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Biomedical subjects

S Cassin

Publications and source records attributed to S Cassin.

At least 37 records · Page 2Linked to original sources
PubMed1990

The role of lung perfusate PO2 in the control of the pulmonary vascular resistance of exteriorized fetal lambs.

The isolated perfused lower left lung lobe of the exteriorized fetal lamb was used to define quantitatively the relationship between pulmonary perfusate oxygen tension and pulmonary vascular resistance (PVR) in the fetus at multiple oxygen tensions over the range from 8.3 to 433 mm Hg. This allowed variation of the perfusate PO2 over the range of partial pressures from less than 10 mm Hg to over 400 mm Hg while constant values of PCO2, temperature and perfusate flow were maintained. In all animals, calculated pulmonary vascular resistance varied in an inverse manner with the perfusate PO2. The relationship between PVR and perfusate oxygen tension is described by the equation: PVR = 7.67 - 1.54 (log PO2) R2 = 0.70. While others have shown that a single, large increase in blood oxygen tension will decrease the PVR in fetal lambs, these data present the first quantitative description of the role of oxygen tension in the modulation of fetal pulmonary vascular resistance as determined at multiple perfusate oxygen tensions over a fifty-fold range.

Animals↗
PubMed1990

Leukotrienes and prostaglandins in fetal lung liquid.

Several recent studies have suggested that peptidoleukotrienes are involved in or responsible for the pulmonary pressor response to hypoxia as well as the normally high pulmonary vascular resistance of fetal lambs. The present studies were carried out to test these hypotheses. Fetal lambs were prepared with indwelling vascular catheters and tracheal catheters for access to lung liquid. We measured lung liquid levels of leukotrienes C4 (LTC4) and D4 (LTD4) in control unanesthetized fetal lambs with blood gases and pH in the normal range. In the control series, LTC4 and LTD4 were either not detectable or their levels were close to the limit of resolution (LTC4, less than 80 pg/ml; LTD4, less than 50 pg/ml) of the techniques utilized. Leukotriene E4 was measured in a separate study by using pooled samples, and it was also found to be below the detection limit of that assay (10 pg/ml). In a second series of animals, a level of acute hypoxia was induced to decrease fetal arterial PO2 to 12 Torr for 20 min. After hypoxia, tracheal fluid levels of leukotrienes were again below detection limits of the assays used (LTC4, less than 80 pg/ml; LTD4, less than 142 pg/ml). In another study, methodology was altered to lower the detection limits of leukotrienes in lung fluid and to allow the measurement of total peptidoleukotriene concentrations. In this study, even when hypoxia was extended for up to 1 h, leukotriene levels were consistently below the limit of detection of the assay (less than 20 pg/ml for the sum of all leukotrienes).(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1989

The effects of arginine vasopressin and epinephrine on lung liquid production in fetal goats.

The effects of arginine vasopressin (AVP) and epinephrine on lung liquid secretion were investigated in 67 acute fetal goats (116 days of gestation to term) with intact umbilical cords after caesarean section. Secretion was measured by an impermeant tracer technique. AVP was infused intravenously (1.6-39.2 mU/(kg.min); 2 h) into 26 fetuses. All fetuses below 130 days of gestation, except one, showed no response. All above 133 days reduced secretion, or turned to reabsorption, except at the lowest infusion rate. The effect persisted, and usually increased postinfusion. Expansion of the lungs with saline did not change the response. The percentage reductions were linearly related to the logarithm of the infusion rate (threshold, 1.42 mU/(kg.min]. The absolute reductions were linearly related to fetal weight. Epinephrine was infused intravenously (0.30-6.72 micrograms/(kg.min); 1-2 h) into 12 fetuses. All fetuses (118 days to term) reduced secretion or reabsorbed by the second hour. At the highest infusion rate, reabsorption was immediate; at the lowest, secretion increased slightly, then fell significantly in the second hour. Epinephrine acted at levels considered physiological at delivery in the sheep. AVP appears to act at plasma levels found in most vaginal deliveries; it may augment epinephrine-induced reabsorption during stress, and help long-term removal of lung fluid.

Animals↗
PubMed1989

Do inhibitors of lipoxygenase and cyclooxygenase block neonatal hypoxic pulmonary vasoconstriction?

