Correlation of acute with chronic hypoxic pulmonary hypertension in cattle.

We investigated acute and chronic hypoxic pulmonary pressor responses in two groups of calves, one bred to be susceptible, the other resistant to high-altitude pulmonary hypertension. Twelve 5-mo-old susceptible calves residing at 1,524 m increased their mean pulmonary arterial pressure from 26 +/- 2 (SE) to 55 +/- 4 mmHg during 2 h at a simulated altitude of 4,572 m. In 10 resistant calves pressure increased from 22 +/- 1 to 37 +/- 2 mmHg. Five calves were selected from each group for further study. When 9 mo old, the 5 susceptible calves again showed a greater pressor response to acute hypoxia (27 +/- 1 to 55 +/- 4 mmHg) than did 5 resistant calves (23 +/- 1 to 41 +/- 3 mmHg). When 12 mo old, the 5 susceptible calves also developed a greater increase in pulmonary arterial pressure (21 +/- 2 to 9 +/- 4 mmHg) during 18 days at 4,572 m than did the 5 resistant calves (21 +/- 1 to 64 +/- 4 mmHg). Acute and chronic hypoxic pulmonary pressor responses were highly correlated (r = 0.91; P less than 0.001) indicating that they were probably produced through a common mechanism.     

Operation Everest II: elevated high-altitude pulmonary resistance unresponsive to oxygen

High altitude increases pulmonary arterial pressure (PAP), but no measurements have been made in humans above 4,500 m. Eight male athletic volunteers were decompressed in a hypobaric chamber for 40 days to a barometric pressure (PB) of 240 Torr, equivalent to the summit of Mt. Everest. Serial hemodynamic measurements were made at PB 760 (sea level), 347 (6,100 m), and 282/240 Torr (7,620/8,840 m). Resting PAP and pulmonary vascular resistance (PVR) increased from sea level to maximal values at PB 282 Torr from 15 +/- 0.9 to 34 +/- 3.0 mmHg and from 1.2 +/- 0.1 to 4.3 +/- 0.3 mmHg.l-1 X min, respectively. During near maximal exercise PAP increased from 33 +/- 1 mmHg at sea level to 54 +/- 2 mmHg at PB 282 Torr. Right atrial and wedge pressures were not increased with altitude. Acute 100% O2 breathing lowered cardiac output and PAP but not PVR. Systemic arterial pressure and resistance did not rise with altitude but did increase with O2 breathing, indicating systemic control differed from the lung circulation. We concluded that severe chronic hypoxia caused elevated pulmonary resistance not accompanied by right heart failure nor immediately reversed by O2 breathing.     

Prostaglandin synthesis does not mediate the pulmonary vasodilatory effect of acetylcholine.

We wondered if inhibition of hypoxic pulmonary vasoconstriction by acetylcholine was mediated by prostaglandin synthesis. In 5 calves at a simulated altitude of 4,570 m, acetylcholine (10 mug/kg/min) decreased mean pulmonary arterial pressure and total pulmonary resistance by 24 +/- 2 and 35 +/- 3% before and by 21 +/- 2 and 27 +/- 4% after the administration of meclofenamate (2 mg/kg). Since there was no difference in the effect of acetylcholine before and after meclofenamate, it was concluded that pulmonary vasodilation by activation of muscarinic receptors was not dependent on prostaglandin synthesis.     

Effects of sildenafil on hypoxic pulmonary vascular function in dogs.

