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Biomedical subjects

M A Heymann

Publications and source records attributed to M A Heymann.

At least 37 records · Page 2Linked to original sources
PubMed1994

Bradykinin receptor blockade does not affect oxygen-mediated pulmonary vasodilation in fetal lambs.

Both oxygenation and rhythmic stretching of the lungs are factors known to be responsible for pulmonary vasodilation at birth. Based on our previous studies, we proposed that the pulmonary vasodilation caused by oxygen could be mediated, at least in part, through bradykinin release. To test this hypothesis, we evaluated the cardiovascular responses to in utero ventilation during infusion of a B2-subtype bradykinin receptor antagonist (BKA), [N-adamantaneacetyl-D-Arg0,Hyp3,Thi5,8,D-Phe7]bradykinin, at 15-20 micrograms.kg-1.min-1 in eight near-term fetal lambs and during drug vehicle infusion in five control fetal lambs. Prostacyclin synthesis was inhibited by meclofenamate infusion (1.5 mg.kg-1.h-1). Surgical placement of vascular catheters, a flow transducer around the left pulmonary artery, and a tracheostomy tube and formalin infiltration of the ductus arteriosus to maintain its patency in the presence of meclofenamate were performed 72 h before the study. Hemodynamic variables and pulmonary blood flow were measured and pulmonary vascular resistance was calculated before and after in utero ventilation with 100% oxygen. Despite complete blockade by BKA of the pulmonary vasodilation produced by exogenous bradykinin, ventilation with oxygen significantly increased pulmonary blood flow by 676% over baseline state (157.8 +/- 66 to 1224 +/- 265 mL.min-1.100 g-1, p < 0.01) and decreased the pulmonary vascular resistance by 89% from baseline state (0.44 +/- 0.16 to 0.048 +/- 0.01 torr.mL-1.min.100 g, p < 0.01). Such responses to ventilation with oxygen were comparable to those noted in the control animals, in whom bradykinin receptors had not been blocked.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

Effect of endothelium-derived relaxing factor inhibition on the umbilical-placental circulation in fetal lambs in utero.

OBJECTIVE: The purpose of this study was to examine whether basal endothelium-derived relaxing factor release contributes to regulation of resting umbilical-placental vascular resistance. STUDY DESIGN: Because N omega-nitro-L-arginine selectively inhibits the synthesis of nitric oxide, a major endothelium-derived relaxing factor, we investigated the effects of N omega-nitro-L-arginine on umbilical-placental vascular resistance in 10 fetal lambs in utero. We inserted catheters and fitted an umbilical artery electromagnetic flow transducer around the common umbilical artery to measure umbilical blood flow and catheterized the left umbilical arterial hypogastric branch to allow selective umbilical-placental infusion (60 minutes) of pH-matched saline solution (control) or N omega-nitro-L-arginine. RESULTS: In seven normal fetal lambs, N omega-nitro-L-arginine increased umbilical-placental vascular resistance and arterial pressures and decreased umbilical blood flow (p less than 0.05); percentage changes from baseline were 50.8% +/- 18.3%, 40.3% +/- 8.1%, and -9.9% +/- 6.4%, respectively. In three mildly asphyxiated (compromised) fetuses, these changes were 101.4% +/- 28.7%, 31.2% +/- 4.8%, and -37.9% +/- 12.0%. CONCLUSION: These data support the hypothesis that the basal endothelium-derived relaxing factor release plays a role in regulating resting umbilical-placental vascular resistance.

Animals↗
PubMed1992

K+ channel pulmonary vasodilation in fetal lambs: role of endothelium-derived nitric oxide.

