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Furosemide increases prostaglandin production and may be associated with patent ductus arteriosus (PDA). We aimed to clarify the in vivo ductus-dilating effects of furosemide in neonatal rats. Near-term rat pups delivered by a cesarean section were housed at 33 degrees C. After a rapid whole-body freezing, the DA diameter was measured using a microscope and a micrometer. Pregnant rats (gestational day 21) were s.c. injected with furosemide 4 h before delivery, and the neonatal DA was examined 0, 15, 30, 60, and 120 min after birth. Furosemide was also s.c. injected into 60-min-old rats and the DA diameter was examined 30, 60, and 120 min later. The control rats showed a rapid postnatal DA constriction (diameter: 0.80 and 0.08 mm at 0 and 60 min after birth, respectively). Prenatally administered furosemide delayed postnatal DA closure (0.36 mm at 60 min after birth). Furosemide injection in 60-min-old rats dilated the constricted DA at 60 min (0.25 versus 0.02 mm in the controls). Indomethacin inhibited furosemide-induced DA dilatation. Furosemide delays DA closure and dilates the constricted DA in neonatal rats. If furosemide has similar effects in human preterm neonates, caution may be warranted in its use in the treatment of infants with PDA.

Indomethacin is used to constrict the patent ductus arteriosus in premature infants. To clarify possible prostanoid receptor antagonists that can constrict the ductus, we studied in vivo constriction of the fetal and neonatal ductus arteriosus by AE3-208, a prostanoid EP4-receptor antagonist, in rats. Following quick cesarean section of near-term pregnant rats (21 d), neonates were incubated in room air at 33 degrees C. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing of the fetus and neonate, and sectioning of the thorax in the frontal plane on a freezing microtome. In the control, the ductus arteriosus constricted quickly after birth, and the inner diameter was 0.80 mm in the fetus and 0.06 mm at 90 min after birth. AE3-208, administered orogastrically to the dam, constricted the fetal ductus dose dependently. Maximal ductal constriction was observed 4 h after administration, and the ductal diameters were 0.06 mm and 0.26 mm after administration of 10 mg/kg and 10 ng/kg of AE3-208, respectively. In neonatal rats, AE3-208 injected subcutaneously at 30 min after birth, inhibited dilatation of the ductus by PGE1 dose dependently. PGE1 (10 microg/kg) was injected subcutaneously to the 1-h-old neonatal rat, and the ductal diameters were 0.53 mm and 0.19 mm without and with pretreatment of AE3-208 (10 microg/kg), respectively. These results indicate the major role of EP4 in the fetal and neonatal ductus and show that an EP4 antagonist can be used to constrict the patent ductus of premature infants.

A recent in vitro study showed that sildenafil, a type 5 phosphodiesterase inhibitor, dilated the constricted ductus arteriosus of neonatal rabbits. We studied the in vivo ductus-dilating effects of sildenafil in fetal and neonatal rats. Ductus diameters were measured with whole-body freezing and cutting on a freezing microtome. Indomethacin (10 mg/kg) constricted the fetal ductus severely at 4 and 8 h after orogastric administration to the dams. Sildenafil, administered orogastrically and simultaneously with indomethacin, dilated the near-term fetal [21 fetal days (FD)] ductus constricted by indomethacin completely with 1 mg/kg at 8 h after administration. The preterm fetal ductus was more sensitive to sildenafil at 19FD. The ductus constricted rapidly after birth, and the ductal diameter was only 10% of the fetal diameter at 1 h after birth. The ductus-dilating effect of sildenafil was studied by i.p. injection at 1 h after birth, and the ductus diameter was studied 30 and 60 min later. Sildenafil dilated the neonatal constricted ductus moderately with a massive dose (100 mg/kg) and only minimally with 1 mg/kg. In conclusion, sildenafil, a type 5 phosphodiesterase inhibitor, dilated the constricted fetal ductus completely at 8 h with 1 mg/kg in the near-term fetus and completely with a smaller dose (0.1 mg/kg) in the preterm fetus. However, sildenafil dilated the neonatal constricted ductus only moderately with large doses and minimally with 1 mg/kg. Probably, sildenafil is useful clinically for treating idiopathic and secondary fetal ductal constriction and not useful for dilation of the neonatal constricted ductus.

