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Biomedical subjects

R I Clyman

Publications and source records attributed to R I Clyman.

At least 55 records · Page 3Linked to original sources
PubMed1989

Bradykinin produces pulmonary vasodilation in fetal lambs: role of prostaglandin production.

Bradykinin produces pulmonary vasodilation and also stimulates production of other pulmonary vasodilators, including prostaglandin I2 (PGI2) and endothelial-derived relaxing factor. In 12 chronically instrumented fetal lambs, we therefore investigated potential mediation of the bradykinin response by PGI2 or other cyclooxygenase products. A 15-min infusion of bradykinin (approximately 1 microgram/kg estimated fetal wt/min) increased fetal pulmonary blood flow by 522% (P less than 0.05) and decreased pulmonary vascular resistance by 86% (P less than 0.05); plasma 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) concentration also increased (P less than 0.05). After cyclooxygenase inhibition by indomethacin (3 mg), bradykinin increased pulmonary blood flow by only 350% (P less than 0.05) and decreased pulmonary vascular resistance by 83% (P less than 0.05); plasma 6-keto-PGF1 alpha concentrations did not increase. The increase in pulmonary blood flow produced by bradykinin was greater before administration of indomethacin than after (P less than 0.05). These studies demonstrate that bradykinin produces fetal pulmonary vasodilation by at least two mechanisms, one dependent on and the other independent of PGI2 production, the latter mechanism predominating.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Reactive oxygen metabolites relax the lamb ductus arteriosus by stimulating prostaglandin production.

To determine whether oxygen metabolites can cause ductus relaxation, we used rings of fetal ductus obtained from 36 near-term lambs and measured the effects of the oxygen metabolites generated by the combination of hypoxanthine and xanthine oxidase. The oxygen metabolites produced by hypoxanthine plus xanthine oxidase caused relaxation of the ductus that was inhibited by catalase (hydrogen peroxide scavenger) but not by superoxide dismutase (superoxide anion scavenger). In addition, hypoxanthine plus xanthine oxidase produced a 14-fold increase in prostaglandin (PG) E2 production with only twofold increase in 6-keto-PGF1 alpha (the stable metabolite of PGI2). PGE2 is the most potent relaxant of the ductus arteriosus. The presence of either catalase or indomethacin blocked both the increase in prostaglandin production and the relaxation. We conclude that reactive oxygen metabolites relax the ductus arteriosus and oppose the normal constriction that occurs after birth. However, the vasoactive effects of reactive oxygen metabolites in the ductus appear to be mediated exclusively through the generation of PGE2.

Animals↗
PubMed1989

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.

Animals↗
PubMed1989

Effect of patent ductus arteriosus on water accumulation and protein permeability in the lungs of mechanically ventilated premature lambs.

To examine the effect of a patent ductus arteriosus on water accumulation and protein permeability in the premature, ventilated lung, we studied 16 lambs at 121-127 d gestation (term = 145 d). Water accumulation was assessed by the wet:dry wt ratio of the blood-free left lung. Protein permeability was assessed by the albumin content and by the recovery of 125I-albumin in the right lung lavage fluid 1 h after intravenous injection. Using a model that allows mechanical control of ductus patency, we compared nine lambs with patent ductus (left-to-right shunts 42 +/- 18% to left ventricular output) with seven lambs with closed ductus. The animals were studied over 3 h. In the open ductus lambs, 0.85 +/- 0.36 and 1.76 +/- 1.87%/h of the injected 125I-albumin was recovered in the lavage fluid and lung tissue, respectively. In the closed ductus lambs, the corresponding amounts were 0.71 +/- 0.21 and 0.71 +/- 0.22%/h; these differences were not statistically significant. Similarly, blood-free wet:dry ratios did not differ significantly between the two groups (7.01 +/- 1.28 open ductus versus 6.55 +/- 0.82 closed ductus). We concluded that patency of the ductus arteriosus does not significantly affect water accumulation and net protein transudation into the airways of preterm lambs in the first hours of life. Therefore, some other feature of immaturity must be responsible for the large protein leaks previously observed by others.