Sildenafil has been shown to be an effective treatment of pulmonary arterial hypertension and is believed to present with pulmonary selectivity. This study was designed to determine the site of action of sildenafil compared with inhaled nitric oxide (NO) and intravenous sodium nitroprusside (SNP), known as selective and nonselective pulmonary vasodilators, respectively. Inhaled NO (40 ppm), and maximum tolerated doses of intravenous SNP and sildenafil, (5 microg x kg(-1) x min(-1) and 0.1 mg x kg(-1) x h(-1)), respectively, were administered to eight dogs ventilated in hypoxia. Pulmonary vascular resistance (PVR) was evaluated by pulmonary arterial pressure (Ppa) minus left atrial pressure (Pla) vs. flow curves, and partitioned into arterial and venous segments by the occlusion method. Right ventricular hydraulic load was defined by pulmonary arterial characteristic impedance (Zc) and elastance (Ea) calculations. Right ventricular arterial coupling was estimated by the ratio of end-systolic elastance (Ees) to Ea. Decreasing the inspired oxygen fraction from 0.4 to 0.1 increased Ppa - Pla at a standardized flow of 3 l x min(-1) x m(-2) from 6 +/- 1 to 18 +/- 1 mmHg (mean +/- SE). Ppa - Pla was decreased to 9 +/- 1 by inhaled NO, 14 +/- 1 by SNP, and 14 +/- 1 mmHg by sildenafil. The partition of PVR, Zc, Ea, and Ees/Ea was not affected by the three interventions. Inhaled NO did not affect systemic arterial pressure, which was similarly decreased by sildenafil and SNP, from 115 +/- 4 to 101 +/- 4 and 98 +/- 5 mmHg, respectively. We conclude that inhaled NO inhibits hypoxic pulmonary vasoconstriction more effectively than sildenafil or SNP, and sildenafil shows no more selectivity for the pulmonary circulation than SNP.     

Effects of substance P and calcitonin gene-related peptide on the pulmonary circulation.

To assess the in vivo effects of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) on the pulmonary vascular bed, the hemodynamic responses to both CGRP and SP were examined in the in situ-perfused lung lobe of open-chest anesthetized pigs. Peptides were infused into the lobar artery under conditions of elevated pulmonary vascular tone by prostaglandin F2 alpha (PGF2 alpha, 20 micrograms/min). Pulmonary airway lobar dynamic compliance (Cdyn) and airway resistance (Re) were computed from simultaneously measured airway pressure and airflow entering the lobe through a Carlens endobronchial divider. PGF2 alpha infusion slightly reduced Cdyn (-20%) and increased Re (+11%) while lobar arterial pressure rose from 14 +/- 1 to 31 +/- 2 mmHg (n = 12). In these conditions, lobar artery infusion of SP (0.5-50 pmol/min) or CGRP (15-5,000 pmol/min) produced a dose-dependent decrease in the pressor response to PGF2 alpha, reaching -54 +/- 3 and -64 +/- 7%, respectively, without alterations in lung mechanics. On a molar basis, SP was more effective than CGRP; its vasodilatory effect was more rapid and of shorter duration. Higher CGRP infusion rates were not studied because of marked systemic hypotension. SP infused at 150, 500, and 1,000 pmol/min significantly reduced Cdyn by 12 +/- 2, 24 +/- 4, and 62 +/- 7%, respectively, but also induced a rise in lobar arterial pressure and a fall in systemic arterial pressure. The results show that both SP and CGRP are potent pulmonary vasodilators. In contrast to CGRP, which did not affect lung mechanics, high infusion rates of SP decreased Cdyn and increased Re.(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)     

Pulmonary vasodilator responses to atrial natriuretic factor and sodium nitroprusside

The objective of this study was to determine the direct actions of atrial natriuretic factor (ANF) on the pulmonary vascular bed and to compare these actions with those of sodium nitroprusside (SNP). The responses to incremental infusion rates of 1, 5, 10, and 50 ng.kg-1.min-1 synthetic human ANF and to 1-2 micrograms.kg-1.min-1 SNP were examined in the in situ autoperfused lung lobe of open-chest anesthetized pigs under conditions of normal and elevated pulmonary vascular tone. During basal conditions, ANF and SNP caused small but significant reductions in pulmonary artery pressure (Ppa) and pulmonary venous pressure (Ppv) with no change in lobar vascular resistance (LVR). When pulmonary vascular tone was increased by prostaglandin F2 alpha (20 micrograms/min), ANF infusion at doses greater than 1 ng.kg-1.min-1 decreased Ppa and LVR in a dose-related fashion. Infusion of 50 ng.kg-1.min-1 ANF and of 2 micrograms.kg-1.min-1 SNP maximally decreased Ppa, from 33 +/- 3 to 20 +/- 2 mmHg (P less than 0.001) and from 31 +/- 4 to 18 +/- 1 mmHg (P less than 0.001), respectively. At these doses, ANF reduced systemic arterial pressure by only 11.5 +/- 3% compared with 34 +/- 4% decreased with SNP (P less than 0.001). The results indicate that ANF, similarly to SNP, exerts a direct potent vasodilator activity in the porcine pulmonary vascular bed, which is dependent on the existing level of vasoconstrictor tone.     

