Hypoxic pulmonary vasoconstriction does not affect hydrostatic pulmonary edema formation

We studied the effects of regional hypoxic pulmonary vasoconstriction (HPV) on lobar flow diversion in the presence of hydrostatic pulmonary edema. Ten anesthetized dogs with the left lower lobe (LLL) suspended in a net for continuous weighing were ventilated with a bronchial divider so the LLL could be ventilated with either 100% O2 or a hypoxic gas mixture (90% N2-5% CO2-5% O2). A balloon was inflated in the left atrium until hydrostatic pulmonary edema occurred, as evidenced by a continuous increase in LLL weight. Left lower lobe flow (QLLL) was measured by electromagnetic flow meter and cardiac output (QT) by thermal dilution. At a left atrial pressure of 30 +/- 5 mmHg, ventilation of the LLL with the hypoxic gas mixture caused QLLL/QT to decrease from 17 +/- 4 to 11 +/- 3% (P less than 0.05), pulmonary arterial pressure to increase from 35 +/- 5 to 37 +/- 6 mmHg (P less than 0.05), and no significant change in rate of LLL weight gain. Gravimetric confirmation of our results was provided by experiments in four animals where the LLL was ventilated with an hypoxic gas mixture for 2 h while the right lung was ventilated with 100% O2. In these animals there was no difference in bloodless lung water between the LLL and right lower lobe. We conclude that in the presence of left atrial pressures high enough to cause hydrostatic pulmonary edema, HPV causes significant flow diversion from an hypoxic lobe but the decrease in flow does not affect edema formation.     

Pulmonary arterial distension does not cause pulmonary vasoconstriction

Distension of the main pulmonary artery or its major branches with an intraluminal balloon has been reported to cause pulmonary vasoconstriction by an unknown mechanism. This study was an attempt to confirm the pressor response and explore its cause. Several balloon distension methods were tried and discarded because they caused unintentional obstruction. Ultimately, I inflated a balloon placed retrogradely and confined to the left main pulmonary artery of six anesthetized open-chest dogs after ligating left lobar arterial branches. Blood flow and systemic gas composition were controlled by interposing an external pump oxygenator between the left ventricle and aorta. Pressures in the aorta, main pulmonary artery, and left atrium were recorded. Alveolar hypoxia was used as an independent test of pulmonary vasoreactivity. Although hypoxic pressor responses occurred, challenges with arterial distension did not change lung perfusion pressure. Silicone rubber casts were made of the arteries of six dogs used in pilot experiments. These revealed the limited lengths in which distenders can be placed without unintentional encroachment on flow. I could not support the conclusion that arterial distension causes vasoconstriction and am suspicious that the perfusion pressure increases reported by others may have been caused by undetected obstruction of a major arterial branch.     

Ventilation heterogeneity does not change following pulmonary microembolism.

By using the multiple-breath helium washout technique, ventilation heterogeneity (VH) after embolic injury in the lung can be quantitatively partitioned into the conductive and acinar components. Total VH, represented by the normalized slope of the phase III alveolar plateau, Sn(III (total)), was studied for 120 min in three groups of anesthetized and paralyzed mongrel dogs. Group 1 (n = 3) received only normal saline and served as controls. Group 2 (n = 4) received repeated infusions of polystyrene beads (250 microm) into the right atrium at 10, 40, 80, and 120 min. Group 3 (n = 3) was similarly treated, except that the embolic beads used were 1,000 microm in diameter. The data show that, despite repeated embolic injury by polystyrene beads of different diameters, there was no significant increase in total VH. The acinar component of Sn(III), which represents VH in the distal airways, accounts for over 90% of the total VH. The conductive component of Sn(III), which represents VH between larger conductive airways, remains relatively constant and a minor component. We conclude that pulmonary microembolism does not result in significant redistribution of ventilation.     

Regional alveolar hypoxia does not affect air embolism-induced pulmonary edema

We studied the effects of regional alveolar hypoxia on permeability pulmonary edema resulting from venous air embolization. Anesthetized dogs had the left upper lobe removed and a double-lumen tube placed so that right lung and left lower lobe (LLL) could be ventilated independently. Air was infused into the femoral vein for 1 h during bilateral ventilation at an inspiratory O2 fraction (FIO2) of 1.0. After cessation of air infusion the LLL was then ventilated with a hypoxic gas mixture (FIO2 = 0.05) in six animals and an FIO2 of 1.0 in six other animals. Lung hydroxyproline content was measured as an index of lung dry weight. LLL bloodless lobar wet weight-to-hydroxyproline ratio was 0.33 +/- 0.06 mg/micrograms in the animals exposed to LLL hypoxia and 0.37 +/- 0.03 mg/micrograms (NS) in the animals that had a LLL FIO2 of 1. Both values were significantly higher than our laboratory normal values of 0.19 +/- 0.01 mg/micrograms. We subsequently found in four more dogs exposed to global alveolar hypoxia before and after air embolism that the air injury itself significantly depressed the hypoxic vasoconstrictor response. We conclude that regional alveolar hypoxia has no effect on pulmonary edema formation due to air embolism. The most likely reason for these findings is that the air embolism injury itself interfered with hypoxic pulmonary vasoconstriction.     

