PubMed Health⌕ Search

Biomedical subjects

R I Clyman

Publications and source records attributed to R I Clyman.

At least 19 recordsLinked to original sources
PubMed2006

Patent ductus arteriosus: pathophysiology and management.

Patent ductus arteriosus (PDA) in preterm newborns prior to 28 weeks of gestation has led to many challenges regarding the type and timing of treatment regimens. A PDA results in increased pulmonary blood flow and redistribution of flow to other organs. Several co-morbidities (i.e., necrotizing enterocolitis, intracranial hemorrhage, pulmonary edema/hemorrhage, bronchopulmonary dysplasia, and retinopathy) are associated with the presence of a PDA, but whether or not a PDA is responsible for their development is still unclear. The prostaglandin inhibitor, indomethacin, is effective in the treatment of PDA. Questions regarding the optimal timing of the intervention--early prophylaxis or treatment, once signs and symptoms become evident--have challenged physicians for decades. Both evidence and experience are explored in this article. Comparative physiology between the full-term and preterm newborn and the barriers preventing the necessary cascade of events leading to permanent constriction of the PDA are reviewed.

Cardiac Surgical Procedures↗
PubMed2001

In utero remodeling of the fetal lamb ductus arteriosus: the role of antenatal indomethacin and avascular zone thickness on vasa vasorum proliferation, neointima formation, and cell death.

BACKGROUND: The ductus arteriosus (DA) of newborn infants exposed in utero to indomethacin is resistant to postnatal indomethacin; we hypothesized that this is due to ductus constriction in utero, with subsequent remodeling of the vessel. METHODS AND RESULTS: Infusion of fetal lambs with indomethacin for 48 hours constricted the DA and increased the thickness of the avascular zone of the DA, which in turn induced the expression of vascular endothelial growth factor, endothelial nitric oxide synthase (due to ingrowth of vasa vasorum), neointima formation, and loss of smooth muscle cells; moderate degrees of DA constriction in utero increased NO production, which inhibited DA contractility. Marked degrees of DA constriction decreased tissue distensibility and contractile capacity. CONCLUSIONS: DA patency is no longer controlled primarily by prostaglandins once it has been exposed to indomethacin in utero.

6-Ketoprostaglandin F1 alpha↗
PubMed2001

Characterization of PGE2 receptors in fetal and newborn ductus arteriosus in the pig.

We compared the total density and the relative expression of EP receptor (EP) subtypes in ductus arteriosus (DA) of the newborn with that of the fetal piglet. Saturation binding experiments showed 3-fold less PGE2 receptors in the newborn than in the fetus because of loss of EP3 and EP4 receptors thus explaining, at least partly, the reduced responsiveness to PGE2 of the newborn DA. Displacement experiments showed that the relative proportions of EP2, EP3, and EP4 were similar in the fetal DA but only EP2 was detected in the DA of the newborn pig. Hence, PGE2 effects in the newborn DA seem to be exclusively mediated by EP2 receptors both in vitro and in vivo. These findings may help to propose more specific therapies for regulation of DA's tone in certain newborns for whom conventional therapy is contraindicated.

Animals↗
PubMed2001

Characterization of PGE2 receptors in fetal and newborn lamb ductus arteriosus.

Although the role of PGE2 in maintaining ductus arteriosus (DA) patency is well established, the specific PGE2 receptor subtype(s) (EP) involved have not been clearly identified. We used late gestation fetal and neonatal lambs to study developmental regulation of EP receptors. In the fetal DA, radioligand binding and RT-PCR assays virtually failed to detect EP1 but detected EP2, EP3D, and EP4 receptors in equivalent proportions. In the newborn lamb, DA total density was one-third of that found in the fetus and only EP2 was detected. Stimulation of EP2 and EP4 increased cAMP formation and was associated with DA relaxation. Though stimulation of EP3 inhibited cAMP formation, it surprisingly relaxed the fetal DA both in vitro and in vivo. This EP3-induced relaxation was specifically diminished by the ATP-sensitive K(+) (K(ATP)) channel blocker glibenclamide. In conclusion, PGE2 dilates the late gestation fetal DA through pathways that involve either cAMP (EP2 and EP4) or K(ATP) channels (EP3). The loss of EP3 and EP4 receptors in the newborn DA is consistent with its decreased responsiveness to PGE2.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

Factors that increase the contractile tone of the ductus arteriosus also regulate its anatomic remodeling.

