Cromolyn sodium decreases the pulmonary vascular response to alveolar hypoxia in lambs

We investigated the effect of cromolyn sodium, a mast cell stabilizing agent, on the pulmonary vascular response to alveolar hypoxia in six chronically instrumented lambs aged 9 to 11 days. Each lamb was instrumented on day 6 or 7 for measurements of systemic arterial, pulmonary arterial and left atrial pressures, and pulmonary blood flow. The animals were allowed to recover from surgery at least 3 days before they were studied. Each animal was studied twice, once with a cromolyn sodium infusion and once with a normal saline infusion (placebo). These paired experiments were separated by 24 h. Physiologic measurements were made during a 1-min predose control period, after an 8-min drug or placebo infusion, and after a 15-min period of alveolar hypoxia. Cromolyn sodium infusion alone did not affect baseline cardiovascular variables. Alveolar hypoxia following placebo infusion produced an increase in pulmonary arterial pressure and pulmonary vascular resistance; these responses were blocked in the animals given cromolyn sodium prior to induction of hypoxia. These results show that cromolyn sodium blocks the pulmonary vascular response to hypoxia and provide indirect evidence that mast cell degranulation, with subsequent release of vasoactive agents, mediates the pulmonary vascular response to hypoxia in newborn lambs.     

Pulmonary vascular response to digoxin in newborn lambs

The effects of digoxin on pulmonary vascular resistance (PVR) were evaluated in normoxic (N) and hypoxic (H) newborn lambs with normal and elevated PVR, respectively. Lambs were anesthetized and instrumented to enable continuous measurement of mean pulmonary arterial pressure (PPA), mean left atrial pressure (PLA), mean pulmonary blood flow (Qp), and mean aortic pressure (PAO). Digoxin (10-20 micrograms/kg) was injected via central venous catheters in 11 N lambs and 4 H lambs. Under N conditions, baseline PVR was equal to 0.12 mm Hg/ml/min/kg, PPA was 33 mm Hg, PLA was 6 mm Hg, Qp was 235 ml/min/kg, and PAO was 69 mm Hg. Following digoxin, mean PVR increased by 24% (P less than 0.001) and PPA increased by 23% (P less than 0.001) for an average duration of 199 sec while QP increased by 5% (P less than 0.02) and PLA was constant suggesting a direct vasoconstrictive effect. Under H conditions, baseline PVR was equal to 0.26 mm Hg/ml/min/kg, PPA was 58 mm Hg, PLA was 4 mm Hg, Qp was 208 ml/min/kg, and PAo was 65 mm Hg. Following digoxin, mean PVR, Qp, PLA, and PAo did not change appreciably although PPA had a uniform increase of 5% (P less than 0.001). The blunted response may suggest that either the pulmonary vascular bed was maximally constricted or that digoxin and hypoxia share a common mechanism. In conclusion, digoxin has a direct pulmonary vasoconstrictor action in newborn lambs. Because of its short duration, this action probably should not alter the clinical use of this drug in newborn humans.     

Effect of dopamine infusion on pulmonary gas exchange in lambs

We studied the effects of dopamine HCl, a potent vasoactive catecholamine, on ventilation-perfusion matching and pulmonary hemodynamics in infant lambs breathing room air and a hypoxic gas mixture. Neither alveolar hypoxia alone, nor dopamine infusion alone during room air breathing, significantly altered the ventilation-perfusion (VA/Q) distribution or intrapulmonary shunt size. Dopamine infusion during room air breathing did increase pulmonary blood flow (PBF; p less than 0.05). Dopamine infusion plus alveolar hypoxia was associated with a significant increase in minute ventilation, PBF, and pulmonary arterial pressure (Ppa), a doubling (p less than 0.01) of the fraction of PBF to low VA/Q lung regions, and a significant increase (p less than 0.05) in intrapulmonary shunt when compared to results obtained during hypoxic gas breathing without dopamine infusion. We conclude the dopamine infusion increased PBF during room air breathing, and perturbed ventilation-perfusion matching and increased Ppa and minute ventilation with no net change in arterial pO2 during the breathing of a hypoxic gas mixture.     