Lipoxygenase products have been suggested as mediators of the hypoxic pulmonary pressor response in newborn animals. Data supporting this suggestion are equivocal, since lipoxygenase and leukotriene receptor antagonists that have been used may produce vasodilation because of phosphodiesterase inhibition. We used a leukotriene receptor antagonist L 649923, which appears not to have smooth muscle relaxant activity. L 649923 blocks pressor responses to leukotriene D4 (LTD4) without diminishing the pressor response to hypoxia. Also, BW 755C did not block the pressor response to hypoxia in newborn sheep and goats, whereas the pressor response to LTD4 (75 ng/kg) was depressed significantly. In newborn sheep there was an augmented response to hypoxia with BW 755C, which is consistent with cyclooxygenase inhibition. Finally, the thromboxane receptor antagonist SQ 29548 was investigated in both species. With this agent the pressor response to LTD4 in contrast to that of hypoxia was completely inhibited. We conclude that thromboxanes are involved in the pressor response to LTD4 in newborn lambs and goats. These data do not support the view that leukotrienes are involved in the ovine or caprine neonatal pulmonary pressor response to hypoxia.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1989

Ethanol induces acute pulmonary vasoconstriction in salt-perfused rat lungs.

Ethanol is a pulmonary vasoconstrictor in rat lungs perfused in situ with Krebs-Henseleit salt solution. Pentobarbital-anesthetized rats were tracheotomized, and an in situ recirculating isolated lung perfusion was instituted using a Krebs-Henseleit buffer with 3% bovine albumin at 37 degrees C. Changes in pulmonary arterial pressure and tracheal inspiratory pressure during intravenous ethanol infusion at four different cumulative doses were measured in normoxic (n = 6) and hyperoxic (n = 6) lungs, compared to normoxic perfusate (no ethanol infusion) controls (n = 6). Perfusate alcohol levels progressively increased in experimental groups. Perfusate gas and pH values were normal and not altered by ethanol. PAP increased by the end of ethanol infusion from 9.7 +/- 2 to 26 +/- 13 mm Hg in the normoxic group and from 10.6 to 22 +/- 9 mm Hg in the hyperoxic lungs (p less than .02); no change occurred in control lungs. Severe pulmonary edema occurred in 83% of the ethanol exposed lungs (vs. 0% of perfusate controls). Postethanol wet/dry weight ratios were twice normal (p less than .02). Pulmonary arterial pressure rose in two stages. First there was a 25-100% increase before airway pressure increased, representing pulmonary vasoconstriction. This was followed by a precipitous 100-500% transmitted pressure rise as severe pulmonary edema developed. Thus, we conclude that the vasoconstrictor effect of ethanol on the pulmonary circulation occurs in rats as well as in lambs, dogs, and humans. In isolated perfused rat lungs, the response is locally mediated.

Animals↗
PubMed1988

Carboxy- and oxyhemoglobin in pregnant ewe and fetus after inhalation of marijuana, marijuana placebo and tobacco cigarette smoke.

We measured carboxyhemoglobin (HbCO) and oxyhemoglobin (HbO2) percent saturations and blood gases in four near-term pregnant ewes and their fetuses, during and for 6 hours after 9-12 minutes of smoke inhalation from one high-potency marijuana cigarette (M), a marijuana placebo cigarette (P), and a reference tobacco cigarette (T). Maternal HbCO reached maximum levels at or soon after the exposure (M, 2.8%; P, 3.5%; T, 6.3% above baseline) and fell to baseline values by 6 hours. Fetal HbCO rose slowly reaching a plateau at 3 hours (M, 0.7%; P, 1.1%; T, 2.0% above baseline) which was maintained for at least three additional hours. Reductions in maternal and fetal HbO2 after exposure to marijuana placebo and reference tobacco cigarettes reflected these rises in HbCO. After exposure to marijuana cigarettes, however, fetal HbO2 dropped precipitously by 17% of baseline and showed a prolonged rate of return to presmoking HbO2 levels. Although P exposure caused a greater change in HbCO in the fetus than did M, it had a less-profound effect on fetal oxygenation.

Animals↗
PubMed1988

Specificity of FPL 57231 for leukotriene D4 receptors in fetal pulmonary circulation.