Permanent closure of the full-term newborn ductus arteriosus (DA) occurs only if profound hypoxia develops within the vessel wall during luminal obliteration. We used fetal and newborn baboons and lambs to determine why the immature DA fails to remodel after birth. When preterm newborns were kept in a normoxic range (Pa(O(2)): 50-90 mmHg), 86% still had a small patent DA on the sixth day after birth; in addition, the preterm DA wall was only mildly hypoxic and had only minimal remodeling. The postnatal increase in Pa(O(2)) normally induces isometric contractile responses in rings of DA; however, the excessive inhibitory effects of endogenous prostaglandins and nitric oxide, coupled with a weaker intrinsic DA tone, make the preterm DA appear to have a smaller increment in tension in response to oxygen than the DA near term. We found that oxygen concentrations, beyond the normoxic range, produce an additional increase in tension in the preterm DA that is similar to the contractile response normally seen at term. We predicted that preterm newborns, kept at a higher Pa(O(2)), would have increased DA tone and would be more likely to obliterate their lumen. We found that preterm newborns, maintained at a Pa(O(2)) >200 mmHg, had only a 14% incidence of patent DA. Even though DA constriction was due to elevated Pa(O(2)), obliteration of the lumen produced profound hypoxia of the DA wall and the same features of remodeling that were observed at term. DA wall hypoxia appears to be both necessary and sufficient to produce anatomic remodeling in preterm newborns.

6-Ketoprostaglandin F1 alpha↗
PubMed2001

Prostanoid receptors: ontogeny and implications in vascular physiology.

Prostanoids exert significant effects on circulatory beds. They play a role in the response of the vasculature to adjustments in perfusion pressure and oxygen and carbon dioxide tension, and they mediate the actions of numerous factors. The role of prostanoids in governing circulation of the perinate is suggested to surpass that in the adult. Prostanoids are abundantly generated in the perinate. They have been implicated in autoregulation of blood flow as studied in brain and eyes. Prostaglandins are also dominant regulators of ductus arteriosus tone. The effects of these autacoids are mediated through specific G protein-coupled receptors. In addition to the pharmacological characterization of the prostanoid receptors, important advances in understanding the biology of these receptors have been made in the last decade. Their cloning and the development of animals with disrupted genes of these receptors have been very informative. The involvement of prostanoid receptors in the developing subject, especially on brain and ocular vasculature and on ductus arteriosus, has also begun to be investigated; the expression of these receptors changes with development. Some but not all of the ontogenic changes in these receptors are attributed to homologous regulation. Interestingly, in the process of elucidating their effects, functional perinuclear prostaglandin E2 receptors have been uncovered. This article reviews prostanoid receptors and addresses implications on the developing subject with attention to vascular physiology.

Animals↗
PubMed2001

Combined prostaglandin and nitric oxide inhibition produces anatomic remodeling and closure of the ductus arteriosus in the premature newborn baboon.

