Circulatory effects of prolonged hypoxia before and during antihistamine.

Five chronically instrumented healthy dogs were exposed to a 5-day period of breathing 10% oxygen in a chamber. The response to hypoxia was found to be time dependent. During the first 24 h of hypoxia the circulatory response was characterized by increases in cardiac output, heart rate, pulmonary and systemic arterial blood pressures, and pulmonary vascular resistance. Systemic vascular resistance increased; left atrial pressure decreased. During the early part of hypoxia the animals became hypocapnic; the arterial blood pH rose significantly. During the rest of the hypoxic period cardiac output, heart rate, and arterial blood pH returned to the control values; pulmonary and systemic arterial pressures and pulmonary vascular resistance remained significantly elevated. Systemic vascular resistance rose; left atrial pressure remained below control. This response to hypoxia was not substantially modified when the experiment was repeated during the administration of the antihistamine promethazine, an H1-receptor blocking agent, in a dose which blocked the pulmonary vasoconstrictor response to small doses of exogenous histamine. The circulatory response to acute hypoxia in five anesthetized dogs was not modified by intravenous administration of metiamide, an H2-receptor blocking agent.     

Effect of progressive exercise on lung fluid balance in sheep

The purpose of this study is to determine the roles of cardiac output and microvascular pressure on changes in lung fluid balance during exercise in awake sheep. We studied seven sheep during progressive treadmill exercise to exhaustion (10% grade), six sheep during prolonged constant-rate exercise for 45-60 min, and five sheep during hypoxia (fraction of inspired O2 = 0.12) and hypoxic exercise. We made continuous measurements of pulmonary arterial, left atrial, and systemic arterial pressures, lung lymph flow, and cardiac output. Exercise more than doubled cardiac output and increased pulmonary arterial pressures from 19.2 +/- 1 to 34.8 +/- 3.5 (SE) cmH2O. Lung lymph flow increased rapidly fivefold during progressive exercise and returned immediately to base-line levels when exercise was stopped. Lymph-to-plasma protein concentration ratios decreased slightly but steadily. Lymph flows correlated closely with changes in cardiac output and with calculated microvascular pressures. The drop in lymph-to-plasma protein ratio during exercise suggests that microvascular pressure rises during exercise, perhaps due to increased pulmonary venous pressure. Lymph flow and protein content were unaffected by hypoxia, and hypoxia did not alter the lymph changes seen during normoxic exercise. Lung lymph flow did not immediately return to base line after prolonged exercise, suggesting hydration of the lung interstitium.     

Peripheral chemoreceptor modulation of the pulmonary vasculature in the cat.

The present study was undertaken to determine whether stimulation of the carotid and aortic bodies (cb and ab) could affect the pulmonary vasculature. Our hypothesis was that each promoted vasodilation and thus could modulate the pulmonary vasoconstrictor response to hypoxia. The experimental design of the first set of experiments took advantage of the facts that 1) the ab, but not the cb, increases its neural output in response to CO, whereas both respond to a decreased arterial PO2 (hypoxic hypoxia, HH) and 2) the aortic nerves in cats are easily transected. Hence, both cb and ab sent neural activity to the brain stem when the intact cat was exposed to 10% O2 in N2. Only the ab sent information during CO hypoxia (COH intact). Only the cb did so during HH in the cat in which the aortic nerves had been transected, removing the aortic body (HH abr); neither ab nor cb did so during COH abr. Fifteen anesthetized paralyzed artificially ventilated cats were fit with catheters in the femoral artery and vein, right and left atria, left ventricle, and pulmonary artery and with an aortic flow probe. In the HH intact and HH abr conditions, there was a significant rise in cardiac output, whereas pulmonary arterial pressure (Ppa) rose initially but then leveled off while cardiac output continued to rise. During the 15-min exposure to HH, pulmonary vascular resistance [PVR = (Ppa - Pla)/cardiac output, where Pla is left atrial pressure] rose initially and then decreased significantly at 2-3 min. In response to COH, PVR showed only a significant decrease. In the second set of experiments, seven cats were instrumented as above and had loops placed in the common carotid arteries for selectively perfusing the cbs. In response to a brief infusion of venous blood mixed with 0.3-0.5 micrograms NaCN, which selectively stimulated only the cb, aortic flow remained relatively constant while heart rate and Ppa - alveolar pressure difference decreased significantly; so also did PVR. These data are consistent with the hypothesis that stimulation of the ab and cb singly or together can provoke a significant pulmonary vasodilation in the anesthetized paralyzed artificially ventilated cat.     