Factors affecting perfusion distribution in canine oleic acid pulmonary edema

Factors affecting perfusion distribution in oleic acid pulmonary edema were examined in 28 anesthetized open-chest dogs. Sixteen had unilobar oleic acid edema produced by left lower lobe pulmonary artery infusion of 0.03 ml/kg of oleic acid, and 12 had the same amount of edema produced by left lower lobe endobronchial instillation of hypotonic plasma. Lobar perfusion (determined from flow probes) and lobar shunt (determined from mixed venous and lobar venous blood) were measured at base line, 1.5 h after edema, and 10 min after 10 cmH2O positive end-expiratory pressure (PEEP). Fourteen dogs (8 oleic acid, 6 plasma) received sodium nitroprusside (11.72 +/- 7.10 micrograms X kg-1 X min-1). Total and lobar shunts increased to the same extent in all animals. Lobar perfusion decreased by 49.8 +/- 4.8% without nitroprusside and 34.0 +/- 3.6% with nitroprusside in the oleic acid group, corresponding values being 40.3 +/- 0.8% and 26.4 +/- 1.7% in the hypotonic plasma group. PEEP returned perfusion and shunt to base line. In oleic acid edema, most of the decreased perfusion results from mechanical effects of the edema, a smaller fraction results from other vascular effects of the oleic acid, and approximately 30% is reversible by nitroprusside. PEEP normalizes the perfusion distribution.     

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.     

Intravenous injection of propylene glycol causes pulmonary hypertension in sheep

Propylene glycol (30%) is the carrier base for pentobarbital sodium in preparations often used in research laboratories. It has caused pulmonary hypertension in calves, and we found it caused pulmonary hypertension in sheep as well. To investigate the mechanism of pulmonary hypertension with propylene glycol, we injected an average loading dose of 30% propylene glycol (0.5 ml/kg) into adult sheep, which was followed by a rise in thromboxane levels (P less than 0.05) in systemic arterial plasma and lung lymph and by a dramatic increase in pulmonary arterial pressure (17 +/- 1 to 35 +/- 4 mmHg, P less than 0.05) and a fall in cardiac output (2.7 +/- 0.5 to 1 +/- 0.2 l/min). Indomethacin pretreatment blocked the rise in thromboxane in lung lymph and arterial plasma and substantially, although not entirely, blocked the rise in pulmonary arterial pressure. Pulmonary intravascular macrophages (PIMS), which are present in sheep and calves, can release thromboxane in response to a stimulus. To test whether PIMS might be the source of the thromboxane and pulmonary hypertension, we injected propylene glycol into guinea pigs and dogs, which are reported to have no PIMS, as well as into newborn lambs, which are not believed to develop many PIMS until the 2nd wk of life. In dogs and guinea pigs there was no response to propylene glycol. In lambs there was a rise in pulmonary vascular resistance but significantly less than in adult sheep; indomethacin blocked this response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Potent vasodilator responses to human urotensin-II in human pulmonary and abdominal resistance arteries