After birth, the full-term ductus arteriosus actively constricts and undergoes extensive histologic changes that prevent subsequent reopening. These changes are thought to occur only if a region of intense hypoxia develops within the ductus wall after the initial active constriction. In preterm infants, indomethacin-induced constriction of the ductus is often transient and is followed by reopening. Prostaglandins and nitric oxide both play a role in inhibiting ductus closure in vitro. We hypothesized that combined inhibition of both prostaglandin and nitric oxide production (with indomethacin and N-nitro-L-arginine (L-NA), respectively) may be required to produce the degree of functional closure that is needed to cause intense hypoxia. We used preterm (0.67 gestation) newborn baboons that were mechanically ventilated for 6 d: 6 received indomethacin alone, 7 received indomethacin plus L-NA, and 16 received no treatment (control). Just before necropsy, only 25% of control ductus and 33% of indomethacin-treated ductus were closed on Doppler examination; in contrast, 100% of the indomethacin-plus-L-NA-treated ductus were closed. Control and indomethacin-treated baboons developed negligible-to-mild ductus hypoxia (EF5 technique). Similarly, there was minimal evidence of ductus remodeling. In contrast, indomethacin-plus-L-NA-treated baboons developed intense hypoxia in regions where the ductus was most constricted. The hypoxic muscle strongly expressed vascular endothelial growth factor, and proliferating luminal endothelial cells filled and occluded the lumen. In addition, cells in the most hypoxic regions were undergoing DNA fragmentation. In conclusion, preterm newborns are capable of remodeling their ductus, just like the full-term newborn, if they can reduce their luminal blood flow to a point that produces intense ductus wall hypoxia. Combined prostaglandin and nitric oxide inhibition may be necessary to produce permanent closure of the ductus and prevent reopening in preterm infants.

Animals↗
PubMed2000

Prophylactic indomethacin: factors determining permanent ductus arteriosus closure.

BACKGROUND: Permanent closure of the ductus arteriosus (DA) requires both effective muscular constriction to block luminal blood flow and anatomic remodeling to prevent later reopening. OBJECTIVE: We examined the role of prophylactic indomethacin in producing permanent DA closure and the mechanism by which this occurs. METHODS: We studied 2 separate approaches to managing a patent DA in 257 preterm infants (gestation 24 to 27 weeks): (1) prophylactic indomethacin (all infants treated during the first 15 hours after birth) or (2) symptomatic treatment (infants in this group received indomethacin only if clinical symptoms appeared; infants whose ductus closed spontaneously and never received indomethacin were included in this group). Echocardiography was performed 24 to 36 hours after the last dose of indomethacin was administered or by age 5 days if spontaneous closure occurred. Infants were monitored for the development of ductus reopening. RESULTS: The prophylactic treatment group had a greater degree of initial ductus constriction, a higher rate of permanent anatomic closure, and a decreased need for surgical ligation than did the symptomatic treatment group. The degree of initial ductus constriction was the most important factor determining the rate of ductus reopening. Post-treatment echocardiography proved to be the best test for predicting eventual reopening. CONCLUSION: Prophylactic indomethacin improved the rate of permanent ductus closure by increasing the degree of initial constriction. Prophylactic indomethacin did not affect the remodeling process, nor did it alter the inverse relationship between infant maturity and subsequent reopening. Even when managed with prophylactic indomethacin, the rate of ductus reopening remained unacceptably high in the most immature infants.

Cardiovascular Agents↗
PubMed2000

Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo.

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents; however, they also have adverse fetal effects such as constriction of the fetal ductus arteriosus. Recently, selective COX-2 inhibitors have been used in the management of preterm labor in the hope of avoiding fetal complications. However, both COX-1 and -2 are expressed by cells of the ductus arteriosus. We used fetal lambs (0.88 gestation) to assess the ability of selective COX-2 inhibitors celecoxib and NS398 to affect the ductus arteriosus. Both selective COX-2 inhibitors decreased PGE(2) and 6ketoPGF(1alpha) production in vitro; both inhibitors constricted the isolated ductus in vitro. The nonselective COX-1/COX-2 inhibitor indomethacin produced a further reduction in PG release and an additional increase in ductus tension in vitro. We used a prodrug of celecoxib to achieve 1.4 +/- 0.6 microg/ml, mean +/- standard deviation, of the active drug in vivo. This concentration of celecoxib produced both an increase in pressure gradient and resistance across the ductus; celecoxib also decreased fetal plasma concentrations of PGE(2) and 6ketoPGF(1alpha). Indomethacin (0.7 +/- 0.2 microg/ml) produced a significantly greater fall in ductus blood flow than celecoxib and tended to have a greater effect on ductus resistence in vivo. We conclude that caution should be used when recommending COX-2 inhibitors for use in pregnant women, because COX-2 appears to play a significant role in maintaining patency of the fetal ductus arteriosus.