Contribution of endothelin to pulmonary vascular tone under normoxic and hypoxic conditions

The contribution of endothelin to resting pulmonary vascular tone and hypoxic pulmonary vasoconstriction in humans is unknown. We studied the hemodynamic effects of BQ-123, an endothelin type A receptor antagonist, on healthy volunteers exposed to normoxia and hypoxia. Hemodynamics were measured at room air and after 15 min of exposure to hypoxia (arterial PO(2) 99.8 +/- 1.8 and 49.4 +/- 0.4 mmHg, respectively). Measurements were then repeated in the presence of BQ-123. BQ-123 decreased pulmonary vascular resistance (PVR) 26% and systemic vascular resistance (SVR) 21%, whereas it increased cardiac output (CO) 22% (all P < 0.05). Hypoxia raised CO 28% and PVR 95%, whereas it reduced SVR 23% (all P < 0.01). During BQ-123 infusion, hypoxia increased CO 29% and PVR 97% and decreased SVR 22% (all P < 0.01). The pulmonary vasoconstrictive response to hypoxia was similar in the absence and presence of BQ-123 [P = not significant (NS)]. In vehicle-treated control subjects, hypoxic pulmonary vasoconstriction did not change with repeated exposure to hypoxia (P = NS). Endothelin contributes to basal pulmonary and systemic vascular tone during normoxia, but does not mediate the additional pulmonary vasoconstriction induced by acute hypoxia.     

Regional hemodynamic responses to hypoxia in polycythemic dogs

Polycythemia increases blood viscosity so that systemic O2 delivery (QO2) decreases and its regional distribution changes. We examined whether hypoxia, by promoting local vasodilation, further modified these effects in resting skeletal muscle and gut in anesthetized dogs after hematocrit had been raised to 65%. One group (CON, n = 7) served as normoxic controls while another (HH, n = 6) was ventilated with 9% O2--91% N2 for 30 min between periods of normoxia. Polycythemia decreased cardiac output so that QO2 to both regions decreased approximately 50% in both groups. In compensation, O2 extraction fraction increased to 65% in muscle and to 50% in gut. When QO2 was reduced further during hypoxia, blood flow increased in muscle but not in gut. Unlike previously published normocythemic studies, there was no initial hypoxic vasoconstriction in muscle. Metabolic vasodilation during hypoxia was enhanced in muscle when blood O2 reserves were first lowered by increased extraction with polycythemia alone. The increase in resting muscle blood flow during hypoxia with no change in cardiac output may have decreased O2 availability to other more vital tissues. In that sense and under these experimental conditions, polycythemia caused a maladaptive response during hypoxic hypoxia.     

Furosemide reduces lung fluid filtration in lambs with lung microvascular injury from air emboli

To study the effects of furosemide on the neonatal pulmonary circulation in the presence of lung injury, we measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, and concentrations of protein in lymph and plasma of nine lambs that received furosemide, 2 mg/kg iv, during a continuous 8-h intravenous infusion of air. Air embolism increased pulmonary vascular resistance by 71% and nearly tripled steady-state lung lymph flow, with no change in lymph-to-plasma protein ratio. These findings reflect an increase in lung vascular protein permeability. During sustained lung endothelial injury, diuresis from furosemide led to a rapid reduction in cardiac output (average 29%) and a 2-Torr decrease in left atrial pressure. Diuresis also led to hemoconcentration, with a 15% increase in both plasma and lymph protein concentrations. These changes were associated with a 27% reduction in lung lymph flow. In a second set of studies, we prevented the reduction in left atrial pressure after furosemide by inflating a balloon catheter in the left atrium. Nevertheless, lymph flow decreased by 25%, commensurate with the reduction in cardiac output that occurred after furosemide. In a third series of experiments, we minimized the furosemide-related decrease in cardiac output by opening an external fistula between the carotid artery and jugular vein immediately after injection of furosemide. In these studies, the reduction in lung lymph flow (average 17%) paralleled the smaller (17%) decrease in cardiac output. These results suggest that changes in lung vascular filtration pressure probably do not account for the reduction in lung lymph flow after furosemide in the presence of lung vascular injury.(ABSTRACT TRUNCATED AT 250 WORDS)     

缺氧对右心室最大心肌心血流量的影响

为了探讨氧对冠状血管贮备方法的影响,我们观察了缺氧对血流动力学及右心室最大心肌血汉量的变化。结果表明,急性缺氧引起的ＰａＯ２、心输出量及氧运送量降低,但右心室心肌血流量增加,右心室最大与安静血流量比值降低,生缺氧时ＰａＯ２降低,血球比积和右心室生理指数增加,氧运送量和右心室血流量正常,但最大血流量降低,小动脉增厚、外胶元增加,以上结果提示,慢性缺氧对冠状血管贮备减少可能是小动脉壁增厚、外胶元增加和     