The peptide human urotensin-II (hUT-II) and its receptor have recently been cloned. The vascular function of this peptide in humans, however, has yet to be determined. Vasoconstrictor and vasodilator responses to hUT-II were investigated in human small muscular pulmonary arteries [approximately 70 microm internal diameter (ID)] and human abdominal resistance arteries (approximately 200 microm ID). Vasodilator responses were investigated in endothelin-1 (3 nM) precontracted vessels and, in the small pulmonary vessels, compared with the known vasodilators adrenomedullin, sodium nitroprusside, and acetylcholine. In human small pulmonary arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [-log M concentration causing 50% of the maximum vasodilator effect (pIC(50)) 10.4 +/- 0.5; percentage of reduction in tone (E(max)) 81 +/- 8% (vs. 23 +/- 11% in time controls), n = 5]. The order of potency for vasodilation was human urotensin-II = adrenomedullin (pIC(50) 10.1 +/- 0.4, n = 6) > sodium nitroprusside (pIC(50) 7.4 +/- 0.2, n = 6) = acetylcholine (pIC(50) 6.8 +/- 0.3, n = 6). In human abdominal arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [pIC(50) 10.3 +/- 0.7; E(max) 96 +/- 8% (vs. 43 +/- 16% in time controls), n = 4]. This is the first report that hUT-II is a potent vasodilator but not a vasoconstrictor of human small pulmonary arteries and systemic resistance arteries.     

N omega-nitro-L-arginine methyl ester selectively inhibits pulmonary vasodilator responses to acetylcholine and bradykinin.

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor (EDRF) production, on vascular tone and responses were investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was elevated with U-46619, intralobar injections of acetylcholine, bradykinin, sodium nitroprusside, isoproterenol, prostaglandin E1 (PGE1), lemakalim, and 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intravenous administration of L-NAME elevated lobar arterial and systemic arterial pressures without altering left atrial pressure. When U-46619 was infused after L-NAME to raise lobar arterial pressure to levels similar to those attained during the control period, vasodilator responses to acetylcholine and bradykinin were reduced significantly, whereas responses to PGE1, lemakalim, and 8-bromo-cGMP were not altered, and responses to nitroprusside were increased. There was a small effect on the response to the highest dose of isoproterenol, and pressor responses to BAY K 8644 and angiotensin II were not altered. These results are consistent with the hypothesis that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine and that EDRF production may have a role in the regulation of tone and in the mediation of responses to acetylcholine and bradykinin in the pulmonary vascular bed of the cat.     

Characterization of thromboxane and prostacyclin effects on pulmonary vascular resistance.

Although thromboxane and prostacyclin (PGI2) have long been described as major controllers of pulmonary vascular resistance, little has been reported on the characteristics of the interactions between the two arachidonic acid products. The current study uses segmental vascular resistance and compliance measurements to evaluate the actions of thromboxane and PGI2 in isolated blood-perfused rat lung. The thromboxane analogue U-46619 increases pulmonary vascular resistance by increasing only small artery resistance and decreases pulmonary vascular compliance in the middle compartment. Among the vascular effects of U-46619 are a maximum increase in resistance (RmaxU-46619) of 60.3 +/- 15.6 cmH2O.l-1.min.100 g-1 and a concentration required for 50% of maximum increase (K0.5,U-46619) of 1.60 +/- 0.85 nM for small artery resistance, a minimum vascular compliance (CminU-46619) of -0.93 +/- 0.58 cmH2O, and a K0.5,U-46619 of 1.10 +/- 1.60 nM for middle compartment compliance. Similar results were obtained for total resistance and total compliance. The effects of PGI2 on thromboxane-induced resistance and compliance changes were evaluated using K0.5,PGI2, RmaxPGI2, and CmaxPGI2 at each dose of thromboxane. PGI2 was more effective in reversing the thromboxane constriction at higher concentrations of thromboxane. These data show that the absolute concentration of PGI2 and thromboxane and not a simple ratio of thromboxane to PGI2 determines vascular tone.     

