Effect of indomethacin on pulmonary vascular response to ventilation of fetal goats

Leffler, Charles W.; Tyler, T.; Cassin, S.

doi:10.1152/ajpheart.1978.234.4.h346

Cited by 46 publications

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“…Altered metabolite production and inhibition could have attenuated the slow second phase of the decrease in pulmonary vascular resistance in those studies, as characterized by Leffler et a/. (22). Evidence for this possibility is that this slow second phase, which lasts for 10-20 min after the rapid first phase, has been shown to be attenuated by the prostaglandin synthesis inhibitor, indomethacin (22).…”

Section: Discussionmentioning

confidence: 85%

“…(22). Evidence for this possibility is that this slow second phase, which lasts for 10-20 min after the rapid first phase, has been shown to be attenuated by the prostaglandin synthesis inhibitor, indomethacin (22). [In contrast, the first phase, a rapid decrease that lasts for only 30 s, is not altered by indomethacin but may be altered by direct mechanical effects of ventilation: the establishment of a gas-liquid interface in the alveoli may decrease perivascular pressures and thus distend the small arterioles and decrease resistance (22).]…”

Section: Discussionmentioning

confidence: 99%

“…Evidence for this possibility is that this slow second phase, which lasts for 10-20 min after the rapid first phase, has been shown to be attenuated by the prostaglandin synthesis inhibitor, indomethacin (22). [In contrast, the first phase, a rapid decrease that lasts for only 30 s, is not altered by indomethacin but may be altered by direct mechanical effects of ventilation: the establishment of a gas-liquid interface in the alveoli may decrease perivascular pressures and thus distend the small arterioles and decrease resistance (22).] Further evidence that prostaglandin metabolites are important in the decrease of pulmonary vascular resistance is that prostaglandin 12, a potent pulmonary vasodilator, is produced in response to either mechanical ventilation (23)(24)(25) or breathing in recently delivered fetal lambs.…”

Section: Discussionmentioning

confidence: 99%

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Changes in the Pulmonary Circulation during Birth-Related Events

1990

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ABSTRACT. At birth, pulmonary vascular resistance decreases dramatically, allowing pulmonary blood flow to increase and oxygen exchange to occur in the lungs. To determine the extent to which ventilation of the fetus's lungs, oxygenation of the lungs, and umbilical cord occlusion can account for this decrease in resistance, we studied 16 chronically instrumented, near-term sheep fetuses in uteuo. We performed the experiment in a sequential fashion: we first studied the effects of ventilation alone (without oxygenation) on pulmonary vascular resistance and blood flow, and then determined the additive effects of oxygenation and cord occlusion. We calculated pulmonary vascular resistance from measurements of vascular pressures and measurements of pulmonary blood flow obtained by injecting radionuclide-labeled microspheres. We found that ventilation alone caused a large but variable increase in pulmonary blood flow, to 401% of control, no change in pulmonary arterial pressure, and a doubling of left atrial pressure. Thus, pulmonary vascular resistance fell dramatically, to 34% of control. Oxygenation caused a modest further increase in pulmonary blood flow and a decrease in mean pulmonary arterial pressure, so resistance fell to 10% of control. Umbilical cord occlusion caused no further changes in pressure, flow, or resistance. Unexpectedly, the fetuses' pulmonary blood flow responses to ventilation fell into two groups: the mean increase was maximal in eight of the 16 fetuses but was only 20% of the cumulative increase in the other eight. We found no differences between the two groups of fetuses to explain their different responses. We conclude that ventilation and oxygenation together can account for the decrease in pulmonary vascular resistance to levels that occur at birth. Moreover, ventilation alone can account for most of this decrease. In the circulation of both fetuses and newborns, the main role of the right ventricle is to deliver blood to the gas exchange circulation for uptake of oxygen and removal of carbon dioxide. In the fetus this delivery is achieved by virtue of the pulmonary vascular resistance being very high. Right ventricular output is thus diverted away from the lungs and toward the placenta, through the ductus arteriosus (1)(2)(3)(4) lungs become the organ of gas exchange, pulmonary vascular resistance must fall dramatically, allowing pulmonary blood flow to increase and oxygen exchange to occur in the lungs. If pulmonary vascular resistance does not fall, the syndrome of persistent pulmonary hypertension of the newborn occurs, often leading to death.Which of the many events that occur at birth are responsible for the normal decrease in pulmonary vascular resistance is not fully understood. Three major events of the birth process that could be responsible are ventilation, or rhythmic gaseous distension, of fetal lungs, oxygenation of the lungs, and occlusion of the umbilical cord. Two of these events-ventilation and oxygenation-have been studied in acutely exteriorized fetal sheep. Rhythmic ...