Measurement of bronchial blood flow with radioactive microspheres in awake sheep

Distribution of bronchial blood flow was measured in unanesthetized sheep by the use of two modifications of the microsphere reference sample technique that correct for peripheral shunting of microspheres: 1) A double microsphere method in which simultaneous left and right atrial injections of 15-microns microspheres tagged with different isotopes allowed measurement of both pulmonary blood flow and shunt-corrected bronchial blood flow, and 2) a pulmonary arterial occlusion method in which left atrial injection and transient occlusion of the left pulmonary artery prevented delivery to the lung of microspheres shunted through the peripheral circulation and allowed systemic blood flow to the left lung to be measured. Both methods can be performed in unanesthetized sheep. The pulmonary arterial occlusion method is less costly and requires fewer calculations. The double microsphere method requires less surgical preparation and allows measurement without perturbation of pulmonary hemodynamics. There was no statistically significant difference between bronchial blood flow measured with the two methods. However, total bronchial blood flow measured during pulmonary arterial occlusion (1.52 +/- 0.98% of cardiac output, n = 9) was slightly higher than that measured with the double microsphere method (1.39 +/- 0.88% of cardiac output, n = 9). In another series of experiments in which sequential measurements of bronchial blood flow were made, there was a significant increase of 15% in left lung bronchial blood flow during the first minute of occlusion of the left pulmonary artery. Thus pulmonary arterial occlusion should be performed 5 s after microsphere injection as originally described by Baile et al. (1).(ABSTRACT TRUNCATED AT 250 WORDS)     

缺氧对右心室最大心肌血流量的影响

为了探讨缺氧对冠状血管贮备力的影响,我们观察了缺氧时大鼠血流动力学及右心室最大心肌血流量的变化。结果表明,急性缺氧引起ＰａＯ２、心输出量及氧运送量降低,但右心室心肌血流量增加,右心室最大与安静血流量比值降低。慢性缺氧时ＰａＯ２降低,血球比积和右心室重量指数增加,氧运送量和右心室血流量正常,但最大血流量降低,小动脉增厚、外膜胶元增加。以上结果提示,慢性缺氧对冠状血管贮备减少可能是小动脉壁增厚、外膜胶元增加和血液粘滞性增加及右心室肥大的结果。     

Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 +/- 3 mmHg in hypoxic controls, 24 +/- 1 mmHg in Batimastat-treated hypoxic rats, and 16 +/- 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.     

Reduction of hypoxic pulmonary vasoconstriction during trichloroethylene anesthesia.

A double-lumen tube was inserted into the trachea of dogs anesthetized with intravenous pentobarbital (30-40 mg/kg). Blood flow/unit lung volume in each lung was measured with 133Xe. Both lungs were initially ventilated with oxygen and measurements of pulmonary blood flow, CO2 output, cardiac output, and blood gases were made. When nitrogen was administered to one lung blood flow was diverted to the opposite lung. The diversion of flow was reduced by the inhalation of 1% trichloroethylene but returned after withdrawal of the anesthetic. There were no significant changes in cardiac output. Changes in CO2 output and arterial Po2 were compatible with the xenon results. It is concluded that trichloroethylene may increase arterial hypoxemia by reducing vasoconstriction in hypoxic areas of lung.     

Hypoxia enhances unilateral lung injury by increasing blood flow to the injured lung

We hypothesized that in unilateral lung injury, bilateral hypoxic ventilation would induce vasoconstriction in the normal lung, redirect blood flow to the injured lung, and cause enhanced edema formation. Unilateral left lung injury was induced by intrabronchial instillation of 1.5 ml/kg of 0.1 N HCl. After HCl injury, blood flow to the injured left lung decreased progressively from 0.70 +/- 0.04 to 0.37 +/- 0.05 l/min and percent of flow to the injured left lung (QL/QT) decreased from 37.7 +/- 2.2 to 23.6 +/- 2.2% at 240 min. Exposure to hypoxia (12% O2) for three 10-min episodes did not affect QL/QT in normal animals, but after unilateral HCl injury, it caused blood flow to the injured left lung to increase significantly. A concomitant decrease in blood flow occurred to the noninjured right lung, resulting in a significant increase in QL/QT. The enhanced blood flow to the injured lung was associated with a significant increase in the wet-to-dry lung weight ratio in the dependent regions of the injured lung. These findings demonstrate that in unilateral HCl-induced lung injury, transient hypoxia can enhance blood flow to the areas of injury and increase lung edema formation.     