To define the role and mechanism of action of K+ channels in regulating fetal pulmonary vascular tone, we studied the hemodynamic effects of pinacidil (a K+ channel activator) and glibenclamide (a K+ channel blocker). The effects of pinacidil were compared with those of acetylcholine [an endothelium-derived relaxing factor- (EDRF) dependent pulmonary vasodilator] and 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP, an EDRF-independent pulmonary vasodilator) before and after treatment with N omega-nitro-L-arginine [a competitive inhibitor of an EDRF, endothelium-derived nitric oxide (EDNO), synthesis], or L-arginine (the substrate for the formation of EDNO). In 14 unanesthetized fetal lambs in utero, catheters were inserted into the fetal pulmonary artery, descending aorta, left atrium, and superior vena cava to measure pressures and administer drugs. An ultrasonic flow transducer was placed around the left pulmonary artery to measure flow (QP) continuously. In eight animals, pinacidil, acetylcholine, and 8-bromo-cGMP caused similar acute maximal increases in QP of 128, 137, and 155 ml/min, respectively. After a 60-min infusion of N omega-nitro-L-arginine (2.07 +/- 0.27 mg.kg-1.min-1), the increase in QP caused by acetylcholine and pinacidil was significantly attenuated, by 84 and 68%, respectively, with only a 10% attenuation of the increase in QP caused by 8-bromo-cGMP. In six additional N omega-nitro-L-arginine-pretreated fetal lambs, infusion of L-arginine (32.2 +/- 4.3 mg.kg-1.min-1) restored the vasodilatory effects of acetylcholine and pinacidil. A 20-min infusion of glibenclamide (n = 6; 0.64 +/- 0.07 mg.kg-1.min-1) blocked the vasodilation by pinacidil but not acetylcholine.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

EDRF inhibition attenuates the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs.

At birth, pulmonary vasodilation occurs during rhythmic distension of the lungs and oxygenation. Inhibition of prostaglandin synthesis prevents pulmonary vasodilation during rhythmic distension of the lungs but not during oxygenation. Because endothelium-derived relaxing factor (EDRF) modulates pulmonary vascular tone at birth, at rest, and during hypoxia in older animals, we hypothesized that EDRF may modulate pulmonary vascular tone during oxygenation in fetal lambs. We studied the responses to N omega-nitro-L-arginine, a competitive inhibitor of EDRF synthesis, in nine near-term fetal lambs and to drug vehicle in six of these lambs and the subsequent responses to in utero ventilation with 95% O2 in these fetal lambs. In all fetal lambs, prostaglandin synthesis was prevented by meclofenamate. N omega-nitro-L-arginine increased pulmonary and systemic arterial pressures by 28% (P < 0.05) and 31% (P < 0.05), respectively, and decreased pulmonary blood flow by 83% (P < 0.05). In the controls, ventilation with 95% O2 increased pulmonary blood flow by 1,050% (P = 0.05) without changing pressures, thereby decreasing pulmonary vascular resistance by 88% (P = 0.05). During N omega-nitro-L-arginine infusion, ventilation with 95% O2 increased pulmonary blood flow by 162% (P = 0.05) and decreased pulmonary vascular resistance by 74% (P = 0.05). This suggests that EDRF may play an important role in modulating resting pulmonary vascular tone in fetal lambs and in the vasodilatory response to ventilation with O2 in utero.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

N omega-nitro-L-arginine attenuates endothelium-dependent pulmonary vasodilation in lambs.

To investigate the role of endothelium-derived relaxing factor (EDRF) in the regulation of resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation, we studied the hemodynamic effects of N omega-nitro-L-arginine (a new stereospecific EDRF inhibitor) in 10 spontaneously breathing lambs and then compared the hemodynamic responses to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimetic) or N omega-nitro-L-arginine. N omega-nitro-L-arginine caused a significant dose-dependent increase in pulmonary arterial pressure. Pretreatment with L-arginine blocked this increase, but pretreatment with D-arginine did not, suggesting that N omega-nitro-L-arginine is a competitive inhibitor of L-arginine for EDRF production. During U-46619 infusions, acetylcholine, ATP-MgCl2, isoproterenol, sodium nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) decreased pulmonary arterial pressure. During N omega-nitro-L-arginine infusions, the decrease in pulmonary arterial pressure caused by acetylcholine and ATP-MgCl2 (endothelium-dependent vasodilators) was significantly attenuated, but the decrease caused by isoproterenol, sodium nitroprusside, and 8-bromo-cGMP (endothelium-independent vasodilators) was unchanged. This study supports the hypothesis that EDRF in part mediates resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation. N omega-nitro-L-arginine is useful for studying EDRF inhibition in intact animals.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

In vivo attenuation of endothelium-dependent pulmonary vasodilation by methylene blue.