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Changes in the Pulmonary Circulation during Birth-Related Events

1990

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“…PGI 2 , the main cyclo-oxygenase product of arachidonic acid in the vascular tissue, is a potent vasodilator and its actions are mediated by cAMP (1,2). It is one of the important mediators of the decrease in PVR at birth (3,4). PGI 2 has been used widely in the treatment of adults with PH.…”

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confidence: 99%

Effects of Prostacyclin and Milrinone on Pulmonary Hemodynamics in Newborn Lambs With Persistent Pulmonary Hypertension Induced by Ductal Ligation

et al. 2006

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Prostacyclin (PGI 2 ) stimulates adenyl cyclase to synthesize cAMP within the vascular smooth muscle resulting in vasodilatation. Milrinone inhibits cAMP clearance by phosphodiesterase type III. We studied the dose response of pulmonary and systemic hemodynamics to intratracheal (IT) PGI 2 in newborn lambs with pulmonary hypertension (PH) and whether intravenous milrinone potentiate these effects. IT-PGI 2 at varying doses was administered to lambs with PH induced by prenatal ductal ligation. IT-PGI 2 doses were repeated in the presence of intravenous milrinone (bolus-100 g/kg followed by infusion at 1 g/kg/min). Increasing doses of IT-PGI 2 significantly decreased mean pulmonary arterial pressures (PAP) and pulmonary vascular resistance (PVR) and increased pulmonary blood flow (PBF). Intravenous milrinone by itself produced a significant reduction in PVR and a significant increase in PBF. Intravenous milrinone significantly shortened the onset, prolonged the duration and degree of pulmonary vasodilation produced by PGI 2 . We conclude that intravenous milrinone potentiates the pulmonary vasodilator effects of PGI 2 at lower doses. (Pediatr Res 60: 624-629, 2006) P PHN is a disorder of term and near term infants with significant morbidity and mortality. PPHN results from disruption of the normal decrease in PVR at birth. PGI 2 , the main cyclo-oxygenase product of arachidonic acid in the vascular tissue, is a potent vasodilator and its actions are mediated by cAMP (1,2). It is one of the important mediators of the decrease in PVR at birth (3,4). PGI 2 has been used widely in the treatment of adults with PH. Although there are reports of PGI 2 being used anecdotally in human infants (5,6), systematic studies on the dose response effects of PGI 2 in PPHN are lacking. Milrinone selectively inhibits PDE3, resulting in accumulation of cAMP in myocardium and vascular smooth muscle, improving myocardial performance and producing vasodilation. Milrinone has been used in patients to improve pulmonary hemodynamics in association with systemic hemodynamic dysfunction (7,8). Studies on the use of milrinone in neonates are lacking. Figure 1 shows the PGI 2 -cAMP signal transduction pathway in the vascular smooth muscle. PGI 2 and milrinone in combination can act synergistically in increasing cAMP levels and hence enhance the relaxation of the vascular smooth muscle.The newborn pulmonary circulation is different from the adult pulmonary circulation in its anatomy and physiology (9,10). The response of the infant with PPHN to NO is closer to that of newborn lambs with persistent pulmonary hypertension induced by ligation of the ductus arteriosus (11) than it is to the response of adult humans with PH. Examination of the responses to manipulating cAMP with PGI 2 and milrinone in such lambs seemed warranted in advance of clinical trials. Thus we studied the dose response to IT PGI 2 , the response to intravenous milrinone and enhancement of the effect of PGI 2 by milrinone in newborn lambs with PH induced by ligation o...