Peripheral vascular responses to hypoxic hypoxia after aortic denervation

We wished to see whether aortic chemoreceptors and other vagal afferent traffic played an essential role in the circulatory adjustments to hypoxic hypoxia. Aortic chemoreceptors were denervated (AD) in one group (n = 6) of anesthetized dogs, bilateral cervical vagotomy (V) was done on a second group (n = 6), and a third group (n = 6) was sham-operated to serve as a control. Venous outflow from the left hindlimb was isolated. After a 20-min control period of ventilation with room air, the animals were ventilated for 60 min with 9% of O2 in N2. Arterial, mixed venous, and hindlimb venous blood samples were taken every 20 min. The cardiac output response to hypoxic hypoxia was attenuated at 40 and 60 min in both the AD and V groups (p less than 0.05). Hindlimb blood flow increased equally in all three groups during hypoxia. The pressor response at the onset of hypoxia (20 min) was abolished in the AD and V groups, but mean arterial pressure fell to similar levels in all three groups by 60 min of hypoxia. We concluded that reflex aortic chemoreceptor stimulation during hypoxia augmented cardiac output mostly by effects on the venous side of the circulation but played no role in skeletal muscle vascular responses to hypoxic hypoxia.     

Effect of alpha adrenergic blockade on brain blood flow and ventilation during hypoxia in newborn piglets.

The influence of cardiovascular changes on ventilation has been demonstrated in adult animals and humans (Jones, French, Weissman & Wasserman, 1981; Wasserman, Whipp & Castagna 1974). It has been suggested that neonatal hypoxic ventilatory depression may be related to some of the hemodynamic changes that occur during hypoxia (Brown & Lawson, 1988; Darnall, 1985; Suguihara, Bancalari, Bancalari, Hehre & Gerhardt, 1986). To test the possible relationship between the cardiovascular and ventilatory response to hypoxia in the newborn, eleven sedated spontaneously breathing piglets (age: 5.9 +/- 1.6 days; weight: 1795 +/- 317 g; SD) were studied before and after alpha adrenergic blockade with phenoxybenzamine. Minute ventilation (VE) was measured with a pneumotachograph, cardiac output (CO) by thermodilution and total and regional brain blood flow (BBF) with radiolabeled microspheres. Measurements were performed while the animals were breathing room air and after 10 min of hypoxia induced by breathing 10% O2. Hypoxia was again induced one hour after infusion of phenoxybenzamine (6 mg/kg over 30 min). After 10 min of hypoxia, in the absence of phenoxybenzamine, the animals responded with marked increases in VE (P less than 0.001), CO (P less than 0.001), BBF, and brain stem blood flow (BSBF) (P less than 0.02). However, the normal hemodynamic response to hypoxia was eliminated after alpha adrenergic blockade. There were significant decreases in systemic arterial blood pressure, CO, and BBF during hypoxia after phenoxybenzamine infusion; nevertheless, VE increased significantly (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise training improves lung gas exchange and attenuates acute hypoxic pulmonary hypertension but does not prevent pulmonary hypertension of prolonged hypoxia.

Our laboratory has previously shown an attenuation of hypoxic pulmonary hypertension by exercise training (ET) (Henderson KK, Clancy RL, and Gonzalez NC. J Appl Physiol 90: 2057-2062, 2001), although the mechanism was not determined. The present study examined the effect of ET on the pulmonary arterial pressure (Pap) response of rats to short- and long-term hypoxia. After 3 wk of treadmill training, male rats were divided into two groups: one (HT) was placed in hypobaric hypoxia (380 Torr); the second remained in normoxia (NT). Both groups continued to train in normoxia for 10 days, after which they were studied at rest and during hypoxic and normoxic exercise. Sedentary normoxic (NS) and hypoxic (HS) littermates were exposed to the same environments as their trained counterparts. Resting and exercise hypoxic arterial P(O2) were higher in NT and HT than in NS and HS, respectively, although alveolar ventilation of trained rats was not higher. Lower alveolar-arterial P(O2) difference and higher effective lung diffusing capacity for O2 in NT vs. NS and in HT vs. HS suggest ET improved efficacy of gas exchange. Pap and Pap/cardiac output were lower in NT than NS in hypoxia, indicating that ET attenuates the initial vasoconstriction of hypoxia. However, ET had no effect on chronic hypoxic pulmonary hypertension: Pap and Pap/cardiac output in hypoxia were similar in HS vs HT. However, right ventricular weight was lower in HT than in HS, although Pap was not different. Because ET attenuates the initial pulmonary vasoconstriction of hypoxia, development of pulmonary hypertension may be delayed in HT rats, and the time during which right ventricular afterload is elevated may be shorter in this group. ET effects may improve the response to acute hypoxia by increasing efficacy of gas exchange and lowering right ventricular work.     