Albumins↗
PubMed1989

Meclofenamate increases ventilation in lambs.

To investigate the effects of the prostaglandin synthetase inhibitor, meclofenamate, on postnatal ventilation, we studied 11 unanaesthetised, spontaneously-breathing lambs at an average age of 7.9 +/- 1.1 days (SEM; range 5-14 days) and an average weight of 4.9 +/- 0.5 kg (range 3.0-7.0 kg). After a 30-min control period we infused 4.23 mg/kg meclofenamate over 10 min and then gave 0.23 mg/h per kg for the remainder of the 4 h. Ventilation increased progressively from a control value of 515 +/- 72 ml/min per kg to a maximum of 753 +/- 100 ml/min per kg after 3h of infusion (P less than 0.05) due to an increased breathing rate; the effects were similar during both high- and low-voltage electrocortical activity. There were no significant changes in tidal volume, heart rate, blood pressure, arterial pH or PaCO2, the increased ventilation resulted from either an increase in dead space ventilation or an increase in CO2 production. This study indicates that meclofenamate causes an increase in ventilation in lambs but no changes in pH of PaCO2. The mechanism and site of action remain to be defined.

Analysis of Variance↗
PubMed1989

Meclofenamate does not affect lung development in fetal sheep.

Prostaglandins may be involved in some aspects of fetal lung development, including surfactant metabolism, tracheal fluid production, and possibly lung growth. In the fetus, during the days before delivery, plasma PGE2 concentration increases and concurrently, tracheal fluid production decreases and surfactant production increases. To determine whether the increase in PGE2, specifically plasma PGE2 concentration, is responsible for these changes, we continuously infused the prostaglandin synthetase inhibitor, meclofenamate (0.7 mg/h per kg), into 8 fetal sheep for 5-13 days before delivery; 5 control fetuses received a continuous infusion of solvent for 5-11 days before delivery. Meclofenamate infusion significantly decreased plasma PGE2 concentrations until the day of delivery. However, meclofenamate did not affect tracheal fluid production or its decrease before delivery, fetal plasma cortisol concentration, surfactant content of tracheal fluid and lung tissue, organ weights, lung weights, or lung DNA and protein content. We conclude that the changes in lung development during the days before delivery are not dependent on the usual high fetal plasma concentration of PGE2 or its increase before delivery.

Animals↗
PubMed1988

Effects of prostaglandin D2 on pulmonary arterial pressure and oxygenation in newborn infants with persistent pulmonary hypertension.

We studied the effects of prostaglandin D2 (PGD2) in six newborn infants, 1 to 2 days of age, who had persistent pulmonary hypertension syndrome and a PaO2 less than 75 torr during mechanical hyperventilation with an inspired oxygen concentration of 100%. Tolazoline and dopamine were used to treat some of the patients. No patients had congenital heart disease or sepsis. Catheters were placed to measure pulmonary and systemic arterial blood pressures. PGD2 was infused intravenously at doses of 1 to 25 micrograms/kg/min. Pulmonary and systemic arterial blood pressures, heart rate, and descending aortic blood gas values were measured before each dose change. Only two of six patients had a transient increase in PaO2. All had an increase in heart rate. Two of six patients had an increase in pulmonary arterial blood pressure. No deleterious effects occurred during the infusion. Four of six patients subsequently died. Although PGD2 is a specific pulmonary vasodilator in fetal and newborn animals, it did not lower pulmonary arterial blood pressure nor improve oxygenation in newborn infants with persistent pulmonary hypertension syndrome.

Blood Pressure↗
PubMed1988

Indomethacin and patent ductus arteriosus: effects on renal function in preterm lambs.

