Antagonism of leukotriene receptors and administration of a 5-lipoxygenase inhibitor do not affect hypoxic vasoconstriction

The role of leukotrienes in hypoxic vasoconstriction remains controversial. Our previous study using the lipoxygenase inhibitor BW 755C in dogs failed to show a substantive role for leukotrienes in hypoxic vasoconstriction. To clarify further the role of leukotrienes, we designed 3 protocols. In the first protocol, we examined the effects of LTD₄ boluses on the pulmonary circulation in 6 anesthetized dogs. LTD₄, 1 μg/kg, (a large dose relative to other species) produced no detectable constriction of the pulmonary artery, while systemic vascular resistance increased 41±17% (SD), left atrial pressure rose 3.5±1.5 mmHg, and cardiac output fell 18±8%. Two leukotriene receptor antagonists, LY171883 and L-648051, decreased these effects by more than 50%. In the second protocol, we tested these antagonists in 7 anesthetized, paralyzed, closed-chest dogs with acute left lower lobe atelectasis. Two manifestations of hypoxic vasoconstriction were examined: shunt fraction (as an inverse indicator of regional constriction in response to local hypoxia) and the pulmonary pressor response to global alveolar hypoxia (as an index of general hypoxic vasoconstriction). During normoxia before administration of the inhibitor, shunt fraction, measured using an SF₆ infusion, was 25±7%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient (PDG) produced by 10% O₂ inhalation, averaged +10.5±3.6 mmHg. The increase in pulmonary vascular resistance (PVR) with hypoxia was +2.4±1.7 mmHg/L/min. Then, during normoxia, 1 of the 2 antagonists was administered. Shunt fraction was unchanged (26±4%; p=0.5). The pressor response to hypoxia was slightly less but remained substantial (the increase in PDG with hypoxia was +7.9±2.8 mmHg; p<0.05; the increase in PVR was +1.8±1.2 mmHg/L/min, p<0.10). In the third protocol we gave RG 5901, a relatively specific 5-lipoxygenase inhibitor, to 5 dogs with lobar atelectasis. The indices of hypoxic vasoconstriction were not affected by RG 5901. Shunt fraction was 29.5±8.1% before and 27.0±7.4% after RG 5901 (p>0.05). The pressor response to hypoxia was + 8.9±2.1 mmHg before and +8.7±3.7 mmHg after RG 5901 (p>0.05). We conclude that in dogs, hypoxic vasoconstriction does not appear to be mediated by leukotrienes.     

The effect of instrumental dead space on measurement of breathing pattern and pulmonary mechanics in the newborn

The effect of the instrumental dead space on breathing pattern and the values of pulmonary mechanics was evaluated because of concern about the relatively large dead space of 26 mL in a commercially available system. Sixty-three healthy newborn infants were studied with a system as commercially supplied, and with the dead space eliminated using a 2 L/min biased flow. This led to a significant reduction in mean (± SD) values of respiratory rate from 56.8 (±11.7) to 48.2 (±11.7) breath/min (P < 0.0001), tidal volume from 5.2 (±1.3) to 4.9 (±0.9) mL/kg (P < 0.05), minute volume from 284 (±68) to 220 (±63) mL/min/kg (P < 0.0001), and work of breathing from 13.7 (±6.6) to 11.8 (±7.6) g · cm/kg (P < 0.02). There was a significant increase in dynamic lung compliance from 5.2 (±1.5) to 5.6 (±1.2) mL/cm H₂O (P < 0.01) but no difference for total pulmonary resistance 39.6 (±22.8) and 38.8 (±22.2) cm H₂O/L/sec. This shows that the instrumental dead space prevents measurement of the basal breathing patterns and alters the values of pulmonary mechanics. It is, therefore, important to use equipment with low dead space or make efforts to remove it by using a biased flow system such as we describe when measuring breathing patterns and pulmonary mechanics in the newborn. Pediatr Pulmonol. 1993; 16:316–322. © 1993 Wiley-Liss, Inc.     