The effects of leukotriene D4 and the putative leukotriene receptor antagonist FPL 57231 were studied on the pulmonary circulation of alpha-chloralose-anesthetized fetal lambs close to term. At constant pulmonary inflow leukotriene D4 (LTD4, 0.1-10 micrograms), as bolus injections, caused dose-dependent increases in pulmonary vascular resistance. FPL 57231 (1.0-10 mg/kg) not only blocked the pressor responses to LTD4 but also lowered the normal pulmonary vascular resistance in a dose-dependent fashion. However, FPL 57231 also decreased the pulmonary pressor response to U 46619, a thromboxane A2 mimic, as well as the pressor response to phenylephrine HCl. Furthermore, the pressor responses to LTD4 were markedly reduced by cyclooxygenase inhibition. In preliminary experiments we demonstrated that the phenidone derivative, BW755C, which is a dual inhibitor of both cyclooxygenase and 5-lipoxygenase enzymes, did not block the pressor response to hypoxia. We conclude that FPL 57231 decreases fetal pulmonary vascular resistance by nonspecific mechanisms. Also the action of LTD4, is indirect and by way of the cyclooxygenase system. Although exogenous leukotrienes are able to produce a marked pulmonary pressor response, endogenous leukotrienes are probably not responsible for the hypoxic pulmonary pressor response of the fetal lung or its normally high pulmonary vascular resistance.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

Pressor responses to arachidonic acid in pump-perfused sheep lungs.

The reported actions of arachidonic acid in the adult pulmonary circulation are controversial. Some authors reported that arachidonic acid causes only pulmonary vasoconstriction; others have found decreases in pulmonary vascular resistance with low-dose infusions. We have previously reported that arachidonic acid causes only pulmonary vasoconstriction in perinatal lambs during both normoxia and hypoxia. The effects of arachidonic acid on pulmonary vascular resistance were determined in adult sheep using an in situ pump-perfused left lower lung preparation. Arachidonic acid infusions (10.5-31.9 micrograms/kg . min) resulted in pulmonary vasoconstriction. The pulmonary vascular response to arachidonic acid was not altered by hypoxia or by infusion of PGF2 alpha. However, the pulmonary pressor response to hypoxia was increased by concomitant arachidonate infusions. Infusions of arachidonic acid during hypoxia resulted in systemic hypotension. Thus, pulmonary arachidonate metabolism appears to be unaffected by hypoxia or PGF2 alpha; however, hypoxia may enhance the formation of dilator PG's from the lung.

Animals↗
PubMed1986

Effects of prostaglandin H2 on perinatal pulmonary circulation.

A pivotal intermediate in prostaglandin (PG) biosynthesis is the endoperoxide PGH2. This endoperoxide is capable of eliciting direct responses in biological systems without undergoing conversion to other PGs. Effects of PGH2 include stimulation of platelet aggregation and vascular smooth muscle contraction in vitro; injections of PGH2 in vivo cause increases in pulmonary arterial pressure. The response of the pulmonary vasculature of perinatal lambs to PGH2 was measured using an in situ pump-perfused left lower lung preparation. Intrapulmonary injections of PGH2 (0.24-0.61 microgram/kg) into six unventilated fetal lambs (0.93-0.97 gestation) produced decreases in pulmonary vascular resistance (PVR) of 10-21%. The fall in PVR was rapid in onset, reached a peak at 10 s after injection, and returned to baseline within 35 s. Following ventilation (FIO2 = 0.21) of fetal lambs, injections of PGH2 (0.24-0.61 microgram/kg) caused increases in PVR (ave increase = 50% over control PVR). The pulmonary pressor response to PGH2 in ventilated fetal lambs was depressed almost 50% by inhibition of thromboxane synthetase. Injections of a "heat-inactivated" PGH2 did not affect PVR in ventilated fetuses. We did not observe any effects on systemic blood pressure or heart rate of intrapulmonary arterial injections of PGH2. These findings suggest a metabolism of PGH2 to dilator PGs before ventilation and constrictor PGs and thromboxanes after ventilation, and/or direct effects of PGH2 on vascular smooth muscle that are dependent on existing vascular tone.

Animals↗
PubMed1986

The effects of bumetanide and furosemide on lung liquid secretion in fetal sheep.

Thirty-four experiments were carried out on the effects of loop diuretics on lung liquid secretion in 20 fetal sheep (128-145 days gestation) with indwelling catheters. Bumetanide placed in the lung liquid at 2.19 +/- 0.52 X 10(-4) M produced immediate reabsorption of fluid, and effects lasted 3 hr (n = 6). Bumetanide at 1.1 +/- 0.17 X 10(-5) M reduced secretion significantly for 2 hr (n = 4), but at 1.07 +/- 0.06 X 10(-6) M there was no clear effect (n = 6). Controls showed no significant change (n = 6). Furosemide was less effective. At 3.1 +/- 0.07 X 10(-3) M it produced an immediate reabsorption, which lasted 3 hr, but at 1.0 +/- 0.04 X 10(-4) M it increased secretion slightly (n = 4); controls showed no significant change (n = 6). The results are consistent with the presence of a chloride transport system, perhaps with sodium cotransport, as the major factor in fetal lung liquid secretion.