The mammalian heart is known to contain only two isoformic myosin heavy chain (MHC) genes, α and β. A previously uncharacterized MHC gene was isolated in Syrian hamster hearts (McCully et al., J Mol Biol 1991). We identified the novel MHC gene as a hamster embryonic skeletal MHC gene based on the developmental stage- and tissue-specific expression pattern: the restricted expression of mRNA to striated muscles was highest in embryonic skeletal muscle and was developmentally down-regulated. We confirmed that the embryonic skeletal MHC gene exhibited higher expression in cardiomyopathic than in normal hamster hearts, and was up-regulated during the development of cardiomyopathy. The sporadic expression was highly localized in the endocardium. The present study identified that a very small number of undifferentiated myogenic cells existed in adult hamster endocardium. Moreover, using RT-PCR, a homologue of embryonic skeletal MHC mRNA was also expressed in human embryonic, but not adult ventricles. Our data provide a new insight into the regulatory mechanisms of MHCs in the cardiomyopathic hamster heart.

The role of endothelin in oxygen-induced contraction remains controversial. The present study was designed to investigate the role of endothelin in O2-induced contraction in the isolated ductal preparation of rabbit and rat, using the endothelin receptor antagonists, bosentan (antagonist for both ET-A and ET-B receptors) and BQ 485 (an ET-A selective antagonist). The ductus was isolated from fetal rabbits at 30 days of gestation (term 31 days) and fetal rats at 21 days of gestation (term 22 days). In the rabbit ductus with intact endothelium, 13% of the O2-induced contraction was inhibited by bosentan and 14% by BQ 485. In the rabbit ductus without endothelium, bosentan did not cause significant inhibition of the oxygen-induced contraction. In the rat ductus with intact endothelium, about 44% of the O2-induced contraction was inhibited by bosentan. In the rat ductus without endothelium, O2-induced contraction was 20% less than that in the ductus with intact endothelium. In the rat ductus without endothelium, bosentan further decreased the oxygen-induced contraction by about 24%. These data suggest that (1) endothelin plays a significant role in O2-induced contraction in the isolated ductus arteriosus, (2) there is a species difference in the degree of contribution of endothelin to the O2-induced ductal contraction, and (3) there is a species difference in the degree of contribution of the endothelium and vascular smooth muscle cells to the release of endothelin from the ductus arteriosus.

Endogenous retinoic acid may play a role in inducing smooth muscle differentiation in the fetal ductus arteriosus. Maternal administration of retinoic acid may accelerate the process. This study was designed to investigate the effect of vitamin A on developmental changes in the contractile system of the ductus. Vitamin A was injected into pregnant rats and the ductus was isolated from the fetus at 19, 20, or 21 d of gestation. The fetus at 19 d of gestation served as a model of the preterm fetus. The force of contraction and [Ca]i were measured. Membrane depolarization caused by high KCl induced ductal contraction in all age groups studied. In the 19-d fetus, O2 did not cause significant contraction or changes in [Ca]i in the control group, but it did induce a significant contraction and increases in [Ca]i in the vitamin A-treated group. In the 20- and 21-d fetuses, 5% O2-induced contraction in the vitamin A-treated group was significantly greater than in the control group. In the 19-d fetus, noradrenaline-induced contraction and increases in [Ca]i, indicators of the size of the intracellular Ca pool, were observed and they were similar in the control group and in the vitamin A-treated group. These data suggest that 1) in the preterm fetus, the contractile system, including membrane depolarization, [Ca]i increase, and its activation of contractile proteins, is already functioning, but the O2-sensing mechanism is underdeveloped, 2) vitamin A accelerates the development of the O2-sensing mechanism of the ductus arteriosus.

In adult patients with severe chronic mitral regurgitation, many predictors for estimating postoperative left ventricular systolic function have been proposed. However, none has been defined in children. We analyzed the relationship between such predictors and postoperative left ventricular fractional shortening in children with isolated congenital mitral regurgitation. Eight patients with isolated congenital mitral regurgitation were examined before and after surgery with echocardiography. Fractional shortening, left ventricular end-diastolic and end-systolic dimension indices, and left ventricular end-systolic wall stress/left ventricular end-systolic dimension index in the preoperative status were poorly correlated with postoperative left ventricular fractional shortening. Predictive wall stress, which was calculated from preoperative data of end-diastolic dimension, end-diastolic wall thickness, and diastolic blood pressure, correlated well with postoperative left ventricular fractional shortening (r = -0.90, p = 0.0024). It is important to consider not only myocardial contractility but also postoperative afterload for estimating postoperative left ventricular performance in chronic severe mitral regurgitation.