Estimated Functional Diameter of Alveolar Septal Microvessels at the Zone I-II Border

Objective : To measure the functional diameter of alveolar septal microvessels under conditions in which the pulmonary arterial pressure and the lung inflation pressure are equal, at 25 cm H₂O (zone I-II border), and to compare these results with those obtained when inflation pressure exceeded arterial pressure by 5 or 10 cm H₂O (zone I). Methods : We perfused isolated rat lungs (P_A 25, P_PA 25, P_LA 0 cm H₂O) with fluorescent latex particles of specific diameters (0.49, 1.05, 2.0, 4.0, or 10 μm) and then prepared samples for histology. Using a confocal, laser-scanning fluorescence microscope, we measured latex particle densities within the septal plane of individual alveoli. We compared these particle densities with those in arterioles supplying the septa and calculated the density ratio. We fit curves produced by the Verniory equation to these ratios to estimate the septal microvessel functional diameter. Results : Particle densities in septa ranged from 0.06 ± 0.02 particles per μm² ‘for 0.49-μm-diameter particles to 0.007 ± 0.004 particles per μm² for 4.0-μm-diameter particles. The 10-μm particles did not enter septa. Calculations based on these data suggest a septal microvessel functional diameter of 6–8 μm. Conclusions : In a previous study, conducted at the same value of P_inflat, but with P_PA set at 15 or 20 (5 or 10 cm H₂O into zone I), we estimated the capillary diameter to be 1.7 μm. Thus, the septal capillary diameter seems to increase by three- to fourfold as P_PA is raised to equal P_inflat.     

Effects of alveolar hypoxia during partial mitral valve obstruction in unanesthetized sheep

The effects of elevated left atrial pressure (Pla) on the pulmonary hemodynamic responses to hypoxia and infused prostaglandin-H2 analog (PGH2-A) were studied in 10 chronically instrumented unanesthetized sheep. Sheep were studied with isocapnic hypoxia (fraction of inspired O2, 0.12) or infused PGH2-A (0.2 to 1.0 micrograms X kg-1 X min-1 adjusted to increase pulmonary artery pressure (Ppa) by approximately 15 cm H2O) when Pla was normal or elevated to 10 or 20 cm H2O. The Pla was elevated by inflating a Foley catheter positioned in the mitral valve orifice. Elevation of Pla did not block the increase in Ppa or cardiac output (CO) caused by hypoxia but did block the increase in pulmonary vascular resistance (PVR). When Pla was elevated to 10 or 20 cm H2O, hypoxia caused Pla to increase further, and PGH2-A caused Ppa and PVR to increase whether Pla was elevated or not; PGH2-A did not cause CO to increase or Pla to increase further under any experimental condition. Neither hypoxia nor PGH2-A had any effect on left ventricular end-diastolic pressure under any experimental condition. We hypothesize that when Pla is elevated, the increase in CO may dilate the pulmonary circulation, obscuring hypoxic vasoconstriction. When Pla is elevated, the direct effects of hypoxic pulmonary vasoconstriction cannot overcome the increased intraluminal pressure, and PVR does not increase. The pulmonary vessels are still able to respond to a potent vasoconstrictor such as PGH2-A when Pla is elevated. We conclude that the further increase in Pla caused by hypoxia when Pla is elevated is primarily due to increased flow across a mitral valve behaving as a relatively fixed resistor.     

Inhalation of Simulated Smog Atmospheres Affects Cardiac Function in Mice

The health effects of individual criteria air pollutants have been well investigated. However, little is known about the health effects of air pollutant mixtures that more realistically represent environmental exposures. The present study was designed to evaluate the cardiac effects of inhaled simulated smog atmospheres (SA) generated from the photochemistry of either gasoline and isoprene (SA-G) or isoprene (SA-Is) in mice. Four-month-old female mice were exposed for 4 h to filtered air (FA), SA-G, or SA-Is. Immediately and 20 h after exposure, cardiac responses were assessed with a Langendorff preparation using a protocol consisting of 20 min of global ischemia followed by 2 h of reperfusion. Cardiac function was measured by index of left-ventricular developed pressure (LVDP) and cardiac contractility (dP/dt) before ischemia. Pre-ischemic LVDP was lower in mice immediately after SA-Is exposure (52.2?±?5.7 cm H₂O compared to 83.9?±?7.4 cm H₂O after FA exposure; p?=?0.008) and 20 h after SA-G exposure (54.0?±?12.7 cm H₂O compared to 79.3?±?7.4 cm H₂O after FA exposure; p?=?0.047). Pre-ischemic left ventricular contraction dP/dt_max was lower in mice immediately after SA-Is exposure (2025?±?169 cm H₂O/sec compared to 3044?±?219 cm H₂O/sec after FA exposure; p?<?0.05) and 20 h after SA-G exposure (1864?±?328 cm H₂O/sec compared to 2650?±?258 cm H₂O/sec after FA exposure; p?=?0.05). In addition, SA-G reduced the coronary artery flow rate 20 h after exposure compared to the FA control. This study demonstrates that acute SA-G and SA-Is exposures decrease LVDP and cardiac contractility in mice, indicating that photochemically-altered atmospheres affect the cardiovascular system.     