Inotropic response of the neonatal canine myocardium to dopamine

The inotropic responsiveness of the developing myocardium to dopamine and isoproterenol was evaluated using isolated, perfused ventricles and atrial strips from puppies ages 15 hr to 33 days. Responses were compared to those in adult animals. The maximum percentage of increase of left ventricular dF/dt increased from 12 +/- 5 (mean +/- SEM) at 0-7 days (n = 6) to 100 +/- 40 at 21-33 days (n = 3) of postnatal age. At 7-14 days (n = 4) and 15-20 days (n = 5) of age the maximum percentage of increase of left ventricular dF/dt was 28 +/- 10 and 39 +/- 17, respectively. Puppy ventricle responded to isoproterenol at all ages equally (maximum percentage increase of left ventricular dF/dt = 46 +/- 13). Atrial muscle strips from puppies, ages 15 hr to 35 days (n = 22), and adult dogs (n = 19) demonstrated equal responsiveness to dopamine as well as to isoproterenol. The maximum percentage of increase of dF/dt was 117 +/- 18 with dopamine. Maximum percentage of increase of dF/dt with dopamine after propranolol (10(-7) M) was 52 +/- 18. Haloperidol (1.10(-7)-2.10(-6) M) did not alter responsiveness of atria to dopamine.     

Alkalosis attenuates hypoxic pulmonary vasoconstriction in neonatal lambs

Hyperventilation (respiratory alkalosis) is an important treatment for persistent pulmonary hypertension in neonates. The precise way that hyperventilation attenuates hypoxic pulmonary vasoconstriction is unclear. We studied the effect of alkalosis on hypoxia-induced pulmonary vasoconstriction in 13 acutely instrumented, pentobarbital anesthetized, neonatal lambs. We specifically examined the relative effects of a metabolic alkalosis versus a respiratory alkalosis on hypoxic pulmonary vasoconstriction and compared these results to the control response to hypoxia without alkalosis. Hypoxic pulmonary vasoconstriction was significantly milder whenever the animal was alkalotic, regardless of whether the alkalosis was respiratory of metabolic. Thus, the elevated pHa rather than decreased PaCO2 during hyperventilation appears to be the major factor in moderating the response of the pulmonary vessels to acute hypoxia in this neonatal lamb model.     

Pulmonary and systemic vascular response to promethazine in conscious lambs

Summary Promethazine is an antihistamine commonly used for sedation in clinical pediatric medicine. We studied the cardiovascular effects of promethazine in normoxic, conscious, chronically instrumented neonatal lambs. Eight lambs received 1.3 mg/kg of promethazine intravenously (i.v.) while at rest. In all lambs, promethazine led to elevations of pulmonary vascular resistance, mean pulmonary arterial pressure, mean transpulmonary pressure, mean left atrial pressure, and the ratio of pulmonary-to-systemic vascular resistance. In addition, five (63%) of the lambs demonstrated an increase in mean systemic arterial pressure and systemic vascular resistance to promethazine. A subgroup of three lambs, which tended to be younger, failed to demonstrate the systemic vascular response to promethazine. Promethazine given i.v. has important cardiovascular effects. We hypothesize that promethazine used for sedation before cardiac catheterization in children may alter subsequent hemodynamic observations.Dr. Gimotty is now located at Michigan Cancer Foundation, 110 East Warren Avenue, Detroit, Michigan, USA.This research was performed at the University of Florida.A portion of this research was presented at the Southern Society for Pediatric Research in New Orleans, Louisiana, USA, January 1981.     

Effect of continuous tolazoline infusion on cardiopulmonary response to dopamine in unanesthetized newborn lambs

We evaluated the cardiopulmonary interaction of tolazoline and low-, medium-, and high-dose dopamine infusion (2.7, 27, and 270 micrograms/kg/min) in 11 normal, chronically instrumented, unsedated neonatal lambs. Concomitant tolazoline and dopamine infusions caused tachycardia at all dopamine doses and blocked alpha-adrenergic-mediated increases in systemic resistance and left atrial pressure caused by medium and high doses of dopamine. Moderate doses of dopamine alone increased cardiac output. During simultaneous tolazoline infusion, dopamine increased cardiac output at both moderate and high doses. The effect of dopamine on pulmonary artery pressure was not modified by tolazoline; pulmonary pressure increased similarly with dopamine alone and with dopamine plus tolazoline. Calculated pulmonary vascular resistance rose with dopamine alone, but not with infusion of tolazoline and dopamine, because pulmonary blood flow rose in proportion to pulmonary artery pressure.     

