure divided by flow) in intrauterine fetal lambs at 93-95 days and at 136 days of gestation (term is 145-148 days). In addition, we used a hyperbaric chamber to increase oxygen tension in the fetuses and measured the effect on the pulmonary circulation. When corrected for wet weight of the lungs, pulmonary blood flow did not change with advancing gestation (139 +/- 42 to 103 +/- 45 ml.100 g-1.min-1). Pulmonary arterial pressure increased (42 +/- 5 to 49 +/- 3 mmHg); thus total pulmonary resistance increased with advancing gestation from 0.32 +/- 0.12 to 0.55 +/- 0.21 mmHg.100 g.min.ml-1. If the blood flow is corrected for dry weight of the lungs, neither pulmonary blood flow nor total pulmonary resistance changed with advancing gestation. Increasing oxygen tension increased pulmonary blood flow 10-fold in the more mature fetuses but only 0.2-fold in the less mature fetuses. At the normal low oxygen tension of the fetus, pulmonary blood flow does not increase between these two points of gestation in the fetal lamb despite the increase in vessel density in the lungs. However, during elevated oxygen tension, pulmonary blood flow does increase in proportion to the increase in vessel density.     

Pulmonary vascular response to endothelin in rats

This study investigated the pulmonary vascular response to endothelin (ET) in rats. In conscious rats, an incremental intravenous bolus of ET-1 (100-1,000 pM) caused, after an initial drop in systemic arterial pressure (Psa), a secondary dose-dependent increase of Psa concomitant with a decrease of cardiac output (CO) and heart rate (HR). Pulmonary arterial pressure (Ppa) remained unchanged, and pulmonary vascular resistance (PVR) increased significantly only after 1,000 pM (+ 40.0 +/- 10.4 at 15 min). Meclofenamate (6 mg/kg iv) did not alter hemodynamic response to ET (300 pM). After autonomic blockade with hexamethonium (6 mg/kg iv) plus atropine (0.75 mg/kg iv), bradycardia response to ET (300 pM) was blocked, but CO decreased, systemic vascular resistance increased, and PVR remained unchanged as in controls. In anesthetized ventilated rats, bolus injections of ET (10-1,000 pM) induced a transient dose-related decrease in compliance (-10.9 +/- 1.8% after 1,000 pM) but no change of conductance. In isolated lungs, Ppa increased at doses greater than 100 pM, and edema developed in response to 1,000 pM ET. The rise of Ppa in response to 300 pM was not altered by meclofenamate (3.2 x 10(-6) M) but was potentiated by inhibitors of endothelium-derived relaxing factor(s) (EDRF), methylene blue (10(-4) M), pyrogallol (3 x 10(-5) M), and NG-monomethyl-L-arginine (6 x 10(-4) M) (3.9 +/- 0.3, 4.6 +/- 0.5, and 5.9 +/- 0.3 mmHg, respectively, compared with 1.5 +/- 0.5 mmHg in control lungs). These results suggest that circulating ET is a more potent constrictor of the systemic circulation than of the pulmonary vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of lung volume and alveolar surface tension on pulmonary vascular resistance

Utilizing the arterial and venous occlusion technique, the effects of lung inflation and deflation on the resistance of alveolar and extraalveolar vessels were measured in the dog in an isolated left lower lobe preparation. The lobe was inflated and deflated slowly (45 s) at constant speed. Two volumes at equal alveolar pressure (Palv = 9.9 +/- 0.6 mmHg) and two pressures (13.8 +/- 0.8 mmHg, inflation; 4.8 +/- 0.5 mmHg, deflation) at equal volumes during inflation and deflation were studied. The total vascular pressure drop was divided into three segments: arterial (delta Pa), middle (delta Pm), and venous (delta Pv). During inflation and deflation the changes in pulmonary arterial pressure were primarily due to changes in the resistance of the alveolar vessels. At equal Palv (9.9 mmHg), delta Pm was 10.3 +/- 1.2 mmHg during deflation compared with 6.8 +/- 1.1 mmHg during inflation. At equal lung volume, delta Pm was 10.2 +/- 1.5 mmHg during inflation (Palv = 13.8 mmHg) and 5.0 +/- 0.7 mmHg during deflation (Palv = 4.8 mmHg). These measurements suggest that the alveolar pressure was transmitted more effectively to the alveolar vessels during deflation due to a lower alveolar surface tension. It was estimated that at midlung volume, the perimicrovascular pressure was 3.5-3.8 mmHg greater during deflation than during inflation.     