Dibutyryl cyclic AMP inhibits acute hypoxic pulmonary vasoconstriction in conscious sheep

We examined the effects of cell-permeable dibutyryl cyclic AMP (DBcAMP) on acute hypoxic pulmonary vasoconstriction (HPV) in conscious sheep. Mean left and right atrial, pulmonary, and systemic pressures (Pla, Pra, Ppa, and Psa, mm Hg), cardiac output (CO, L/min), and heart rate were measured continuously. Systemic (SVR) and pulmonary vascular resistances (PVR) were calculated by (Psa-Pra)/CO and (Ppa-Pla)/CO, respectively. Five groups of experiments were performed using the same sheep (n = 6). After a 30-min baseline period, sheep inhaled a hypoxic gas mixture (O2:N2 = 1:9) for 40 min. Pretreatment with DBcAMP (200 micrograms/kg/min) inhibited HPV (Ppa, 12.0 +/- 2.3 to 20.0 +/- 2.3 versus 13.2 +/- 2.5 to 14.3 +/- 1.4 mm Hg, p less than 0.01; PVR, 2.61 +/- 0.81 to 4.15 +/- 1.14 versus 2.30 +/- 0.87 to 2.52 +/- 0.59 mm Hg/L/min, p less than 0.01). DBcAMP treatment (200 micrograms/kg/min) after induction of HPV also significantly attenuated hypoxic pulmonary response (Ppa, 19.0 +/- 1.7 to 14.2 +/- 2.3 mm Hg, p less than 0.01; PVR, 3.92 +/- 0.39 to 2.34 +/- 0.34 mm Hg/L/min, p less than 0.01) without significant decreases in Psa and SVR. Pretreatment with DBcAMP (200 micrograms/kg/min) did not significantly alter pulmonary pressor responses to bolus injections of prostaglandin F2 alpha (PGF2 alpha) (10 micrograms/kg) and norepinephrine (4 micrograms/kg). These results may suggest that intracellular augmentation of cyclic AMP plays a crucial role in modulating HPV.     

氮气洗入/洗出法测定急性肺损伤患者肺复张容积的研究

  目的 探讨氮气洗入/洗出法测急性肺损伤(ALI)患者肺复张容积的准确性及可行性。方法 将15例有创机械通气的ALI患者纳入本研究,根据ARDSnet法和跨肺压法滴定2种呼气末正压(PEEP) 水平,分别通气30 min,记录各PEEP水平下潮气量(Vt)、气道平台压等呼吸力学及血流动力学指标,并利用氮气洗入/洗出法测2种PEEP水平的呼气末肺容积(EELV),根据公式推算氮气洗入/洗出法测的肺复张容积,同时根据低流速压力-容积(P-V)曲线法获得肺复张容积,比较2种方法获得的肺复张容积的相关性及一致性。结果 (1)ARDSnet法滴定的PEEP为（7±2） cm H₂O（1 cm H₂O=0.098 kPa）,气道峰压为（23±5） cm H₂O,气道平台压为(17±4） cm H₂O;跨肺压法滴定的PEEP为（14±5 )cm H₂O,气道峰压为（28±6） cm H₂O,气道平台压为（22±6） cm H₂O,2种方法比较差异有统计学意义(P<0.05)。(2) 低流速P-V曲线法测的肺复张容积为100（-25~185）ml,氮气洗入/洗出法测的肺复张容积为180（-19~255）ml,两者具有较好的相关性,R²=0.755,P<0.0001,且测量误差为46（8~80）ml。结论 氮气洗入/洗出法可测定ALI患者的肺复张容积。        

Favorable effects of hydralazine on the hemodynamic response to isometric exercise in chronic severe aortic regurgitation