Air trapping causes a Ca2(+)-channel-mediated increase in pulmonary vascular resistance in neonatal lambs.

Air trapping and alveolar hyperinflation may occur during mechanical ventilation in the presence of severe airway obstruction, during fast ventilator rates, and when expiratory time is compromised. Inadvertent positive end-expiratory pressure may occur with air trapping and increased mean airway pressure. The pulmonary artery pressure response to air trapping, produced during volume-regulated time-cycled ventilation, was studied in neonatal lamb lungs, isolated in situ, and perfused at a constant flow rate (50-75 ml.kg-1.min-1), both before and after Ca2(+)-channel blockade with verapamil (5 mg). The hub of the endotracheal tube was narrowed to a 1.5-mm orifice to produce fixed proximal airway obstruction. Air trapping was then produced by lengthening inspiratory time from 25 to 80%, at zero end-expiratory pressure. The magnitude of inadvertent positive end-expiratory pressure due to air trapping was estimated by end-expiratory occlusion pressure. End-expiratory occlusion pressure was 0.20 +/- 0.03 kPa (1.7 +/- 0.2 mm Hg) and 1.60 +/- 0.01 kPa (11.8 +/- 1.0 mm Hg), at 25 and 80% inspiratory times, respectively. On lengthening inspiratory time, mean pulmonary artery pressure (mPpa) increased briskly within 30 s followed by a gradual increase over the next 4 min. Verapamil blunted both the brisk and the gradual increase in mPpa on lengthening inspiratory time. Lengthening inspiratory time increased the mPpa by 2.0 +/- 0.1 kPa (14.7 +/- 0.8 mm Hg) from baseline, and verapamil reduced this increase to 1.3 +/- 0.1 kPa (10.1 +/- 0.6 mm Hg; p less than 0.05 by analysis of variance).(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of granulocytes in the pulmonary response to group B streptococcal toxin in young lambs

Marked leukopenia and sequestration of granulocytes in the lung are consistently seen in severe early onset group B streptococcal (GBS) disease in human infants. To investigate the role of granulocytes as potential mediators in the pulmonary pathophysiology of this disease, the effects of intravenously administered GBS type III toxin were studied in young lambs before and after granulocyte depletion with hydroxyurea. Granulocyte depletion markedly reduced the 4-fold increase in total lung resistance and the decrease in dynamic compliance observed after GBS toxin. Granulocyte depletion significantly attenuated the pulmonary hypertension, hypoxemia and increased minute ventilation present during the first phase of the response (0.5-1 h after GBS toxin). It did not significantly alter the increase in body temperature, the marked increase in lung lymph thromboxane B2 concentrations during the first phase or the increase in lung lymph flow and protein clearance during the second phase of the response (3.5-5 h after GBS toxin). The results indicate that granulocytes are involved as mediators of the changes in lung mechanics seen after GBS toxin infusion in young lambs. Granulocytes contribute to the pulmonary hypertension and decrease in arterial oxygenation, but other mediators appear to be responsible for the injury of the vascular endothelium.     

Endothelin B receptor blockade attenuates pulmonary vasodilation in oxygen-ventilated fetal lambs