6-Ketoprostaglandin F1 alpha↗
PubMed2000

Tissue hypoxia inhibits prostaglandin and nitric oxide production and prevents ductus arteriosus reopening.

Regulation of ductus arteriosus (DA) tension depends on a balance between oxygen-induced constriction and PG and nitric oxide (NO)-mediated relaxation. After birth, increasing Pa(O(2)) produces DA constriction. However, as the full-term ductus constricts, it develops severe tissue hypoxia in its inner vessel wall (oxygen concentration <0.2%). We used isolated rings of fetal lamb DA to determine why the constricted ductus does not relax and reopen as it becomes hypoxic. We used a modification of the 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide (EF5) technique (Clyman RI, Chan CY, Mauray F, Chen YQ, Cox W, Seidner SR, Lord EM, Weiss H, Wale N, Evan SM, and Koch CJ. Pediatr Res 45: 19-29, 1999) to determine mean tissue oxygen concentration. A decrease in the ductus' mean tissue oxygen concentration from 1.4 to 0.1% lowers the isometric tone of the ductus by 15 +/- 10% of its maximal active tension (the maximal tension that can be produced by the ductus). Although decreases in oxygen concentration diminish ductus tension, most of the vasoconstrictor tone in the ductus is independent of ambient oxygen concentration. This oxygen-independent tone is equivalent to 64 +/- 10% of the maximal active tension. At mean tissue oxygen concentrations >0.2%, endogenous PGs and NO inhibit more than 40% of the active tension developed by the ductus. However, when tissue oxygen concentrations drop below 0.2%, the constitutive relaxation of the ductus by endogenous PGs and NO is lost. In the absence of PG and NO production, tension increases to a level normally observed only after treatment of the ductus with indomethacin and nitro-L-arginine methyl ester (inhibitors of PG and NO production). Therefore, under conditions of severe hypoxia (tissue oxygen concentration <0.2% oxygen), the loss of PG- and NO-mediated relaxation more than compensates for the loss of oxygen-induced tension. We hypothesize that this increased ductus tone enables the vessel to remain closed as it undergoes tissue remodeling.

Animals↗
PubMed1999

Developmental changes in prostaglandin E(2) receptor subtypes in porcine ductus arteriosus. Possible contribution in altered responsiveness to prostaglandin E(2).

BACKGROUND: Prostaglandin E(2) (PGE(2)) is important in ductus arteriosus (DA) patency, but the types of functional PGE(2) receptors (EP) in the developing DA are not known. We postulated that age-dependent alterations in EP and/or their subtypes may possibly contribute to the reduced responsiveness of the newborn DA to PGE(2). METHODS AND RESULTS: We determined PGE(2) receptor subtypes by competition binding and immunoblot studies on the DA of fetal ( approximately 75% and 90% gestation) and newborn (<45 minutes old) pigs. We studied the effects of EP receptor stimulation on cAMP signaling in vitro and on term newborn (<3 hours old) DA patency in vivo. Fetal pig DA expressed EP(2), EP(3), and EP(4) receptors equivalently, but not EP(1). In neonatal DA, EP(1), EP(3), and EP(4) were undetectable, whereas EP(2) density was similar in fetus and newborn. Prostaglandin-induced changes in cAMP mirrored binding data. 16,16-Dimethyl PGE(2) and 11-deoxy PGE(1) (EP(2)/EP(3)/EP(4) agonist) produced more cAMP in fetus than newborn, but butaprost (selective EP(2) agonist) caused similar cAMP increases in both; EP(3) and EP(4) ligands (M&B28767 and AH23848B, respectively) affected cAMP production only in fetus. After birth, administration of butaprost alone was as effective as 11-deoxy PGE(1) and 16,16-dimethyl PGE(2) in dilating DA in vivo. CONCLUSIONS: The data reveal fewer PGE(2) receptors in the DA of the newborn than in that of the fetus; this may contribute to the decreased responsiveness of the DA to PGE(2) in newborn. Because EP(2) receptors seem to mediate the effects of PGE(2) on the newborn DA, one may propose that a selective EP(2) agonist may be preferred as a pharmacological agent to maintain DA patency in infants with certain congenital heart diseases.