Peroxynitrite does not impair pulmonary and systemic vascular responses.

The effects of peroxynitrite (ONOO-) on vascular responses were investigated in the systemic and hindquarters vascular bed and in the isolated perfused rat lung. Intravenous injections of ONOO- decreased systemic arterial pressure, and injections of ONOO- into the hindquarters decreased perfusion pressure in a dose-related manner. Injections of ONOO- into the lung perfusion circuit increased pulmonary arterial perfusion pressure. Responses to ONOO- were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis. Repeated injections of ONOO- did not alter systemic, hindquarters, or pulmonary responses to endothelium-dependent vasodilators or other vasoactive agonists and did not alter the hypoxic pulmonary vasoconstrictor response. Injections of sodium nitrate or nitrite or decomposed ONOO- had little effect on vascular pressures. Pulmonary and hindquarters responses to ONOO- were not altered by a cyclooxygenase inhibitor in a dose that attenuated responses to arachidonic acid. These results demonstrate that ONOO- has significant pulmonary vasoconstrictor, systemic vasodepressor, and vasodilator activity; that short-term repeated exposure does impair vascular responsiveness; and that responses to ONOO- are not dependent on cyclooxygenase product release.     

L-NAME does not affect exercise-induced pulmonary hypertension in Thoroughbred horses

The present study was carried out to examine theeffects of nitric oxide synthase inhibition withN-nitro-L-arginine methyl ester(L-NAME) on the right atrial as well as on the pulmonary arterial, capillary, and venous blood pressures of horses during rest and exercise performed at maximal heartrate (HR_max). Experiments werecarried out on seven healthy, sound, exercise-trained Thoroughbredhorses. Using catheter-tip manometers, with signals referenced at thepoint of the shoulder, we determined phasic and mean right atrial andpulmonary vascular pressures in two sets of experiments [control(no medications) and L-NAME (20 mg/kg iv given 10 min before exercise studies)]. The studies werecarried out in random order 7 days apart. Measurements were made atrest and during treadmill exercise performed on a 5% uphill grade at6, 8, and 14.2 m/s. Exercise on a 5% uphill grade at 14.2 m/s elicitedHR_max and could not be sustainedfor >90 s. In quietly standing horses,L-NAME administration caused asignificant rise in right atrial, as well as pulmonary arterial, capillary, and venous pressures. This indicates that nitric oxide synthase inhibition modifies the basal pulmonary vasomotor tone. Inboth treatments, exercise caused progressive significant increments inright atrial and pulmonary vascular pressures, but the values recordedin the L-NAME study were notdifferent from those in the control study. The extent ofexercise-induced tachycardia was significantly decreased in theL-NAME study at 6 and 8 m/s butnot at 14.2 m/s. Thus, L-NAMEadministration may not modify the equine pulmonary vascular tone duringexercise at HR_max. However, asindicated by a significant reduction in heart rate,L-NAME seems to modify thesympathoneurohumoral response to submaximal exercise.

     

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 μg/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 dependant on prostaglandin synthesis.     

Risk factors for immersion pulmonary edema: hyperoxia does not attenuate pulmonary hypertension associated with cold water-immersed prone exercise at 4.7 ATA

Hyperoxia has been shown to attenuate the increase in pulmonary artery (PA) pressure associated with immersed exercise in thermoneutral water, which could serve as a possible preventive strategy for the development of immersion pulmonary edema (IPE). We tested the hypothesis that the same is true during exercise in cold water. Six healthy volunteers instrumented with arterial and PA catheters were studied during two 16-min exercise trials during prone immersion in cold water (19.9-20.9°C) in normoxia [0.21 atmospheres absolute (ATA)] and hyperoxia (1.75 ATA) at 4.7 ATA. Heart rate (HR), Fick cardiac output (CO), mean arterial pressure (MAP), pulmonary artery pressure (PAP), pulmonary artery wedge pressure (PAWP), central venous pressure (CVP), arterial and venous blood gases, and ventilatory parameters were measured both early (E, 5-6 min) and late (L, 15-16 min) in exercise. During exercise at an average oxygen consumption rate (Vo(2)) of 2.38 l/min, [corrected] CO, CVP, and pulmonary vascular resistance were not affected by inspired (Vo(2)) [corrected] or exercise duration. Minute ventilation (Ve), alveolar ventilation (Va), and ventilation frequency (f) were significantly lower in hyperoxia compared with normoxia (mean ± SD: Ve 58.8 ± 8.0 vs. 65.1 ± 9.2, P = 0.003; Va 40.2 ± 5.4 vs. 44.2 ± 9.0, P = 0.01; f 25.4 ± 5.4 vs. 27.2 ± 4.2, P = 0.04). Mixed venous pH was lower in hyperoxia compared with normoxia (7.17 ± 0.07 vs. 7.20 ± 0.07), and this result was significant early in exercise (P = 0.002). There was no difference in mean PAP (MPAP: 28.28 ± 8.1 and 29.09 ± 14.3 mmHg) or PAWP (18.0 ± 7.6 and 18.7 ± 8.7 mmHg) between normoxia and hyperoxia, respectively. PAWP decreased from early to late exercise in hyperoxia (P = 0.002). These results suggest that the increase in pulmonary vascular pressures associated with cold water immersion is not attenuated with hyperoxia.     