Animals↗
PubMed1985

Asphyxia and hyaline membrane disease in neonatal monkeys.

An animal model for studying the relationship between perinatal asphyxia and hyaline membrane disease (HMD) is described. The HMD developed in these Macaca mulatta (rhesus) and M. arctoides (stump tail) monkeys was clinically, physiologically, and histologically similar to that seen in human infants. The monkeys were delivered by cesarean section at a gestational age of 85-91% of term when surfactant, though present, was less than mature levels. Asphyxia at birth proved to be an important factor in disease development. Five minutes of asphyxia immediately before the first breath greatly increased the incidence and severity of HMD when compared to nonasphyxiated controls of a similar gestational age. Amniotic fluid L/S ratios did not differ significantly in the asphyxiated and control groups but data based on static pressure-volume studies of the excised lungs indicated that the surfactant activity of the asphyxiated group was significantly less. Lung maturity with regard to surfactant production appears to be a critical factor. The data from these experiments, together with data cited in the literature, strongly suggest that the lung and its surfactant system is most vulnerable to hypoxia and/or acidosis during the early stages of surfactant production. The asphyxiated non-human primate model used here should prove valuable for studying the pathogenesis of HMD and especially for further clarifying the relationship between perinatal asphyxia and HMD.

Amniotic Fluid↗
PubMed1985

Thromboxane synthase inhibition and perinatal pulmonary response to arachidonic acid.

Arachidonic acid causes dose-dependent increases in pulmonary vascular resistance in perinatal lambs. The specific metabolites that produce this effect are not known; however, a role for thromboxanes (TX's), potent constrictors of vascular smooth muscle, has been proposed. The effects of a specific inhibitor of TX synthase, OKY-1581, were tested in newborn and ventilated fetal lambs using an in situ pump-perfused lower left lobe preparation. Pulmonary and systemic responses of newborns and ventilated fetuses to infusions of arachidonic acid were evaluated in the presence and absence of OKY-1581. Increases in pulmonary vascular resistance caused by arachidonic acid were diminished by TX synthase inhibition. The degree of systemic hypotension observed with arachidonic acid infusions was significantly greater in animals receiving OKY-1581 than in animals without the inhibitor. The effect of OKY-1581 on periods of hypoxia was also evaluated in newborn lambs. There were no significant differences in the hypoxic pressor response in lambs with and without TX synthase inhibition. These results suggest that OKY-1581 can reduce most of the pulmonary vasoconstriction produced by arachidonic acid in perinatal lambs.

Acrylates↗
PubMed1985

Hemodynamic effects of postpulmonary administration of prostaglandin D2 in fetal animals.

Dose-response relationships in pulmonary vascular resistance (PVR), mean systemic arterial pressure (SAP), and heart rate (HR) to left atrial administration of prostaglandin D2 (PGD2) were determined in five fetal lambs. Fetuses were delivered by cesarean section from chloralose anesthetized ewes with the umbilical circulation maintained intact. Fetuses were prevented from breathing thus maintaining pulmonary vascular tone in the elevated fetal state. Blood was withdrawn from the inferior vena cava and pumped at constant flow into the lower left lobe of the fetal lung. Postpulmonary infusions of PGD2 brought about dose-dependent decreases in pulmonary vascular resistance. Heart rate tended to increase in fetal lambs. Mean systemic arterial pressure increased in the fetal lambs at all doses tested except for the largest dose (44.14 micrograms/kg X min), which produced slight hypotension. These data demonstrate that exposure to the systemic circulation prior to entering the pulmonary vasculature does not alter the preferential dilator action of PGD2 on fetal pulmonary vessels nor does it produce significant systemic hypotension.

Animals↗
PubMed1985

The rate of production of lung liquid in fetal goats, and the effect of expansion of the lungs.