Animals↗
PubMed1999

Incidence and outcome of a 10-fold indomethacin overdose in premature infants.

We reviewed the incidence and morbidity of a 10-fold medication error among all premature infants treated with indomethacin. We detected 4 incidents among 1059 indomethacin doses given to infants weighing less than 1000 g. None of the infants had intracranial hemorrhage, necrotizing enterocolitis, or significant deterioration of renal function.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Cyclooxygenase-2 plays a significant role in regulating the tone of the fetal lamb ductus arteriosus.

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents but have adverse effects on the fetal ductus arteriosus. We hypothesized that COX-2 inhibitors may not affect the ductus if the predominant COX isoform is COX-1. To examine this hypothesis, we used ductus arteriosus obtained from late-gestation fetal lambs. In contrast to our hypothesis, fetal lamb ductus arteriosus expressed both COX-1- and COX-2-immunoreactive protein (by Western analysis). Although COX-1 was found in both endothelial and smooth muscle cells, COX-2 was found only in the endothelial cells lining the ductus lumen (by immunohistochemistry). The relative contribution of COX-1 and COX-2 to PGE2 synthesis was consistent with the immunohistochemical results: in the intact ductus, PGE2 formation was catalyzed by both COX-1 and COX-2 in equivalent proportions; in the endothelium-denuded ductus, COX-2 no longer played a significant role in PGE2 synthesis. NS-398, a selective inhibitor of COX-2, was 66% as effective as the selective COX-1 inhibitor valeryl salicylate and the nonselective COX inhibitor indomethacin in causing contraction of the ductus in vitro. At this time, caution should be used when recommending COX-2 inhibitors for use in pregnant women.

Animals↗
PubMed1999

Permanent anatomic closure of the ductus arteriosus in newborn baboons: the roles of postnatal constriction, hypoxia, and gestation.

Permanent closure of the ductus arteriosus requires loss of cells from the muscle media and development of neointimal mounds, composed in part of proliferating endothelial cells. We hypothesized that postnatal ductus constriction produces hypoxia of the inner vessel wall; we also hypothesized that hypoxia might lead to cell death and the production of vascular endothelial cell growth factor (VEGF), a hypoxia-inducible growth factor that stimulates endothelial proliferation. We mapped the distribution of hypoxia in newborn baboons and correlated it with the appearance of cell death (TUNEL technique), VEGF expression, and endothelial proliferation (proliferating cell nuclear antigen expression). In the full-term baboon (n=10), the ductus was functionally closed on Doppler examination by 24 h after delivery. Regions of the ductus where the lumen was most constricted were associated with moderate/intense hypoxia; VEGF expression was increased in the hypoxic muscle media, and luminal endothelial cells, adjacent to the hypoxic media, were proliferating. Cells in the most hypoxic regions of the ductus wall were undergoing DNA fragmentation. In contrast, regions of the ductus with mild degrees of hypoxia had no evidence of cell death, VEGF expression, or endothelial proliferation. Cell death and endothelial proliferation seemed to be limited to regions of the full-term ductus experiencing moderate/intense hypoxia. In the premature baboon (67% gestation) (n=24), only 29% closed their ductus by Doppler examination before d 6. None of the premature baboons, including those with a closed ductus by Doppler, had evidence of moderate/intense hypoxia; also, there was no evidence of cell death, VEGF expression, endothelial proliferation, or neointima formation by d 6. Therefore, the premature ductus is resistant to developing hypoxia, even when its lumen is constricted; this may make it susceptible to later reopening.

Animals↗
PubMed1998

Expression of cyclooxygenases in ductus arteriosus of fetal and newborn pigs.