The effect of closing the ductus arteriosus on the pulmonary circulation of the fetal sheep

In the mammalian fetus the ductus arteriosus allows right ventricular output to be shunted away from the lungs to the systemic circulation. This study was performed to determine how closing the ductus arteriosus of the fetal sheep would affect the pulmonary circulation. Under halothane anaesthesia 6 near-term fetal sheep were delivered with the umbilical circulation intact. Catheters were placed in the right atrium, the pulmonary artery, and the aorta. Pulmonary blood flow was measured by injecting radioactive microspheres into the right atrium while a reference sample was withdrawn from the pulmonary artery. Closing the ductus arteriosus increased pulmonary arterial pressure by 22% from 51 +/- 3 to 62 +/- 3 mmHg and increased pulmonary blood flow disproportionately by 198% from 232 +/- 74 to 692 +/- 80 ml/min per 100g. Thus, pulmonary vascular resistance decreased by 75% from 0.451 +/- 0.65 to 0.095 +/- 0.010 mmHg 100g min/ml. These findings extend the observation that pressure and flow in the pulmonary circulation of the air-breathing lung do not have a linear relationship passing through the origin to include a striking example in the fluid-filled lung of the intact fetus. They also raise questions about the nature of the elevated vascular resistance in the fetal lung.     

Calcitonin gene-related peptide vasodilation of human pulmonary vessels

Human calcitonin gene-related peptide (CGRP) is localized to sensory neurons in pulmonary vessels and is a potent vasodilator. We have characterized the effects of CGRP in human pulmonary vessels and localized the receptors for this peptide by autoradiography. Fresh human lung tissue was obtained from eight patients undergoing surgery and small (200-400 microns ID) pulmonary arteries and veins were dissected free of surrounding connective and pulmonary tissue. Pairs of vessels were studied and in one of each pair the endothelium was left intact and from the other of each pair the endothelium was removed by gentle abrasion. For functional studies arteries (n = 9) and veins (n = 9) were suspended in an organ bath, precontracted with 1 microM prostaglandin F2 alpha. CGRP (10 pM to 10 microM) was added in a cumulative manner. CGRP caused a dose-dependent relaxation of endothelium intact human pulmonary arteries and veins with log EC50 values of -8.01 +/- 0.35 and -8.70 +/- 0.40, respectively (not significant). Removal of the endothelium did not diminish the vasodilator potency of CGRP in either vessel. For autoradiographic studies, cryostat sections of the small human pulmonary vessels with or without endothelium were used. 125I-CGRP densely labeled CGRP receptors on vascular smooth muscle and endothelial removal did not have any effect on grain density. We concluded that CGRP is a potent vasodilator of human pulmonary arteries and veins that is not dependent on an intact endothelium. These functional studies correlate with the distribution of CGRP receptors as localized by autoradiography.     

K+ channel pulmonary vasodilation in fetal lambs: role of endothelium-derived nitric oxide.

To define the role and mechanism of action of K+ channels in regulating fetal pulmonary vascular tone, we studied the hemodynamic effects of pinacidil (a K+ channel activator) and glibenclamide (a K+ channel blocker). The effects of pinacidil were compared with those of acetylcholine [an endothelium-derived relaxing factor- (EDRF) dependent pulmonary vasodilator] and 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP, an EDRF-independent pulmonary vasodilator) before and after treatment with N omega-nitro-L-arginine [a competitive inhibitor of an EDRF, endothelium-derived nitric oxide (EDNO), synthesis], or L-arginine (the substrate for the formation of EDNO). In 14 unanesthetized fetal lambs in utero, catheters were inserted into the fetal pulmonary artery, descending aorta, left atrium, and superior vena cava to measure pressures and administer drugs. An ultrasonic flow transducer was placed around the left pulmonary artery to measure flow (QP) continuously. In eight animals, pinacidil, acetylcholine, and 8-bromo-cGMP caused similar acute maximal increases in QP of 128, 137, and 155 ml/min, respectively. After a 60-min infusion of N omega-nitro-L-arginine (2.07 +/- 0.27 mg.kg-1.min-1), the increase in QP caused by acetylcholine and pinacidil was significantly attenuated, by 84 and 68%, respectively, with only a 10% attenuation of the increase in QP caused by 8-bromo-cGMP. In six additional N omega-nitro-L-arginine-pretreated fetal lambs, infusion of L-arginine (32.2 +/- 4.3 mg.kg-1.min-1) restored the vasodilatory effects of acetylcholine and pinacidil. A 20-min infusion of glibenclamide (n = 6; 0.64 +/- 0.07 mg.kg-1.min-1) blocked the vasodilation by pinacidil but not acetylcholine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Postnatal changes in pulmonary vein responses to endothelin-1 in the normal and chronically hypoxic lung