In vitro evidence suggests that resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation are mediated by changes in vascular smooth muscle concentrations of guanosine 3',5'-cyclic monophosphate (cGMP). We investigated this hypothesis in vivo in 19 mechanically ventilated intact lambs by determining the hemodynamic effects of methylene blue (a guanylate cyclase inhibitor) and then by comparing the hemodynamic response to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimic) or methylene blue. Methylene blue caused a significant time-dependent increase in pulmonary arterial pressure. During U-46619 infusions, acetylcholine, ATP-MgCl2, sodium nitroprusside, isoproterenol, and 8-bromo-cGMP decreased pulmonary arterial pressure. During methylene blue infusions, the decreases in pulmonary arterial pressure caused by acetylcholine and ATP-MgCl2 (endothelium-dependent vasodilators) and sodium nitroprusside (an endothelium-independent guanylate cyclase-dependent vasodilator) were attenuated by greater than 50%. The decreases in pulmonary arterial pressure caused by isoproterenol and 8-bromo-cGMP (endothelium-independent vasodilators) were unchanged. This study in intact lambs supports the in vitro evidence that changes in vascular smooth muscle cell concentrations of cGMP in part mediate resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Prostaglandin inhibition prevents the fall in pulmonary vascular resistance as a result of rhythmic distension of the lungs in fetal lambs.

Prostaglandins (PG) are vasoactive factors involved in the regulation of pulmonary vascular resistance at birth. However, their physiologic importance is unclear. We hypothesized that PG are important regulators of pulmonary vascular resistance during static and rhythmic distension of the lungs. To test this hypothesis, we studied seven near-term fetal lambs treated with meclofenamate (a PG synthetase inhibitor) and six controls. The fetal lambs were instrumented on a long-term basis with vascular catheters to measure pulmonary arterial pressures, left atrial pressures, and pulmonary blood flow (radionuclide-labeled microsphere method). The fetal airway was intubated, and the ductus arteriosus wall was infiltrated with formalin to assure full patency during the study period. Pulmonary vascular resistance was calculated during baseline and during sequential in utero static distension of the fetal lungs, rhythmic distension, and ventilation with oxygenation. We found that during rhythmic distension, inhibition of PG synthesis abolished the 4-fold decrease in pulmonary vascular resistance seen in the control group. In contrast, during static distension, pulmonary vascular resistance did not change in either group, and during ventilation with oxygenation, pulmonary vascular resistance decreased 12-fold in both groups. We conclude that PG are important regulators of pulmonary vascular resistance during rhythmic distension but are not essential for the regulation of pulmonary vascular resistance during static distension or during ventilation with oxygenation.

Animals↗
PubMed1990

Leukotrienes C4, D4, and E4 in fetal lamb tracheal fluid.

Previously, we demonstrated that either putative leukotriene receptor antagonists or a synthesis inhibitor markedly decreased pulmonary vascular resistance in the near-term fetal lamb and concluded that leukotrienes may play a role in maintaining the high pulmonary vascular resistance in the fetus. To further investigate the role of leukotrienes, we measured concentrations of leukotriene (LT) C4, LTD4, and LTE4 in 17 tracheal fluid samples from 8 of 9 near-term (129-139 days, term = 145 days), chronically-catheterized, fetal lambs during normoxia to evaluate their possible role in regulating resting tone and in seven of the nine before and during hypoxia to evaluate their possible role in hypoxic vasoconstriction. The tracheal fluid samples collected by gravity over 1-3 min, on ice, were immediately treated with cold ethanol, centrifuged, and the supernatant covered with N2 and stored in a -70 degrees C freezer for a maximum of 3 weeks. Purification and separation of leukotrienes was done by reverse-phase high performance liquid chromatography using a gradient elution method, and fractions corresponding to LTC4, LTD4, and LTE4 standards were quantified immediately by radioimmunoassay. During normoxia (descending aortic PaO2 2.9 +/- 0.3 kPa [21.5 +/- 2.5 mmHg]; mean +/- SD), all 3 leukotrienes were detected in 16 of the 17 samples: LTC4 29 +/- 28 pg/ml (range 0-119 pg/ml); LTD4 66 +/- 51 pg/ml (range 9-177 pg/ml); and LTE4 43 +/- 50 pg/ml (range 0-204 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Regulation of the pulmonary circulation in the perinatal period and in children.