OBJECTIVE: We studied the ontogeny of the expression of cyclooxygenase-1 and cyclooxygenase-2 in the ductus arteriosus and evaluated their functional significance. STUDY DESIGN: The expression of cyclooxygenase-1 and cyclooxygenase-2 was studied in ductus arteriosus of fetal (at approximately 75% gestation) and term newborn pig. Effects of selective inhibitors of cyclooxygenase-1 and cyclooxygenase-2 on ductal patency were evaluated by Doppler ultrasonography. RESULTS: Ductus arteriosus of the fetus expressed virtually only cyclooxygenase-1 immunoreactive protein and activity. In contrast, the ductus of the term newborn pig (<45 minutes old) contained proteins of both cyclooxygenase-1 and cyclooxygenase-2, but the latter contributed to >90% of prostaglandin E2 formation. The selective cyclooxygenase-2 inhibitor DuP697 reduced prostaglandin E2 levels in the ductus arteriosus, albeit not in plasma, but did not affect ductal patency in the newborn pig (<1(1/2) hours old); in contrast, the cyclooxygenase-1 inhibitor valeryl salicylate, like indomethacin, markedly reduced levels of prostaglandin E2 in the plasma and ductus arteriosus and caused significant constriction of the ductus arteriosus. CONCLUSION: The ductus arteriosus of the term newborn pig, in contrast to that of the fetus, expresses cyclooxygenase-2, but circulating prostaglandins, arising mostly from cyclooxygenase-1, seem to exert the major control on ductal patency in vivo. Our data suggest that cyclooxygenase-2 inhibitors might be better alternatives for the fetus than nonselective cyclooxygenase blockers if indicated for maternal conditions such as inflammation or for tocolysis.

Animals↗
PubMed1998

Risk factors associated with infant death among very low birth weight infants after discharge from an intensive care nursery.

Low birth weight infants have an increased incidence of death after discharge from the intensive care nursery (ICN). To evaluate factors associated with death, and especially unexpected death, we conducted a study on 724 infants discharged from our ICN with a birth weight 1500 g or less. Twenty-four infants died during the 1st year after discharge. Univariate analyses and logistic regression analyses were used to examine the effects of birth weight, gestational age, race, gender, growth retardation, chronic lung disease (CLD), intracranial hemorrhage (ICH), and socioeconomic risk on postdischarge death. Of the risk factors studied, only CLD (p = .001) and ICH (p = .004) were independently associated with death, but ICH alone was the most worrisome risk factor associated with sudden, unexpected death in low birth weight infants after discharge from an ICN.

Child↗
PubMed1998

Endothelin-receptor blockade does not alter closure of the ductus arteriosus.

Endothelin-1 (ET-1) is synthesized within the wall of the ductus arteriosus (DA) and is a potent constrictor of the DA in vitro. However, the role of endogenous ET-1 in closure of the DA at birth remains unclear. Therefore, we studied the effects of a selective ETA-receptor antagonist (PD-156707), or its vehicle, on DA closure in 13 late-gestation fetal lambs during the first 5 h after birth. We also studied the effects of ETA-receptor blockade on DA constriction induced by oxygen, indomethacin (a cyclooxygenase inhibitor), and LY-83583 (a soluble guanylate cyclase inhibitor) in vitro (n = 9 ductus arteriosus rings). In vehicle-treated lambs in vivo, the DA constricted during the 5-h study period after birth: DA resistance increased (from 0.007 +/- 0.01 to 3.406 +/- 4.15 mmHg. ml-1. min. kg-1; P < 0.05); the pressure gradient across the DA increased (from 1.4 +/- 2.1 to 25.2 +/- 9.4 mmHg; P < 0.05); and DA blood flow decreased (from 193.5 +/- 48.0 to 19.3 +/- 14.3 ml. kg-1. min-1; P < 0.05). In vitro, the DA was constricted by exposure to 30% oxygen (23 +/- 14% net active tension; P < 0.05), indomethacin (5 x 10(-6) M, 22 +/- 5% net active tension; P < 0.05), LY-83583 (10(-5) M, 24 +/- 10% net active tension; P < 0.05), and ET-1 (10(-7) M, 19 +/- 4% net active tension; P < 0.05). Although PD-156707 blocked both the in vivo and in vitro effects of exogenous ET-1, it had no effect on postnatal ductus constriction nor on in vitro ductus contractile responses to oxygen, indomethacin, or LY-83583. This study suggests that endogenous ET-1 does not play an important role in closure of the DA at birth.

Animals↗