BACKGROUND: Endothelin-1 (ET-1) contributes to the regulation of pulmonary vascular tone in the normal ovine fetus and in models of perinatal pulmonary hypertension. In the fetal lamb lung, the effects of ET-1 depend on the balance of at least two endothelin receptor subtypes: ETA and ETB. ETA receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation. Stimulation of endothelial ETB receptors causes vasodilation through release of nitric oxide and also functions to remove ET-1 from the circulation. However, whether activation of ETB receptors contributes to the fall in pulmonary vascular tone at birth is unknown. OBJECTIVE AND METHODS: To determine the role of acute ETB receptor blockade in pulmonary vasodilation in response to birth-related stimuli, we studied the hemodynamic effects of selective ETB receptor blockade with BQ-788 during mechanical ventilation with low (<10%) and high FiO2 (100%) in near-term fetal sheep. RESULTS: Intrapulmonary infusion of BQ-788 did not change left pulmonary artery (LPA) blood flow and pulmonary vascular resistance (PVR) at baseline. In comparison with controls, BQ-788 treatment attenuated the rise in LPA flow with low and high FiO2 ventilation (p <0.001 vs. control for each FiO2 concentration). PVR progressively decreased during mechanical ventilation with low and high FiO2 in both groups, but PVR remained higher after BQ-788 treatment throughout the study period (p <0.001). CONCLUSIONS: We conclude that selective ETB receptor blockade attenuates pulmonary vasodilation at birth. We speculate that ETB receptor stimulation contributes to pulmonary vasodilation at birth in the ovine fetus.     

Influence of increased pulmonary vascular pressures on the closure of the ductus arteriosus in newborn lambs

Neonatal conditions associated with increased pulmonary artery pressure have an increased incidence of patent ductus arteriosus. We operated on 15 near term fetal lambs and placed mechanical occluders into or around both branch pulmonary arteries so that main pulmonary artery blood pressure could be controlled. The lambs were delivered and ventilated for 4 h. In seven lambs, the branch vessels were obstructed so that pulmonary artery pressure increased to equal aortic pressure; in eight lambs (control), the branch vessels were not obstructed. There were no significant differences between the two groups in circulating prostaglandin E2 or 6 keto F1 alpha concentrations, PaO2, pH, or PaCO2. Despite these similarities, ductus resistance in the lambs with elevated pulmonary pressure was significantly less than that in the control lambs. After the 4 h measurements, we studied the ductus in vitro. We have previously found that ductus arteriosus constriction produces ischemia of its muscle wall that limits its ability to dilate or constrict any further. Ductus from lambs with elevated pulmonary pressure had a significantly increased ability to respond to oxygen, prostaglandin E2, and indomethacin compared with ductus from control lambs; these findings are consistent with less ductus constriction in vivo. Thus, the high incidence of patent ductus arteriosus in neonates with elevated pulmonary vascular resistance may be due in part to the increased pulmonary vascular pressure, which opposes ductus constriction and preserves ductus responsiveness. Conversely, the normal drop in pulmonary pressure that occurs in full term infants may facilitate the closure of the ductus after delivery.     

The effect of increased pulmonary blood flow on the pulmonary vascular bed in pigs.

Increased pulmonary blood flow was produced in 1-month-old piglets by means of left pneumonectomy, arteriovenous fistulas in the neck, and a combination of both. Physiologic and histologic studies of the pulmonary vascular bed were done 1-9 months after operation. A progressive, moderate increase in pulmonary artery (PA) pressure was observed, especially between 1 and 6 months after surgery. This was flow related, i.e., the group with the highest flow (pneumonectomy plus fistula) was found to have the most prominent increase in pressure. Mean Pa pressure at 6 months was 28.7 +/- 0.07 mm Hg in this group, vs 24.4 +/- 0.48 mm Hg in the group with pneumonectomy alone and 17.2 +/- 0.48 mm Hg in controls (P less than 0.01). The pressure response to hypoxia in pigs with high pulmonary blood flow was not different from that found in control animals. Histologic studies revealed that small arteries and arterioles of pigs with high pulmonary blood flow had a decreased relative wall thickness because of dilation up to 6 months follow-up. This was flow related, the group with the highest flow having the lowest wall thickness to vessel diameter ratio; relative wall thickness (in percentage of the vessel diameter ) at 6 months was 6.1 +/- 0.44% in pigs with with pneumonectomy plus fistula, vs 9.6 +/- 0.40% in the group with pneumonectomy alone and 11.2 +/- 0.61% in controls (P less than 0.01). In the group with the highest flow, thick walled arterioles appeared at 9 months follow-up, scattered among dilated ones; between 6 and 9 months after operation, ranging from 6.1 +/- 0.44% to 11.3 +/- 0.73% (P less than 0.01). In five animals with high flow, the right PA (main branch) showed patchy intimal thickening, small cystic spaces filled with mucopolysaccharides in the media, and muscular hypertrophy.     