Chronic exercise training does not alter pulmonary vasorelaxation in normal pigs.

Exercise training increases acetylcholine-induced pulmonary vasorelaxation in pigs with coronary occlusion. The present study tested the hypothesis that chronic exercise training enhances endothelium-mediated vasorelaxation in pulmonary arteries from normal pigs. Yucatan miniswine exercised for 16 wk on a treadmill (Ex); control pigs (Sed) remained in pens. Pulmonary artery rings (2- to 3-mm OD) were studied using standard isometric techniques. Contractile responses to 80 mM KCl and norepinephrine (NE) were determined. Vessels were constricted with levels of NE that resulted in half-maximal contraction to examine endothelium-dependent relaxation to ACh and endothelium-independent relaxation to sodium nitroprusside in the presence and absence of nitric oxide synthase inhibition, cyclooxygenase inhibition, and endothelial denudation. Arteries from Ex pigs developed increased contraction to 80 mM KCl, but the response to NE did not differ between groups. Endothelium-dependent and endothelium-independent responses did not differ between Sed and Ex in the presence or absence of pharmacological inhibitors or denudation. We conclude that chronic exercise training does not alter endothelium-dependent or endothelium-independent vasorelaxation responses of pulmonary arteries from normal pigs.     

Endothelin receptor blockade does not improve hypoxemia following acute pulmonary thromboembolism.

We studied the roles of endothelins in determining ventilation (Va) and perfusion (Q) mismatch in a porcine model of acute pulmonary thromboembolism (APTE), using a nonspecific endothelin antagonist, tezosentan. Nine anesthetized piglets (approximately 23 kg) received autologous clots (approximately 20 g) via a central venous catheter at time = 0 min. The distribution of Va and Q at five different time points (-30, -5, 30, 60, 120 min) was mapped by fluorescent microspheres of 10 different colors. Five piglets (group 1) received tezosentan (courtesy of Actelion) starting at time = 40 min for 2 h, and four piglets (group 2) received only saline and served as control. Our results showed that, in all of the animals at 30 min following APTE but before tezosentan, the mean Va/Q was increased, as was Va/Q heterogeneity (log SD Va/Q), which represented a widening of its main peak. Afterwards, tezosentan attenuated the pulmonary hypertension in group 1 but also produced moderate systemic hypotension. However, it did not improve arterial PO2 or Va/Q mismatch. We concluded that endothelin antagonism had minimal impact on gas exchange following APTE and confirmed our earlier observation that the main mechanism for hypoxemia in APTE was due to the mechanical redistribution of pulmonary regional blood flow away from the embolized vessels, resulting in the creation of many divergent low and high Va/Q regions.     

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.     

Circulating neuropeptide Y does not produce pulmonary hypertension during massive sympathetic activation.

We tested the possibility that neuropeptide Y (NPY) may contribute to the pulmonary hypertension that occurs after massive sympathetic activation produced by intracisternal veratrine administration in the chloralose-anesthetized dog. In six dogs, veratrine caused arterial NPY-like immunoreactivity (NPY-LI) to rise from 873 +/- 150 (SE) pg/ml to peak values of 3,780 +/- 666 pg/ml by 60-120 min. (In 3 animals, adrenalectomy significantly reduced the increases in NPY-LI.) In five additional dogs, we infused porcine NPY for 30 min in doses that increased arterial NPY-LI to 8,354 +/- 1,514 pg/ml and observed only minor changes in pulmonary hemodynamics. In three isolated perfused canine left lower lung lobe (LLL) preparations, increasing doses of NPY were administered, producing levels of plasma NPY-LI, at the highest dose, that exceeded those observed after veratrine administration by three orders of magnitude. No changes in LLL arterial or double-occlusion capillary pressures were observed at any dose. Similarly, no changes in LLL hemodynamics were observed in three additional lobes when NPY was administered while norepinephrine was being infused. We conclude that it is unlikely that NPY plays a role as a circulating vasoactive agent in producing the pulmonary hypertension and edema that occur in this model.