To examine the independent effects of a patent ductus arteriosus and of indomethacin therapy on the renal function of the preterm newborn, we created a preterm lamb model in which ductus diameter could be regulated. We studied 24 preterm newborn lambs. Eight lambs (group 1) had their ductus closed at delivery and received no indomethacin. Eight lambs (group 2) had their ductus closed and then received indomethacin (0.3 mg/kg) at 5.5 h; eight lambs (group 3) had their ductus kept open and then received indomethacin at 5.5 h. Hemodynamic and renal function measurements were made at 5 h (pretreatment) and at 12.5 h. In group 2 lambs there was a significant reduction in inulin clearance (GFR) and osmolal clearance after indomethacin. In contrast, lambs with an open ductus (group 3), when compared with lambs with a closed ductus (groups 1 and 2) at 5 h, already had significantly decreased blood pressure, GFR, urine volume, and osmolal clearance. Following indomethacin treatment, group 3 lambs showed no further decrease in renal function. We suggest that in preterm lambs with patent ductus, the apparent lack of renal dysfunction following indomethacin treatment reflects underlying diminished renal function.

Animals↗
PubMed1988

Effects of meclofenamate on breathing movements in fetal sheep before delivery.

There is evidence that prostaglandins (PG), specifically PGE2, participate in the regulation of fetal breathing movements (FBM). During late gestation, when FBM occur intermittently and primarily during low-voltage electrocortical activity, the concentration of PGE2 in fetal plasma ([PGE2]) is high. During the days before delivery [PGE2] increases and FBM decrease. To determine whether the increase in [PGE2] is responsible for the concurrent decrease in FBM, we infused the prostaglandin synthase inhibitor, meclofenamate (0.7 mg.kg-1.h-1), into eight fetal sheep continuously for 5-13 days before delivery; five control fetuses received a continuous infusion of the solvent for 5-11 days before delivery. Compared with control infusion, meclofenamate caused a significant decrease in [PGE 2] until the day of delivery and a significant increase in FBM [overall and during high-voltage electrocortical activity (HVA)] until 2 days before delivery. Although there were significant correlations between [PGE2] and FBM (overall and during HVA), both groups showed similar decreases in FBM during the 2 days before delivery. We conclude that the decrease in FBM before delivery is not dependent on the concurrent increase in [PGE2].

Animals↗
PubMed1988

Prostaglandin E2 causes hypoventilation and apnea in newborn lambs.

To test the hypothesis that prostaglandin (PG) E2 is a respiratory depressant in the newborn lamb, 12 chronically catheterized, unanesthetized lambs (age 2-6 days) were infused with progressively increasing doses of PGE2 (0.1, 0.5, 1.0, and 5.0 micrograms.kg-1.min-1; 30 min for each dose) into the ascending aorta. PGE2 caused significant progressive decreases in ventilation (due to decreased tidal volume and breathing rate), heart rate, blood pressure, and percent of the time spent in low-voltage electrocortical activity (LVA). PGE2 also caused respiratory acidosis, hypoxemia, and increased frequency and duration of apneic events (greater than 3 s). During the infusion there was a dose-related increase in plasma concentration of PGE2. At 30 min postinfusion, all measured variables showed recovery, although arterial pH, CO2 tension, and plasma PGE2 remained significantly different from control values, and the percent time in LVA was even higher than during control. Infusion of the vehicle alone (n = 5) caused no significant changes in any of the measured variables. The results, taken in combination with previous fetal studies, indicate that PGE2 has marked inhibitory effects on breathing movements both before and after birth.

Animals↗
PubMed1988

The role of beta-adrenoreceptor stimulation and contractile state in the preterm lamb's response to altered ductus arteriosus patency.