The hemodynamic effects of isometric exercise and the response to hydralazine therapy were evaluated in 11 patients with chronic, severe aortic regurgitation (AR). Isometric exercise produced a significant increase in heart rate (from 78 ± 11 to 93 ± 19 beats/min [mean ± standard deviation], p < 0.05), mean blood pressure (from 83 ± 8 to 104 ± 20 mm Hg, p < 0.05), mean right atrial pressure (from 3 ± 2 to 7 ± 5 mm Hg, p < 0.05) and mean pulmonary artery wedge pressure (from 12 ± 7 to 18 ± 10 mm Hg, p < 0.05). Small and insignificant changes were seen in cardiac index (from 3.4 ± 0.8 to 3.9 ± 1.0 liters/min/m²), systemic vascular resistance (from 1,097 ± 257 to 1,171 ± 284 dynes s cm^?5), pulmonary vascular resistance (from 120 ± 76 to 130 ± 89 dynes s cm^?5) and stroke volume index (from 44 ± 10 to 43 ± 12 ml/m²). After oral hydralazine administration (100 to 300 mg), hemodynamic values during isometric exercise were: Heart rate increased further, to 105 ± 14 beats/min (p < 0.05), mean blood pressure was 102 ± 16 mm Hg (difference not significant [NS]) cardiac index increased markedly, to 5.2 ± 1.4 liters/min/m² (p < 0.05), stroke volume index increased to 49 ± 12 ml/m² (p < 0.05), right atrial pressure decreased slightly, to 5 ± 5 mm Hg (NS), pulmonary artery wedge pressure decreased to 14 ± 7 mm Hg (p < 0.05), systemic vascular resistance decreased to 903 ± 288 dynes s cm^?5 (p < 0.05), and pulmonary vascular resistance changed to 100 ± 66 dynes s crrr^?5 (NS). Thus, isometric exercise in patients with chronic severe AR is associated with only a slight and insignificant increase in systemic vascular resistance, but a marked increase in pulmonary artery wedge pressure. Direct arteriolar vasodilation with hydralazine results in a significant attenuation of pulmonary artery wedge pressure increase during isometric exercise and leads concomitantly to a significant augmentation of stroke volume and cardiac output. These findings substantiate the value of hydralazine therapy in patients with chronic, severe AR.     

Pulmonary Microvascular Pressure Profile During Development of Hydrostatic Edema

Objective: To measure, in intact closed chest, the pressure in the pulmonary microvasculature during transition to mild interstitial edema. Methods: In anesthetized spontaneously breathing rabbits, the pulmonary artery and left atrium were cannulated. Pleural windows were prepared to view the superficial pulmonary microvascular network through the intact parietal pleura. After intravenous infusion of 96.4 ± 12.3 ml of saline at a rate of 0.5 ml/kg h, the hydraulic pressure in the pulmonary microvessels (15–240 μm in diameter) were measured using glass pipettes driven through the pleural window and connected to a servonull system. Results: After saline, plasma protein concentration decreased from 6 ± 1 to 4.8 ± 0.5 g/dl; pulmonary arterial and left atrial pressures averaged 22.3 ± 6.4 and 2.3 ± 2 cm H₂O in control and 23.1 ± 4.2 and 4.2 ± 2 cm H₂O after infusion. After saline loading, 16.4% of total pressure drop occurred from pulmonary artery to 80-μm arterioles, 60.3% in 30–80-μm arterioles, 6.9% from 30-μm arterioles to 30-μm venules and 16.4% in the downstream segment. Conclusions: Mild interstitial edema induced, with respect to control, constriction of small arterioles and capillary recruitment to maintain a low capillary pressure. Hence, in initial edema, pulmonary circulation prevents further fluid filtration, acting like an intrinsic safety factor to delay development of severe edema.     

Echocardiographic Estimation of Pulmonary Vascular Resistance in Chronic Thromboembolic Pulmonary Hypertension: Utility of Right Heart Doppler Measurements

The ratio of tricuspid regurgitation velocity divided by the velocity‐time integral of right ventricular outflow tract pulsed‐wave Doppler tracing (TRV/VTI_RVOT) has been used to estimate pulmonary vascular resistance (PVR). However, this method has not been validated in chronic thromboembolic pulmonary hypertension (CTEPH). We assessed the utility of TRV/VTI_RVOT in patients with CTEPH and PVR from 2 to 20 WU. All had right heart catheterization (RHC) within 2 days of echocardiography. TRV/VTI_RVOT was calculated and RHC‐derived pressures, PVR, and cardiac outputs were recorded. Mean pulmonary artery pressure was 47 ± 12 mmHg, cardiac output: 4.2 ± 1.1 L/min, PVR: 9 ± 4 WU, right atrial pressure: 12 ± 6 mmHg. Mean VTI_RVOT was 13 ± 5 cm; mean TRV was 4.2 ± 0.8 m/s, mean tricuspid regurgitation severity was 2.5 ± 0.8 (1 = trace, 2 = mild, 3 = moderate, 4 = severe). Regression analysis demonstrated a correlation between RHC PVR and TRV/VTI_RVOT: PVR = 19.4 × (TRV/VTI_RVOT) + 2.4 (r = 0.74, P < 0.001). However, Bland–Altman analysis found a poor degree of agreement between echo‐derived PVR and RHC PVR. We also studied 28 patients with non‐CTEPH pulmonary hypertension. Similar analysis revealed a regression equation of PVR = 20.1 × (TRV/VTI_RVOT) + 0.3 (r = 0.57, P < 0.01). Conclusion: TRV/VTI_RVOT is only marginally useful for estimating PVR in CTEPH (r = 0.74). Moreover, the regression equation in CTEPH differs significantly from previous studies in pulmonary hypertension. Reasons for this may include the markedly elevated PVR levels in this population and specific effects on VTI_RVOT from CTEPH.     