Fetal goats (95-155 days of gestation), delivered by Caesarian section, under chloralose (50 mg/kg), with intact umbilical cords, were monitored for lung fluid production by an impermeant tracer method. The average rate of production was 13.4 +/- 2.3 ml/h, or 6.0 +/- 0.9 ml/h per kg. Production rose exponentially towards birth, by both parameters, significant P less than 0.0001 (ml/h), or P less than 0.0005 (ml/h per kg). This indicated an increase in lung liquid production due to both growth and increased activity of the tissues. However, considerable individual variability, even between twins, suggested that this general pattern was modulated by physiological requirements. In 14 fetuses (plus 12 controls), expansion of the lungs with volumes of saline similar to those of the first inspirations (saline, 15-40 ml, matched to the optical density of the lung fluid; inspiration by spirometer, 20-25 ml), caused reduction of secretion or reabsorption of fluid. Secretion changed to reabsorption at about 50% expansion, and the probable physiological limit was estimated at 62-68% expansion. The logarithm of the % fall in production was linearly related to the % expansion (r = 0.88; P less than 0.0001); therefore, small expansions (equivalent to intrauterine breathing) would have little effect, but larger changes such as first breaths, would produce rapidly escalating effects. Controls showed no similar activity. Changes in Na+ and Cl- ions are in parallel to those of water. However, K+ ions moved into the lungs after expansion, in the opposite direction to Na+ ions, and against their concentration gradient. It is suggested that expansion of the lungs activates a Na+/K+ ATP-ase pump to aid reabsorption of salt and water at birth.

Animals↗
PubMed1984

Arachidonic acid metabolism by neonatal lungs perfused with Krebs bicarbonate buffer.

We characterized and quantified products of exogenous arachidonic acid metabolism by neonatal lamb lungs perfused with Krebs solution and determined effects of alveolar hypoxia upon this metabolism. The predominant metabolite was PGI2 (62.4 +/- 5.8 (SEM)% of the total prostanoids (PGs) produced). An additional 23.1 +/- 6.7% was metabolized PGI2. PGE2 (1.7 +/- 3.0%) was produced also. Little thromboxane B2 (TXB2) (3.3 +/- 1.7%) was synthesized by these platelet-free lungs. Although the pulmonary vasoconstrictor response to arachidonic acid infusion reached a plateau in 71 +/- 19 seconds, the PG efflux was greater 8-15 minutes after beginning arachidonic acid infusion (3066 +/- 1353 ng/min) than 1-8 minutes into the infusion (899 +/- 343 ng/min). Reduction of FIO2 from 20% to 3% O2 which produces vasoconstriction in the absence of exogenous arachidonic acid, did not alter the PG profile nor quantity produced. With respect to the neonatal lamb pulmonary vasculature perfused with Krebs solution, we conclude: 1) exogenous arachidonic acid ultimately is metabolized predominantly to PGI2, 2) arachidonic acid-induced pulmonary vasoconstriction is not caused by TXA2, 3) short term hypoxia does not alter the conversion of excess arachidonic acid to PGs, and 4) a lag between intrapulmonary PG synthesis and pulmonary venous efflux may occur.

Animals↗
PubMed1984

Effect of indomethacin on fetal lung liquid formation.

Experiments were performed on seven anesthetized fetal sheep to evaluate involvement of metabolites of the cyclooxygenase system in lung liquid production. Rates of lung liquid production were determined by dye dilution technique using blue dextran. The control rate of formation of lung liquid in these preparations was 4.6 +/- 0.55 mL X kg-1 X h-1. Administration of indomethacin (1.85 mg/kg) intraarterially to fetuses resulted in a 60% decrease in the rate of formation of lung liquid. The present studies suggest an involvement of products of the cyclooxygenase system in controlling the rate of secretion of lung liquid in fetal animals.

Animals↗
PubMed1984

Perinatal pulmonary responses to arachidonic acid during normoxia and hypoxia.

Dilator prostaglandins are released from the perinatal lung in response to ventilation and also may be involved in the pressor response to hypoxia. However, arachidonic acid, precursor of bisenoic prostaglandins, causes pulmonary vasoconstriction when infused into the pulmonary circulation of perinatal goats. The effects of hypoxia on the arachidonic acid-induced increase in pulmonary vascular resistance (PVR) were evaluated in ventilated fetal and neonatal lambs using an in situ pump-perfused lower left lobe preparation. These studies indicate that pulmonary vascular effects in newborns due to arachidonic acid are not altered by hypoxia. In contrast, ventilated fetuses show a greater response to arachidonic acid infused during hypoxia than during normoxia. However, this increase in PVR is merely additive to the hypoxic pressor response; thus, hypoxia does not appear to affect the actions of exogenous arachidonic acid in the perinatal pulmonary circulation. The decrease in systemic arterial pressure seen with arachidonic acid infusion is greater at the termination of the combined infusion and hypoxia than after infusion alone. This systemic hypotension is also of longer duration and may indicate a greater release of dilator prostaglandins from the lung following hypoxia and arachidonic acid.

Animals↗