Thromboxane does not mediate pulmonary hypertension in phorbol ester-induced acute lung injury in dogs

Thromboxane (Tx) has been suggested to mediate the pulmonary hypertension of phorbol myristate acetate- (PMA) induced acute lung injury. To test this hypothesis, the relationship between Tx and pulmonary arterial pressure was evaluated in a model of acute lung injury induced with PMA in pentobarbital sodium-anesthetized male mongrel dogs. Sixty minutes after administration of PMA (20 micrograms/kg iv, n = 10), TxB2 increased 10-fold from control in both systemic and pulmonary arterial blood and 8-fold in bronchoalveolar lavage (BAL) fluid. Concomitantly, pulmonary arterial pressure (Ppa) increased from 14.5 +/- 1.0 to 36.2 +/- 3.5 mmHg, and pulmonary vascular resistance (PVR) increased from 5.1 +/- 0.4 to 25.9 +/- 2.9 mmHg.l-1.min. Inhibition of Tx synthase with OKY-046 (10 mg/kg iv, n = 6) prevented the PMA-induced increase in Tx concentrations in blood and BAL fluid but did not prevent or attenuate the increase in Ppa. OKY-046 pretreatment did, however, attenuate but not prevent the increase in PVR 60 min after PMA administration. Pretreatment with the TxA2/prostaglandin H2 receptor antagonist ONO-3708 (10 micrograms.kg-1.min-1 iv, n = 7) prevented the pressor response to bolus injections of 1-10 micrograms U-46619, a Tx receptor agonist, but did not prevent or attenuate the PMA-induced increase in Ppa. ONO-3708 also attenuated but did not prevent the increase in PVR. These results suggest that Tx does not mediate the PMA-induced pulmonary hypertension but may augment the increases in PVR in this model of acute lung injury.     

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.     

Repeated inhalation of adrenomedullin ameliorates pulmonary hypertension and survival in monocrotaline rats

Adrenomedullin (AM) is a potent vasodilator peptide. We investigated whether inhalation of aerosolized AM ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Male Wistar rats given MCT (MCT rats) were assigned to receive repeated inhalation of AM (n = 8) or 0.9% saline (n = 8). AM (5 mug/kg) or saline was inhaled as an aerosol using an ultrasonic nebulizer for 30 min four times a day. After 3 wk of inhalation therapy, mean pulmonary arterial pressure and total pulmonary resistance were markedly lower in rats treated with AM than in those given saline [mean pulmonary arterial pressure: 22 +/- 2 vs. 35 +/- 1 mmHg (-37%); total pulmonary resistance: 0.048 +/- 0.004 vs. 0.104 +/- 0.006 mmHg.ml(-1).min(-1).kg(-1) (-54%), both P < 0.01]. Neither systemic arterial pressure nor heart rate was altered. Inhalation of AM significantly attenuated the increase in medial wall thickness of peripheral pulmonary arteries in MCT rats. Kaplan-Meier survival curves demonstrated that MCT rats treated with aerosolized AM had a significantly higher survival rate than those given saline (70% vs. 10% 6-wk survival, log-rank test, P < 0.01). In conclusion, repeated inhalation of AM inhibited MCT-induced pulmonary hypertension without systemic hypotension and thereby improved survival in MCT rats.     

Effects of left atrial pressure on the pulmonary vascular response to hypoxic ventilation.

We investigated the effects of hypoxic ventilation on the pulmonary arterial pressure- (P) flow (Q) relationship in an intact canine preparation. Mean pulmonary P-Q coordinates were obtained during hypoxic ventilation and during ventilation with 100% O2 at normal and at increased left atrial pressure. Specifically, we tested the hypothesis that, over a wide range, changes in left atrial pressure would alter the effects of hypoxic ventilation on pulmonary P-Q characteristics. Seven dogs were studied. When left atrial pressure was normal (5 mmHg), the mean value of the extrapolated intercept (PI) of the linear P-Q relationship was 10.9 mmHg and the slope (incremental vascular resistance, IR) of the P-Q relationship was 2.2 mmHg.l-1.min. Hypoxic ventilation increased PI to 18 mmHg (P less than 0.01) but did not affect IR. Subsequently, during ventilation with 100% O2, when left atrial pressure was increased to 14 mmHg by inflation of left atrial balloon, PI increased to 18 mmHg. IR was 1.6 mmHg.l-1.min. Again, hypoxic ventilation caused an isolated change in PI. Hypoxia increased PI from 18 to 28 mmHg (P less than 0.01). As in the condition of normal left atrial pressure, hypoxic ventilation did not affect IR. We conclude that, in an anesthetized intact canine preparation, hypoxic ventilation causes an isolated increase in the extrapolated pressure intercept of the pulmonary P-Q relationship. Furthermore the effects of hypoxic ventilation on pulmonary P-Q characteristics are not affected by the resting left atrial pressure.     