Vasorelaxant effects of cicletanine and its (+)- and (−)-enantiomers in isolated human pulmonary arteries

The purpose of the study was to investigate, in isolated human pulmonary artery, the ability of cicletanine and its (−) and (+)-enantiomers to attenuate the endothelin-1 (Et-1) induced vasoconstriction, and to potentiate vasorelaxation (relative to plateau of the effect of Et-1) by sodium nitroprusside (SNP) and human atrial natriuretic peptide (ANP). In pulmonary artery rings, Et-1 induced a concentration-dependent vasoconstriction with median effective concentration (EC₅₀ = 26 ± 2.8 nmol/L. Pretreatment of the vessels with 100 μmol/L (±)-cicletanine reduced the effect of Et-1 (EC₅₀ = 36 ± 3.5 nmol/L; P < .01). (−)-enantiomer displayed greater capacity to antagonize the vasoconstrictor action of Et-1 (EC₅₀ = 47 ± 4.2 nmol/L) v (+)-enantiomer (EC₅₀ = 29.9 ± 6.5 nmol/L; P < .01). In arterial rings, precontracted with 10 nmol/L Et-1, ANP caused vasorelaxation (EC₅₀ = 9.7 ± 1.9 nmol/L). The relaxant effect of ANP was potentiated by 100 μmol/L of (−)-(EC₅₀ = 4.2 ± 0.6 nmol/L; P < .01), but not (+)-cicletanine (EC₅₀ = 7.6 ± 0.7 nmol/L). Sodium nitroprusside relaxed pulmonary artery rings precontracted with 10 nmol/L Et-1 (EC₅₀ = 41 ± 11 nmol/L). The effect of SNP was potentiated by 10 μmol/L (±)-cicletanine (EC₅₀ = 9.0 ± 0.7 nmol/L; P < .05). The potentiating effect of 10 μmol/L (+)-cicletanine was weaker (EC₅₀ = 7.9 ± 1.8 nmol/L) than that of (−)-enantiomer (EC₅₀ = 3.3 ± 0.54 nmol/L; P < .05). The relaxant effect of SNP was not further potentiated by 100 μmol/L (±)-cicletanine. The present results demonstrate that, cicletanine antagonizes Et-1 induced vasoconstriction in an isolated human pulmonary artery and potentiates vasorelaxation by two guanylate cyclase activators, ANP and SNP. (−)-Cicletanine displays greater vasorelaxant activity v (+)-enantiomer.     

Endothelium-derived nitric oxide regulates systemic and pulmonary vascular resistance during acute hypoxia in humans