In the fetus, the pulmonary circulation is actively maintained in a constricted state due to low oxygen environment and perhaps leukotrienes. Pulmonary blood flow represents about 8% of fetal cardiac output. Shortly after birth, pulmonary vascular resistance (PVR) and pulmonary arterial pressure fall rapidly, whereas pulmonary blood flow reaches systemic levels. The exact mechanisms by which the dramatic changes in PVR occur with the onset of ventilation at birth are extensively reviewed. They include: oxygen environment and release of vasoactive substances such as bradykinin, PGI2 or PGD2. Thus, regulation of the fetal and immediate postnatal pulmonary circulation reflects a balance between factors producing active pulmonary vasoconstriction and those producing vasodilatation.

Bradykinin↗
PubMed1989

The young lamb can increase cardiovascular performance during isoflurane anesthesia.

Cardiac output and myocardial blood flow decrease dramatically in a dose-dependent pattern in the young lamb during isoflurane anesthesia. This raises important questions about the ability of the young lamb to increase myocardial performance if oxygen delivery were compromised by a decrease in oxygen content during anesthesia and surgery. To investigate the ability of the young lamb to increase oxygen delivery during isoflurane anesthesia, the response to hypoxemia, which is known to increase myocardial performance, was studied in awake 1-week-old lambs. Mean systemic arterial pressure, heart rate, cardiac output, and regional distribution of blood flow were measured during three states: awake, 1.0 minimum alveolar concentration (MAC) of isoflurane in an FIO2 of 1.0, and 1.0 MAC of isoflurane in an FIO2 of 0.09. Stroke volume, total body and myocardial oxygen consumption, and fractional extraction of oxygen were calculated for the total body and for the myocardium. Isoflurane anesthesia decreased mean systemic arterial pressure (70 +/- 8 mmHg), heart rate (222 +/- 29 beats/min), and cardiac output (277 +/- 72 ml.kg-1.min-1) significantly (43 +/- 11 mmHg, 163 +/- 20 beats/min, 191 +/- 34 ml.kg-1.min-1). Hypoxemia returned heart rate to control (191 +/- 23 beats/min), increased stroke volume (1.71 +/- 0.2 ml/kg) above both control (1.23 +/- 0.2 ml/kg) and 1.0 MAC isoflurane levels (1.19 +/- 0.3 ml/kg), and increased cardiac output (325 +/- 61 ml.kg-1.min-1) above the level during 1.0 MAC isoflurane.

Anesthesia, General↗
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

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

Leukotriene antagonists attenuate thromboxane-inducible pulmonary hypertension.

Leukotrienes C4 and D4 and thromboxane A2 are potent vasoconstrictors that may mediate pulmonary vasoconstriction in many clinical situations. There is a complex interaction among leukotrienes and thromboxane A2, because inhibition of thromboxane synthesis prevents some of the hemodynamic effects of exogenous leukotrienes. Similarly, if leukotrienes mediate thromboxane A2-induced pulmonary vasoconstriction, then leukotriene antagonists should attenuate the effects of a thromboxane A2-mimetic such as U46619. First, dose response curves for the hemodynamic effects of U46619 were performed on seven spontaneously breathing newborn lambs. Then a putative leukotriene receptor antagonist, FPL57231, 1 mg/kg/min, or a putative leukotriene synthesis antagonist, U60257, 30 mg/kg, was given before infusing U46619 (1 microgram/kg/min). U46619 caused significant dose-dependent increases in pulmonary and systemic arterial pressures (p less than 0.05) and significant dose-dependent decreases in cardiac output and heart rate (p less than 0.05). A 1 microgram/kg/min infusion of U46619 increased pulmonary arterial pressure by 155.4% +/- 8.9 and systemic arterial pressure by 8.9% +/- 7.7 and decreased cardiac output by 19.7% +/- 12.2 and heart rate by 9.9% +/- 10.6. FPL57231 attenuated the effects of U46619. U60257 had similar effects. Therefore, the hemodynamic effects of thromboxane A2, an important mediator of the pulmonary vasoconstriction produced, for example, by group B streptococci and Escherichia coli, may be mediated by the secondary production of leukotrienes.

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