Effect of beta-adrenergic receptor blockade on responses to acute hypoxemia in lambs

We studied the effects of beta-adrenergic receptor blockade on general circulatory and metabolic responses to moderate (FIO2 = 0.09) acute hypoxemia in newborn (protocol 1) and 3-wk-old (protocol 2) lambs, and on regional blood flow distribution in newborn lambs (protocol 1). Via a left thoracotomy we placed an electromagnetic flow transducer around the ascending aorta and inserted various vascular catheters. After 2 days of recovery, the lambs were studied. In protocol 1, we measured cardiovascular variables and regional blood flow distribution during control conditions, after 45 min of acute hypoxemia, and after 0.5 mg/kg of propranolol during acute hypoxemia. In protocol 2, we measured cardiovascular variables during control conditions and after 45 min of acute hypoxemia with and without propranolol pretreatment. In both groups, propranolol limited the increase in cardiac output and heart rate caused by hypoxemia, and thus decreased oxygen delivery. However, propranolol also decreased oxygen consumption so that pulmonary arterial pO2 was either higher (protocol 1) or the same (protocol 2) as during acute hypoxemia alone. Neither metabolic acidosis nor hypothermia ensued. In protocol 1, propranolol decreased renal, carcass, and most importantly, myocardial blood flows. However, myocardial O2 consumption also fell, coronary sinus pO2 increased, and blood was redistributed toward the subendocardium, suggesting that myocardial perfusion improved. Thus, beta-adrenergic receptor blockade during acute moderate hypoxemia may have a beneficial effect by reducing total body and myocardial oxygen demand in excess of the reduction in oxygen delivery.     

Thromboxane is not responsible for the high pulmonary vascular resistance in fetal lambs

The factors responsible for the high pulmonary vascular resistance in the fetus are not well known. Thromboxane (TX) A2 is a potent pulmonary vasoconstrictor. To determine whether TXA2 may play a role in fetal pulmonary vasoconstriction, we infused the specific TX synthetase inhibitor U63,557A into eight chronically instrumented fetal lambs (134-137 days gestational age, full term 145 days) and measured pulmonary blood flow, pulmonary and systemic arterial pressure, and heart rate. U63,557A (3 mg/kg as a bolus then 3 micrograms/kg/min for 120 min infused in the main pulmonary artery) did not change pulmonary blood flow, pulmonary mean arterial pressure, and pulmonary vascular resistance during the infusion and during 2 h following the end of the infusion. During the infusion, TXB2 arterial plasma concentrations decreased from 106.1 +/- 17.5 to 8.7 +/- 2.9 pg/ml. In three of the fetal lambs, immediately after the 2-h infusion of U63,557A, we infused the leukotriene end-organ antagonist FPL 57231 into the main pulmonary artery (1 mg/kg/min for 60 min). TXA2 synthesis inhibition did not prevent the pulmonary vasodilation induced by FPL 57231. Pulmonary blood flow increased from 64.8 +/- 24.4 to 669.5 +/- 65.6 ml/min/100 g lung tissue during the FPL 57231 infusion. We conclude that TXA2 does not play a role in the maintenance of elevated fetal pulmonary vascular tone, either directly or as a mediator of leukotriene action.     

A sedative effect of dopamine on the respiratory burst in neonatal polymorphonuclear leukocytes

Studies were performed to examine the effect of dopamine on the functions of neonatal polymorphonuclear leukocytes (PMN). Cord blood PMN were treated with dopamine and assayed for their superoxide anion production by the ferricytochrome C reduction method and for their myeloperoxidase-hypochlorous system ability by the luminol-dependent chemiluminescence using a synthetic chemotactic factor, N-formyl-methionyl-leucyl-phenylalanine, as a stimulus. Dopamine inhibited N-formyl-methionyl-leucyl-phenylalanine-induced O2- production by neonatal PMN: when PMN were treated with 10(-5) M and 10(-4) M dopamine, the percentage inhibition values were 51 and 71%, respectively. Dopamine also inhibited the luminol-dependent chemiluminescence. PMN mobility and bactericidal ability were not affected by dopamine. Therapeutic dopamine plasma levels (873.5 +/- 174.0 ng/mL, n = 13, mean +/- SEM) observed in sick infants corresponded with the in vitro dopamine concentrations to inhibit the respiratory burst. Dopamine may be one of the drugs useful for reducing the oxygen-induced tissue damage associated with PMN in neonatal intensive care patients.     