Objectives. This investigation sought to determine whether endothelium-derived nitric oxide contributes to hypoxia-induced systemic vasodilation and pulmonary vasoconstriction in humans.Background. Endothelium-derived nitric oxide contributes to basal systemic and pulmonary vascular resistance. During hypoxia, systemic vasodilation and pulmonary vasoconstriction occur. There are some data indicating that endothelium-derived nitric oxide mediates changes in vascular resistance during hypoxia, but much of it is contradictory, and none has been derived from normal humans.Methods. The hemodynamic effects of N^G-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, were studied in healthy volunteers under normoxic and hypoxic conditions. A Swan-Ganz catheter and radial artery cannula were inserted to measure right atrial, pulmonary artery, pulmonary capillary wedge and systemic blood pressures. Cardiac output was measured by thermodilution. Systemic vascular resistance and pulmonary vascular resistance were calculated. The pharmacokinetics of L-NMMA (300 mg intravenously) was studied during normoxia in six subjects. Hypoxia was induced in eight subjects who inspired a mixture of nitrogen and oxygen through a gas blender adjusted to reduce the partial pressure of oxygen from (mean ± SE) 98 ± 4 to 48 ± 1 mm Hg.Results. During normoxia, L-NMMA increased systemic vascular resistance from 1,108 ± 74 to 1,705 ± 87 dynes·s·cm⁻⁵ and increased pulmonary vascular resistance from 60 ± 5 to 115 ± 9 dynes·s·cm⁻⁵ (p ≤ 0.01 for each). Peak effects occurred within 10 min of L-NMMA administration. Acute hypoxia alone decreased systemic vascular resistance from 1,209 ± 78 to 992 ± 58 dynes·s·cm⁻⁵ (p ≤ 0.05) and increased pulmonary vascular resistance from 92 ± 11 to 136 ± 4 dynes·s·cm⁻⁵ (p ≤ 0.01). While hypoxic conditions were maintained, infusion of L-NMMA increased systemic vascular resistance (to 1,496 ± 97 dynes·s·cm⁻⁵, p ≤ 0.01) and increased pulmonary vascular resistance further (to 217 ± 25 dynes·s·cm⁻⁵, p ≤ 0.01).Conclusions. Endothelium-derived nitric oxide contributes to systemic vasodilation and serves as a counterregulatory mechanism to attenuate pulmonary vasoconstriction during acute hypoxia in healthy human subjects.     

Cardiopulmonary effects of one-lung ventilation in supine patients

The cardiopulmonary effects of one-lung ventilation (OLV), with continuous positive airway pressure (CPAP, 5 cm H₂O) to the nonventilated lung, were compared to the effects of two-lung ventilation (TLV) in 12 supine patients undergoing coronary artery bypass grafting (CABG). Monitoring was performed with electrocardiography (ECG), arterial, and pulmonary artery catheters. Measurements of cardiac index (CO, heart rate (HR), systemic (MAP) and pulmonary artery pressures (PAP), pulmonary artery occlusion pressure (PAOP), mixed venous oxygen saturation (SvO₂), and arterial blood for pH, PaO₂, PaCO₂ and HCO₃- were performed with stable maintenance of anesthesia during both one- and two-lung ventilation. Mean values for CI, HR, MAP, MPAP, PVR, and S_vO₂ demonstrated no significant changes between OLV and TLV; systemic vascular resistance (SVR) and pulmonary artery occlusion pressure (PAOP) were statistically (P < 0.05) different, but of minor clinical significance. The data suggest that OLV, accompanied by CPAP (5 cm H₂0) to the nonventilated lung, produces minimal changes in cardiopulmonary measurements in supine patients.     

Enhancement of Cardiac Performance by Bilevel Positive Airway Pressure Ventilation in Heart Failure

BackgroundRecent studies have reported the clinical usefulness of positive airway pressure ventilation therapy with various kinds of pressure support compared with simple continuous positive airway pressure (CPAP) for heart failure patients. However, the mechanism of the favorable effect of CPAP with pressure support can not be explained simply from the mechanical aspect and remains to be elucidated.Methods and ResultsIn 18 stable chronic heart failure patients, we performed stepwise CPAP (4, 8, 12 cm H₂O) while the cardiac output and intracardiac pressures were continuously monitored, and we compared the effects of 4 cm H₂O CPAP with those of 4 cm H₂O CPAP plus 5 cm H₂O pressure support. Stepwise CPAP decreased cardiac index significantly in patients with pulmonary arterial wedge pressure (PAWP) <12 mm Hg (n = 10), but not in those with PAWP ≥12 mm Hg (n = 8). Ventilation with CPAP plus pressure support increased cardiac index slightly but significantly from 2.2 ± 0.7 to 2.3 ± 0.7 L min^?1 m^?2 (P = .001) compared with CPAP alone, regardless of basal filling condition or cardiac index.ConclusionsOur results suggest that CPAP plus pressure support is more effective than simple CPAP in heart failure patients and that the enhancement might be induced by neural changes and not simply by alteration of the preload level.     