The response of pulmonary arteries to endothelin-1 (ET-1) changes with age in normal pigs and is abnormal in pulmonary hypertension. The purpose of this study was to determine if the same is true of the pulmonary veins. We studied the wall structure and functional response to ET-1 in pulmonary veins from normal pigs from fetal life to adulthood and from pigs subjected to chronic hypobaric hypoxia either from birth for 3 days or from 3 to 6 days of age. In isolated normal veins, the contractile response decreased by 40% between late fetal life and 14 days of age with a concomitant twofold increase in endothelium-dependent relaxant response. The ET(A) antagonist BQ-123 reduced the contractile response significantly more in newborn than older animals, whereas the ET-B antagonist BQ-788 had no effect in fetal animals and maximally increased contraction at 14 days of age. Hypoxic exposure significantly increased pulmonary vein smooth muscle area and contractile response to ET-1. The relaxation response was impaired following hypoxic exposure from birth but not from 3 to 6 days of age. The ET(A) antagonist BQ-123 decreased contractile and increased dilator responses significantly more than in age-matched controls. Thus pulmonary veins show age-related changes similar to those seen in the pulmonary arteries with a decrease in ET(A)-mediated contractile and increase in ET-B-mediated relaxant response with age. Contractile response was also increased in hypoxia as in the arteries. This study suggests that pulmonary veins are involved in postnatal adaptation and the pathogenesis of pulmonary hypertension.     

Cyclooxygenase pathway mediates lung injury induced by phorbol and platelets

The role of platelets in lung injury has not been well defined. In the present study of isolated perfused rat lungs, phorbol myristate acetate (PMA; 0.15 microgram/ml) or platelets (6.7 X 10(4)/ml) alone did not discernibly change the pulmonary arterial pressure (PAP) or lung weight (LW). However, the combination of platelets and PMA drastically increased the PAP and LW (delta PAP 26.2 +/- 1.0 mmHg, delta LW 2.7 +/- 0.4 g). delta PAP was positively correlated with the increase in thromboxane B2 produced by infusion of platelets and PMA (thromboxane B2 = 35.6 + 0.97 delta PAP, r = 0.67, P less than 0.01). The hypertension and edema formation induced by PMA and platelets were strongly attenuated by indomethacin, an inhibitor of platelet cyclooxygenase (delta PAP 5.6 +/- 2.0 mmHg, P less than 0.001; delta LW 0.0 +/- 0.1 g, P less than 0.001), and by imidazole, an inhibitor of thromboxane A2 synthase (PAP 8.0 +/- 2.5 mmHg, P less than 0.001; LW 0.0 +/- 0.3 g, P less than 0.01). Inactivation of platelet lipoxygenase with nordihydroguaiaretic acid mildly depressed pulmonary pressure but did not affect delta LW (delta PAP 18.9 +/- 1.6 mmHg, P less than 0.05; delta LW 3.1 +/- 0.3 g, P greater than 0.05). In vitro experiments showed that the capacity of platelets to release oxygen radicals was only 2.6% of that found for granulocytes. These results suggest that platelets may be activated by PMA to increase PAP and vascular permeability.(ABSTRACT TRUNCATED AT 250 WORDS)     

Estradiol improves pulmonary hemodynamics and vascular remodeling in perinatal pulmonary hypertension

Partial ligation of the ductus arteriosus (DA) in the fetal lamb causes sustained elevation of pulmonary vascular resistance (PVR) and hypertensive structural changes in small pulmonary arteries, providing an animal model for persistent pulmonary hypertension of the newborn. Based on its vasodilator and antimitogenic properties in other experimental studies, we hypothesized that estradiol (E(2)) would attenuate the pulmonary vascular structural and hemodynamic changes caused by pulmonary hypertension in utero. To test our hypothesis, we treated chronically instrumented fetal lambs (128 days, term = 147 days) with daily infusions of E(2) (10 microg; E(2) group, n = 6) or saline (control group, n = 5) after partial ligation of the DA. We measured intrauterine pulmonary and systemic artery pressures in both groups throughout the study period. After 8 days, we delivered the study animals by cesarean section to measure their hemodynamic responses to birth-related stimuli. Although pulmonary and systemic arterial pressures were not different in utero, fetal PVR immediately before ventilation was reduced in the E(2)-treated group (2.43 +/- 0.79 vs. 1.48 +/- 0.26 mmHg. ml(-1). min, control vs. E(2), P < 0.05). During the subsequent delivery study, PVR was lower in the E(2)-treated group in response to ventilation with hypoxic gas but was not different between groups with ventilation with 100% O(2). During mechanical ventilation after delivery, arterial partial O(2) pressure was higher in E(2) animals than controls (41 +/- 11 vs. 80 +/- 35 Torr, control vs. E(2), P < 0. 05). Morphometric studies of hypertensive vascular changes revealed that E(2) treatment decreased wall thickness of small pulmonary arteries (59 +/- 1 vs. 48 +/- 1%, control vs. E(2), P < 0.01). We conclude that chronic E(2) treatment in utero attenuates the pulmonary hemodynamic and histological changes caused by DA ligation in fetal lambs.     

Fetal pulmonary vasodilation after exogenous platelet-activating factor

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