A model of patent ductus arteriosus in premature lambs was created to study the relative importance of beta-adrenoreceptor stimulation and increased myocardial contractility. In 39 fetal lambs (133 +/- 2, +/- SD days gestation, term 145 days), the ductus arteriosus was infiltrated with formalin, and a snare was placed around it to regulate its patency. One day later, the lambs were delivered, given sheep surfactant, paralyzed, and mechanically ventilated. Microsphere measurements of left ventricular output were made between 4 and 6 h after delivery. When the ductus was opened, there was no change in heart rate, but there were significant increases in left ventricular output, stroke volume, left ventricular end-diastolic pressure, and peak dP/dt. The increase in peak dP/dt due to opening the ductus was greater than that due to an increase in left ventricular end-diastolic pressure alone and was accompanied by an increase in norepinephrine secretion from the left ventricle. Propranolol (1 mg/kg) was used to evaluate the effect of beta-adrenergic tone on left ventricular output and contractility. The left atrium was paced in both control and propranolol-treated lambs. When the ductus was closed, propranolol significantly decreased stroke volume and peak dP/dt without changing left ventricular end-diastolic pressure or systemic vascular resistance. During a saline volume load (50 ml/kg over a 3-min period), propranolol-treated lambs had a reduced stroke volume and peak dP/dt despite similar values of left ventricular end-diastolic pressure and resistance as those of control lambs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Cardiovascular effects of patent ductus arteriosus in preterm lambs with respiratory distress.

We created a model for studying the cardiovascular and pulmonary effects of patent ductus arteriosus (PDA) in premature lambs with respiratory distress. In 47 fetal lambs at 129 to 133 days gestation (term, 145 days), we infiltrated the ductus arteriosus with formalin and placed a mechanical occluder about it so that its patency could be regulated. Two days later the lambs were delivered, given sheep surfactant, paralyzed, and their lungs mechanically ventilated. These premature lambs could more than double their left ventricular output when challenged with increasing degrees of left-to-right shunts through the PDA. This was accomplished by an increase in stroke volume, not by an increase in heart rate. During the 40-minute observation period, there was no change in dynamic compliance or functional residual capacity while the ductus was patent. When the ductus was patent, there was a significant increase in arterial PaO2 (even with small left-to-right shunts) and a decrease in PaCO2 (with large shunts). Despite the heart's ability to handle the increased volume load of a PDA, there were significant alterations in individual organ blood flows, resulting from a combination of decreased perfusion pressure and localized vasoconstriction. The abdominal organs had significant reductions in blood flow even with small PDA shunts. This decrease in organ blood flow may explain some of the pathophysiologic manifestations of PDA in preterm infants.

Animals↗
PubMed1987

Effects of prostaglandins on fetal breathing do not involve peripheral chemoreceptors.

In sheep, prostaglandin (PG) E2 inhibits fetal breathing movements and meclofenamate, a PG synthetase inhibitor, causes a marked stimulation of fetal breathing movements; the site of action of these agents is not known. To determine whether these effects are mediated through the peripheral chemoreceptors, we studied 13 fetal sheep at gestational ages of 127 to 138 days. Seven fetuses had bilateral section of the carotid sinus and vagus nerves (denervated); six had sham operations. Beginning at least 6 days after the operation, we infused PGE2 (0.6 microgram X kg-1 X min-1) into five denervated and five sham-operated fetuses and meclofenamate (0.4 mg X kg-1 X h-1) into six denervated and four sham-operated fetuses. Infusions averaged 20 h in duration. During preinfusion control periods, the incidence of fetal breathing movements (% of time) was lower in denervated than in sham-operated fetuses (18.9% vs. 31.5%; P less than 0.005). In both groups, the incidence of fetal breathing movements was decreased by PGE2 and was increased by meclofenamate; when expressed as absolute values, the magnitude of the changes with both agents was greater in sham-operated fetuses than denervated fetuses. However, the effects were similar in both groups when the changes were expressed as a percent of the respective control values. The incidence of fetal breathing movements (% of control) was decreased by PGE2 to 25.4% in denervated and to 28.2% in sham-operated fetuses and was increased by meclofenamate to 297.3% in denervated and to 304.0% in sham-operated fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Respiratory effects of a patent ductus arteriosus in premature newborn lambs.