Lung Neutrophil Retention and Injury After Intestinal Ischemia/Reperfusion

Objective : To define the mechanisms responsible for the lung leukosequestration and injury elicited by intestinal ischemia/reperfusion (I/R). Methods : The effect of 120 minutes of superior mesenteric artery occlusion and 90 minutes of reperfusion on neutrophil deformability, lung neutrophil retention, and pulmonary microvascular permeability was determined. Results : Compared with control surgery, intestinal I/R resulted in a significant increase in neutrophil stiffness (mean yield pressure [P_yieid], 1–533 ± 0.075 and 2.302 ± 0.288 cm H₂O, respectively) and lung neutrophil content (6.3 ± 1.4 and 31.5 ± 6.4 U/g wet weight, respectively). These changes were not affected by inhibition of neutrophil adherence before gut reperfusion. However, the increased lung microvascular permeability elicited by gut I/R (0.111 ± 0.020 [control surgery] and 0.255 ± 0.041 [I/R] mL/min/cm H₂O/100 g lung tissue) was significantly attenuated by administration of antibodies directed against neutrophil or endothelial determinants of leukocyte adhesion. Conclusions : The results of this study suggest that intestinal I/R is a potent inflammatory stimulus that elicits an increase in neutrophil stiffness and lung neutrophil retention independent of neutrophil-endothelial cell adhesion. In contrast, the increased lung microvascular permeability elicited by gut I/R is attenuated by strategies that interfere with neutrophil-endothelial cell adhesion.     

Irreversibility of birth-related changes in the pulmonary circulation

We hypothesized that establishing conditions of hypoxia and fluid filling of the airways in lungs of newborns would reproduce the high levels of pulmonary vascular resistance (PVR) observed in the fetal state. We assessed the hemodynamics of the left pulmonary circulation of 1-to 3-day-old lambs during a variety of airway states while attempting to reestablish fetal conditions. Eleven animals were studied during both normoxemia and hypoxemia in a baseline airway state with a positive end-expiratory pressure (PEEP) of 4 cm H₂O, and in experimental airway states, of atelectasis, and fluid filling to 15 and 30 mL/kg and with PEEP of 12 cm HO. PVR increased while pulmonary blood flow decreased with all airway state changes as compared to baseline, suggesting a passive mechanism for these changes. With the addition of hypoxemia there was a further increase in PVR in all states accompanied by an increase in pulmonary blood flow, indicating that active vasoconstriction was responsible for the increase in PVR. The combined effects of hypoxemia and fluid filling, designed to approximate the fetal state, increased PVR to only 20–30% of fetal values. Thus, additional factors appear to be important in maintaining the high PVR of the fetal state. We speculate that ventilation of the lungs at birth irreversibly alters these factors. Pediatr Pulmonol. 1994;18:368–373. ©1994 Wiley-Liss, Inc.     

Effects of prostaglandin E1 and isosorbide dinitrate on acute hypoxic pulmonary vasoconstriction in conscious sheep

The pulmonary vascular effects of prostaglandin E1 (PGE1) and isosorbide dinitrate (ISD) on acute hypoxic pulmonary vasoconstriction in conscious sheep were studied. While the animals inhaled room air or hypoxic gas (O2:N2 = 1:9), PGE1 (0.5 microgram/kg/min) and ISD (10 microgram/kg/min) were administered intravenously for 20 min, using an infusion pump. The changes of pulmonary arterial pressure (PPA) or pulmonary vascular resistance (PVR) in room air due to PGE1 were not significant, but in the hypoxic condition, PGE1 decreased PPA by 14.7% (p less than 0.05) and PVR by 14.5% (p less than 0.05). The effect of PGE1 in room air on systemic arterial pressure (PSA) remained nearly constant, whereas slight decreases in systemic vascular resistance (SVR) were noticed. In hypoxic condition, PSA levels were slightly decreased by PGE1, but SVR indicated a slight degree of delayed rise. When ISD in room air was administered, the values of PPA, PVR, PSA and SVR decreased by 9% (p less than 0.05), 10.4% (p less than 0.05), 17.7% (p less than 0.05) and 21.8% (p less than 0.05), respectively. In hypoxic condition, ISD decreased the values of PPA, PVR, PSA and SVR by 14.7% (p less than 0.05), 15.8% (p less than 0.05), 10.2% (p less than 0.05) and 6.7% (p less than 0.05), respectively. In summary in hypoxic condition both PGE1 and ISD cause similar decreases of PPA and PVR. Furthermore, there was a very little decrease in PSA during PGE1 infusion in the hypoxic condition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhancement of hypoxic pulmonary vasoconstriction by almitrine in the dog