Diethylcarbamazine on pulmonary vascular response to endotoxin in awake sheep

Diethylcarbamazine (DEC) is an inhibitor of lipoxygenase, with protective effects in several experimental models of anaphylaxis and lung dysfunction. The hypothesis of this study was that DEC would alter the pulmonary response to endotoxin infusion, especially the prolonged pulmonary hypertension, leukopenia, hypoxemia, and high flow of protein-rich lung lymph. We prepared sheep for chronic measurements of hemodynamics and collection of lung lymph. In paired studies we gave six sheep endotoxin (0.5 micrograms/kg iv) either with or without DEC. DEC was given (80-100 mg/kg iv) over 30 min followed by a continuous infusion at 1 mg X kg-1 X min-1. Endotoxin was given after the loading infusion of DEC, and variables were monitored for 4 h. The response to endotoxin was characterized by pulmonary hypertension, leukopenia, hypoxemia, and elevations of thromboxane B2 and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha). Lymph flow and protein content reflected hemodynamic and permeability changes in the pulmonary circulation. DEC did not significantly modify the response to endotoxin by any measured variable, including pulmonary arterial and left atrial pressures, cardiac output, lymph flow and protein content, alveolar-to-arterial PO2 difference, blood leukocyte count, and lymph thromboxane B2 and 6-keto-PGF1 alpha. We could not find evidence of release of leukotriene C4/D4 by radioimmunoassay in lung lymph after endotoxin infusion with or without DEC treatment. We conclude that lipoxygenase products of arachidonic acid may not be a major component of the pulmonary vascular response to endotoxin.     

Leukotriene inhibitors do not block hypoxic pulmonary vasoconstriction in dogs

We studied whether intravenously administered inhibitors of leukotriene synthesis (diethylcarbamazine, DEC) or end-organ effect (FPL-55712) would change the distribution of regional pulmonary blood flow (rPBF) caused by left lower lobe (LLL) alveolar hypoxia in dogs. Both drugs failed to alter rPBF. In addition, the pressor response to whole-lung hypoxia was not blocked by an FPL-55712 infusion. On the other hand, nitroprusside, as a nonspecific vasodilator also administered intravenously, was able to partially reverse the effects of LLL hypoxia on rPBF. Thus our data do not support a role for leukotriene mediation of hypoxic pulmonary vasoconstriction in dogs.     

Effects of prostaglandins of the E-series on pulmonary and systemic circulations of newborn goats during normoxia and hypoxia.

Effects of exogenous prostaglandins of the E-series on pulmonary and systemic circulations of newborn goats were investigated during normoxia and hypoxia. Pulmonary arterial infusion of prostaglandins E1 and E2 decreased pulmonary vascular resistance 20% and 14%, respectively, without systemic effects. Prostaglandin E1 abolished the pulmonary pressor response to hypoxia. Prostaglandin E2 was less effective in counteracting this hypoxic response. The increased pulmonary vascular resistance and augmented response to hypoxia following indomethacin administration was reversed by prostaglandin E1. Infusion of prostaglandin E1 directly into the pulmonary circulation may be of benefit to the distressed newborn with elevated pulmonary vascular resistance.     

Thromboxane synthase inhibition and cardiopulmonary function during endotoxemia in sheep.

We studied the cardiopulmonary response to endotoxin (lipopolysaccharide, LPS) in sheep with and without the administration of a thromboxane synthase inhibitor, OKY-046. The animals were instrumented for crystalographic dimension analysis of the left ventricle (LV) and for measurement of LV, aortic, left atrial, and pulmonary arterial pressures and cardiac index, as well as lung lymph flow. They received 1.0 micrograms/kg of Escherichia coli LPS with (n = 8) and without (n = 8) OKY-046 (10 mg/kg bolus, then 10 micrograms.kg-1.min-1). OKY-046 prevented the increase of pulmonary arterial pressure and the decrease of cardiac index that occurred during the early phase of endotoxemia. Between 8 and 12 h after LPS, cardiac index increased from 6.8 +/- 0.7 to 8.9 +/- 0.51.min-1.m-2. Concomitantly, the end-systolic pressure-diameter relationship (ESPDR, sensitive myocardial contractility index) significantly decreased from 14.7 +/- 0.6 to 7.7 +/- 0.7. Other indexes of the LV contractility (+dP/dtmax) were also reduced. OKY-046 prevented the decreases of ESPDR and +dP/dtmax. OKY-046 also attenuated the increased lung lymph flow changes seen with LPS.