We examined the respiratory effects of a patent ductus arteriosus in 29 premature lambs (131-135 days gestational age) after infiltrating the ductal wall with formaldehyde solution (Formalin) and placing a snare around the ductus to regulate its patency. The lambs were given sheep surfactant, paralyzed, and mechanically ventilated at birth. We first compared 8 lambs with open ductus and 13 lambs with closed ductus during the 12 h after birth. Although lambs with open ductus had greater pulmonary blood flow (301 +/- 36 vs. 188 +/- 11 ml.min-1.kg-1, mean +/- SE, at 12 h of age) and mean pulmonary arterial (44 +/- 3 vs. 33 +/- 2 mmHg) and left ventricular end-diastolic (6 +/- 0.6 vs 4 +/- 0.7 mmHg) pressures, we found no differences in dynamic respiratory compliance (Cdyn = 0.55 +/- 0.07 vs. 0.55 +/- 0.03 ml.cmH2O-1.kg-1), midtidal volume resistance (62 +/- 5 X 10(-3) vs. 62 +/- 7 X 10(-3) cmH2O.ml-1.s), or functional residual capacity (FRC = 27 +/- 3 vs. 26 +/- 2 ml.kg-1). Alveolar-arterial PO2 difference was lower in the lambs with open ductus (238 +/- 65 vs. 362 +/- 37 Torr). Next, we challenged eight lambs with two separate saline infusions (50 ml.kg-1 over 3 min), each given with the ductus alternately closed or open. When the ductus was closed, FRC was unchanged, but Cdyn increased by 18% immediately after the infusion. When the ductus was open, FRC decreased by 16% and Cdyn decreased by 12%. We conclude that the premature lamb is surprisingly resistant to changes in respiratory function from ductal patency during the immediate neonatal period.

Animals↗
PubMed1987

Piriprost: a putative leukotriene synthesis inhibitor increases pulmonary blood flow in fetal lambs.

Leukotrienes may control fetal pulmonary vascular tone since infusions of putative leukotriene receptor antagonists markedly increase pulmonary blood flow and decrease pulmonary vascular resistance in fetal lambs. This hypothesis would be strengthened if inhibition of leukotriene synthesis also produced similar hemodynamic changes. We therefore studied the effects of piriprost (U 60257), a putative leukotriene synthesis inhibitor, on thirteen fetal lambs at 137 to 140 days gestation. In preliminary studies in four fetal lambs, doses of U 60257 greater than 20 mg/kg increased pulmonary blood flow. In the nine other fetal lambs, U 60257 (31.7 +/- 4.1 mg/kg) increased pulmonary blood flow by 502% (p less than 0.05) and decreased pulmonary vascular resistance by 87% (p less than 0.05). Pulmonary arterial and left atrial pressures were unchanged. Descending aortic pressure was increased (p less than 0.05) and heart rate was decreased (p less than 0.05). The abilities of both putative leukotriene synthesis inhibitors and leukotriene receptor antagonists to similarly increase fetal pulmonary blood flow and decrease pulmonary vascular resistance are consistent with the hypothesis that leukotrienes play a role in regulating fetal pulmonary vascular tone.

Animals↗
PubMed1987

How a patent ductus arteriosus effects the premature lamb's ability to handle additional volume loads.

A model of patent ductus arteriosus in premature lambs was created to examine the lamb's ability to handle the volume load imposed by a patent ductus arteriosus and to determine the lamb's ability to handle any additional volume load. Fifteen preterm lambs [133 +/- 2 (+/- SD) days gestation, term 145 days], whose ductal diameter could be regulated with a mechanical occluder, were studied to determine the independent effects of ductus patency and a saline volume load (50 ml/kg over 3 min) on left ventricular output and its distribution. During a saline infusion, preterm lambs with a closed ductus could only increase their stroke volume by 40% above baseline stroke volume. When challenged with a saline infusion, lambs with an open ductus still were able to increase their stroke volume significantly; the maximal increase in stroke volume during the saline load with the ductus open was 70% above baseline stroke volume. We hypothesize that the associated reduced left ventricular afterload plays a significant role in the preterm lamb's ability to increase its stroke volume when challenged with a patent ductus arteriosus. Even with a patent ductus arteriosus, the lamb still has the ability to handle additional volume loads.

Animals↗