In order to test the hypothesis of enhancement of hypoxic pulmonary vasoconstriction by Almitrine, 12 anesthetized and paralyzed dogs with normal lungs were studied under controlled ventilation. They were ventilated in random sequence with air, 12% O2, and 100% O2, and almitrine (0.1 mg/kg body weight) was infused over 30 min during each O2 mixture. The multiple inert gas elimination technique was used to detect alterations in ventilation-perfusion (VA/Q) mismatching before and during the interventions and to measure cardiac output (QT). Arterial, mixed venous and expired gases, inert gas concentrations, and hemodynamic measurements were made while the dogs were breathing the different O2 mixtures before infusing the drug, near the end of 30 min of infusion and 30 min after infusion had ended. There were no significant changes in pH, PaO2, PaCO2, QT, oxygen uptake, oxygen delivery index, systemic vascular resistance, mean systemic arterial pressure, heart rate, stroke volume index, or VA/Q distribution during the experiment. Significant increases in: (a) pulmonary artery pressure (PA), (b) the pressure difference between PA and pulmonary capillary wedge pressure (PCw), and (c) pulmonary vascular resistance (PVR) occurred when the drug was infused during 12% O2 and air, but not during 100% O2. The PVR increased 59.7% with almitrine infusion during 12% O2 and 38.4% during air breathing (p less than or equal to 0.01), but there was no significant change during 100% O2. Vascular responses were not dependent on the order in which the different O2 mixtures were administered. These data strongly suggest that almitrine enhances hypoxic vasoconstriction in the lung, and this effect may explain reported improvement in PaO2 in hypoxic patients given the drug.     

Effects of prostacyclin (PGI2) on hypoxic pulmonary vasoconstriction in the conscious adult sheep

The effects of prostacyclin (PGI2) on alveolar hypoxic pulmonary vasoconstriction were investigated in the conscious adult sheep. In our model, hypoxia also produced increases in pulmonary arterial pressure (PPA) and pulmonary vascular resistance (PVR), indicating pulmonary vasoconstriction. PGI2 was injected rapidly as a 0.5 microgram/kg bolus via the right atrium in five sheep during normoxia and hypoxia. During normoxia, PGI2 increased PPA and cardiac output, and decreased systemic arterial pressure (PSA), systemic vascular resistance (SVR) and PVR. Left atrial pressure did not change. During hypoxia following PGI2 administration, PPA decreased, CO increased, and PVR decreased, suggesting dilator action on the pulmonary resistance vessels. As the same time PSA and SVR decreased, suggesting dilator action on the systemic resistance vessels. However, the degree of the decline in PVR caused by PGI2 was much greater during hypoxia than during normoxia. The decreases in PSA and SVR induced by PGI2 were not significant between hypoxia and normoxia. These findings confirm that PGI2 decreases pulmonary and systemic vascular resistances in normoxic and hypoxic sheep. Moreover, during hypoxia, associated with the increased PPA and PVR, the administration of PGI2 appears to be particularly effective in "normalizing" these parameters.     

A histamine H2 receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade

Histamine has a positive inotropic effect on ventricular myocardium and stimulation of histamine H₂ receptors increases the intracellular cAMP level via Gs protein, as dose stimulation of β-adrenergic receptors, and worsens heart failure. To test whether a histamine H₂ receptor blocker had a beneficial effect in addition to β-adrenergic receptor blockade, we investigated the cardioprotective effect of famotidine, a histamine H₂ receptor blocker, in dogs receiving a β-blocker. We induced heart failure in dogs by rapid ventricular pacing (230 beats/min). Animals received no drugs (control group), famotidine (1 mg/kg daily), carvedilol (0.1 mg/kg daily), or carvedilol plus famotidine. Both cardiac catheterization and echocardiography were performed before and 4 weeks after the initiation of pacing. Immunohistochemical studies showed the appearance of mast cells and histamine in the myocardium after 4 weeks of pacing. In the control group, the left ventricular ejection fraction (LVEF) was decreased after 4 weeks compared with before pacing (71 ± 2 vs. 27 ± 2%, p < 0.05) and mean pulmonary capillary wedge pressure (PCWP) was increased (8 ± 1 vs. 19 ± 3 mmHg). Famotidine ameliorated the decrease of LVEF and increase of PCWP, while the combination of carvedilol plus famotidine further improved both parameters compared with the carvedilol groups. These beneficial effects of famotidine were associated with a decrease of the myocardial cAMP level. Histamine H₂ receptor blockade preserves cardiac systolic function in dogs with pacing-induced heart failure, even in the presence of β-adrenergic receptor blockade. This finding strengthens the rationale for using histamine H₂ blockers in the treatment of heart failure.