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“…This enzyme may also be important in the attenuation of acute hypoxic pulmonary vasoconstriction in the perinatal period because acute hypoxia stimulates pulmonary prostacyclin synthesis (6) and the inhibition of prostaglandin production augments the vasoconstrictor response (7). Furthermore, because the inhibition of prostaglandin synthesis also attenuates the normal decline in pulmonary vascular resistance at the time of birth (8,9), endogenous agonists of adenylate cyclase may contribute to the successful transition of the pulmonary circulation from that of the fetus to that of the newborn.…”

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confidence: 99%

Ontogeny of β-Adrenergic Regulation of Adenylate Cyclase in Intrapulmonary Arteries from Fetal and Postnatal Lambs

1991

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ABSTRACT. The enzyme adenylate cyclase is critically involved in the regulation of vasodilatation in the developing pulmonary circulation in that it mediates the vascular smooth muscle effects of @-adrenergic agonists and vasodilatory prostaglandins. These agonists activate receptors coupled to the catalytic subunit of the enzyme by stimulatory guanine nucleotide-dependent regulatory proteins. We examined the ontogeny of the function of the adenylate cyclase system in intrapulmonary arterial segments from fetal lambs at 110-115 (Fl) and 125-135 d gestation (F2) and from postnatal lambs at 7-14 (PI) and 35-56 d of age (P2). The function of the intact enzyme system and its components was assessed in incubations measuring cAMP accumulation during phosphodiesterase inhibition. @-Adrenergic mediation of adenylate cyclase was examined because the binding characteristics of the smooth muscle receptors can be readily quantified. Nonstimulated (basal) cAMP accumulation was similar in F1 and F2, it increased 8-fold from F2 to PI, and it was equivalent in P1 and P2. cAMP accumulation with isoproterenol increased 5.9-fold from F1 to F2 and was similar in F2, PI, and P2. Radioligand binding studies revealed that the greater response to isoproterenol in F2 versus F1 is not related to an increase in 8-adrenergic receptor density or affinity. cAMP accumulation with forskolin, which activates adenylate cyclase by actions that involve both the stimulatory guanine nucleotide-dependent regulatory protein and the catalytic subunit, was similar in the four age groups, indicating that there are no maturational changes in the function of these enzyme system components. As such, the enhancement in @-adrenergic mediation of the enzyme during the 3rd trimester may be related to changes in receptor-guaninne nucleotide-dependent regulatory protein coupling. It is concluded that there are marked developmental alterations in the function of the adenylate cyclase system in the intrapulmonary arteries during late gestation that may serve to optimize the capacity of this mediator of pulmonary vasodilatation in the perinatal period. (Pediatr Res 30: 610-615,1991 The plasma membrane-bound enzyme adenylate cyclase is critically involved in the regulation of vasodilatation in the developing pulmonary circulation. Stimulators of adenylate cyclase activity in VSM such as 0-adrenergic agonists and vasodilatory prostaglandins, including prostacyclin, prostaglandin E2, and prostaglandin El, elicit pulmonary vasodilatation in the late fetal and newborn lamb (1-4). In addition, vasoconstriction occurs with inhibition of the synthesis of endogenous agonists for adenylate cyclase (i.e. vasodilatory prostaglandins) (5). This enzyme may also be important in the attenuation of acute hypoxic pulmonary vasoconstriction in the perinatal period because acute hypoxia stimulates pulmonary prostacyclin synthesis (6) and the inhibition of prostaglandin production augments the vasoconstrictor response (7). Furthermore, because the inhibition of prostaglandin synthesis a...

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Effect of indomethacin on pulmonary vascular response to ventilation of fetal goats

Cited by 46 publications

References 0 publications

Changes in the Pulmonary Circulation during Birth-Related Events

Changes in the Pulmonary Circulation during Birth-Related Events

Effects of Prostacyclin and Milrinone on Pulmonary Hemodynamics in Newborn Lambs With Persistent Pulmonary Hypertension Induced by Ductal Ligation

Ontogeny of β-Adrenergic Regulation of Adenylate Cyclase in Intrapulmonary Arteries from Fetal and Postnatal Lambs

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