血管内皮生长因子A对缺氧性肺动脉高压新生大鼠肺血管重塑的影响及其机制研究

目的 探讨血管内皮生长因子A（VEGF-A）调控生存素（SVV）在缺氧性肺动脉高压（HPH）新生大鼠肺血管重塑中的作用。方法 96只新生大鼠随机分为HPH+VEGF-A组、HPH组和对照组,每组再随机分为3 d、7 d、10 d和14 d亚组,每个亚组8只大鼠。HPH+VEGF-A组和HPH组分别经气管内转染携带/不携带VEGF-A的腺病毒载体后建立HPH模型,对照组气管内注射0.9% NaCl溶液后常氧下饲养。直接测压法测定新生大鼠平均右心室收缩压（RVSP）;苏木精-伊红染色后光镜下观察肺血管形态学变化,计算肺小动脉中层血管壁厚度占肺小动脉外径的百分比（MT%）和肺小动脉中层横截面积占总横截面积的百分比（MA%）;免疫组化法检测肺组织中VEGF-A和SVV的表达水平。结果 HPH组新生大鼠平均RVSP高于同时间点对照组和HPH+VEGF-A组（P < 0.05）。缺氧7 d,HPH组出现肺血管重塑,HPH+VEGF-A组自缺氧10 d开始出现。缺氧7 d时,HPH组MT%和MA%高于对照组和HPH+VEGF-A组（P < 0.05）;缺氧10 d和14 d时,HPH组及HPH+VEGF-A组MT%和MA%均高于对照组（P < 0.05）。缺氧各时间点HPH组和HPH+VEGF-A组VEGF-A表达均高于对照组（P < 0.05）;缺氧3 d和7 d时,HPH+VEGF-A组VEGF-A表达高于HPH组（P < 0.05）。缺氧14 d时,HPH组SVV表达高于对照组（P < 0.05）;缺氧各时间点HPH+VEGF-A组SVV表达均高于对照组（P < 0.05）;缺氧3 d和7 d时,HPH+VEGF-A组SVV表达高于HPH组（P < 0.05）。结论 预防性外源性气管内给予HPH新生大鼠VEGF-A,可在缺氧早期通过上调SVV表达抑制肺血管重塑,降低肺动脉压力,为新生儿HPH肺血管重塑干预治疗提供了依据。     

The effects of dopamine infusion on regional blood flow in newborn lambs

The purpose of this project was to investigate the effects of high rates of dopamine infusion on cardiac output and regional blood flow in the lamb. We studied eight unanesthetized newborn lambs (mean age 7 +/- 2 days) during a 15-min baseline period and while infusing dopamine at 5-, 20-, 80-, and 160 micrograms/kg/min. We measured cardiac output and mean aortic, pulmonary arterial and left atrial pressures, and organ blood flow using radionuclide-labeled microspheres at each rate of dopamine infusion. Cardiac output increased significantly with increasing rates of infusion up to 80 micrograms/kg/min but decreased at 160 micrograms/kg/min. Aortic, pulmonary arterial, and left atrial pressures increased at rates of infusion above 5 micrograms/kg/min. Blood flow to all organs was unchanged at the 5 micrograms/kg/min rate of infusion of dopamine while blood flow to the brain and heart increased at the 80 micrograms/kg/min rate of infusion and blood flow to the gut and kidney decreased. We conclude that dopamine is an effective inotropic agent in the newborn lamb but that an inotropic:afterload mismatch exists at high infusion rates. Despite an increase in cardiac output at low rates of infusion, dopamine did not selectively vasodilate the vascular bed of any organs tested. Furthermore, at high rates of infusion dopamine actually impaired blood flow to the gut and kidney.