Upregulation of vascular calcium channels in neonatal piglets with hypoxia-induced pulmonary hypertension

Inhibition of voltage-gated, L-type Ca(2+) (Ca(L)) channels by clinical calcium channel blockers provides symptomatic improvement to some pediatric patients with pulmonary arterial hypertension (PAH). The present study investigated whether abnormalities of vascular Ca(L) channels contribute to the pathogenesis of neonatal PAH using a newborn piglet model of hypoxia-induced PAH. Neonatal piglets exposed to chronic hypoxia (CH) developed PAH by 21 days, which was evident as a 2.1-fold increase in pulmonary vascular resistance in vivo compared with piglets raised in normoxia (N). Transpulmonary pressures (DeltaPtp) in the corresponding isolated perfused lungs were 20.5 +/- 2.1 mmHg (CH) and 11.6 +/- 0.8 mmHg (N). Nifedipine reduced the elevated DeltaPtp in isolated lungs of CH piglets by 6.4 +/- 1.3 mmHg but only reduced DeltaPtp in lungs of N piglets by 1.9 +/- 0.2 mmHg. Small pulmonary arteries from CH piglets also demonstrated accentuated Ca(2+)-dependent contraction, and Ca(2+) channel current was 3.94-fold higher in the resident vascular muscle cells. Finally, although the level of mRNA encoding the pore-forming alpha(1C)-subunit of the Ca(L) channel was similar between small pulmonary arteries from N and CH piglets, a profound and persistent upregulation of the vascular alpha(1C) protein was detected by 10 days in CH piglets at a time when pulmonary vascular resistance was only mildly elevated. Thus chronic hypoxia in the neonate is associated with the anomalous upregulation of Ca(L) channels in small pulmonary arteries in vivo and the resulting abnormal Ca(2+)-dependent resistance may contribute to the pathogenesis of PAH.     

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.     

Endothelin-1-induced pulmonary arterial dilation is reduced by N omega-nitro-L-arginine in fetal lambs.

Endothelin-1 (ET-1) is a pulmonary vasodilator in the unventilated fetal lamb. The site and mechanism of this vasodilator response were investigated in isolated blood-perfused lungs from nine fetal lambs delivered at 127-140 days gestation. The vascular occlusion technique was used to partition the total pulmonary pressure gradient into pressure gradients across large and small arteries (delta PLA and delta PSA, respectively) and veins (delta PV). Injection of ET-1 (74 ng/kg) into the pulmonary artery significantly decreased delta PLA from 12.4 +/- 2.1 to 5.2 +/- 1.1 mmHg and delta PSA from 49.2 +/- 2.7 to 31.3 +/- 4.9 mmHg. The pressure measured by double occlusion, an estimate of pulmonary capillary pressure, was not altered by ET-1 (15.5 +/- 1.0 vs. 14.8 +/- 1.0 mmHg), indicating that ET-1 had no effect on pulmonary veins. Addition of N omega-nitro-L-arginine (estimated perfusate concentration 2-6 mM), an analogue of L-arginine that inhibits the production of endothelium-derived relaxing factor (EDRF), significantly attenuated the dilator responses to acetylcholine (10 micrograms) and ET-1 (74 ng/kg) by 35 and 56%, respectively. These results in unventilated fetal lungs indicate that 1) ET-1 dilates both large and small pulmonary arteries with no effect on pulmonary veins, and 2) this effect is mediated in part through the action of the EDRF pathway.