Prostaglandin E is a major dilator of the fetal ductus arteriosus (DA), but the role of nitric oxide in fetal ductal dilation has not been established. We studied the effects of a potent nitric oxide synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), on the fetal DA in rats. L-NAME was injected into the dorsum of pregnant rats, and fetal DA was studied 4 h later with a rapid whole body freezing method. The inner diameters of the DA and the main pulmonary artery were measured on a freezing microtome. The inner diameter ratio of DA to main pulmonary artery (DA/PA) was 1.02+/-0.03 (mean +/- SEM; number of fetuses [n], 21) in normal near-term fetuses. The effect of prostaglandin synthesis inhibition was studied after orogastric administration of indomethacin to pregnant rats. In near-term rats on the 21st day of gestation (term, 21.5 d), a large dose of L-NAME (100 mg/kg) caused only mild ductal constriction, with DA/PA reduced to 0.83+/-0.05 (n = 20). Indomethacin (1 mg/kg) caused moderate ductal constriction, and DA/PA was decreased to 0.65+/-0.05 (n = 21). Combined administration of L-NAME (10 mg/kg) and indomethacin (1 mg/kg) caused severe ductal constriction, with DA/PA of 0.26+/-0.03 (n = 16). In preterm rats on the 19th day of gestation, a moderate dose of L-NAME (10 mg/kg) caused severe ductal constriction, with a DA/PA of 0.32+/-0.05 (n = 24). Indomethacin (1 mg/kg) alone caused only mild ductal constriction, with DA/PA 0.86+/-0.02 (n = 16). In conclusion, prostaglandin has a major role and nitric oxide has a minor role in dilating the DA in the near-term fetal rat. In contrast, nitric oxide has a major role and prostaglandin has a minor role in dilating the DA in preterm fetal rats.

We analyzed the electron-microscopic features of endomyocardial biopsy from pediatric patients with dilated cardiomyopathy (DCM). The specimens examined were taken from the right ventricle of ten patients aged from 2 to 15 years (mean 9.7 years). Biopsy specimens from eight patients with congenital heart disease (tetralogy of Fallot), aged from 3 to 12 (mean 7.3 years), and ten adult patients with DCM, aged from 32 to 60 (mean 45 years), were also examined. Patients considered to have endocardial fibroelastosis, arrhythmogenic right ventricular cardiomyopathy, specific cardiomyopathy, or coronary heart disease were excluded from this study. Specimens from pediatric patients with DCM showed various degrees of ultrastructural abnormalities of myocytes, including myofibrillar fragmentation, mitochondrial abnormalities, and intracellular edema. The ultrastructurally determined contractility failure index based on the severity of myocardial degeneration at the electronmicroscopic level was 4.9 +/- 1.1. This value was significantly higher than that in patients with tetralogy of Fallot (0.9 +/- 0.6, P < 0.001) but was not significantly different from that in adult patients with DCM (6.1 +/- 2.6). The index of pediatric patients with DCM who died within 3 years was high (6.0 +/- 0.8). Basal lamina layering of a capillary (BLL) in the myocardium was revealed in 1 of the 10 (10%) pediatric patients with DCM and in 6 of the 10 (60%) adult patients with DCM (P < 0.05). No BLL was noted in the patients with tetralogy of Fallot. These findings may be related to the pathogenesis of DCM in children and adults.

Maturation of fetal ductus arteriosus is associated with increased constriction in response to maternally administered indomethacin. Recently retinoic acid has been shown to be important in development of the fetal ductus arteriosus. To determine whether retinoid might be of value in the treatment of patent ductus arteriosus in premature infants, we studied the response of fetal ductus arteriosus to indomethacin with and without pretreatment with vitamin A (1 mg (3000 IU)/kg, intramuscular injection) in near-term and preterm rats. Maturation of the ductus arteriosus was studied by measuring the inner diameters of the ductus arteriosus (D) and main pulmonary artery (P) to get D/P ratio 4 h after orogastric administration of 1 mg/kg indomethacin. D/P was 1.0 in the fetus before administration of indomethacin. In near-term fetuses on the 21st d without vitamin A, D/P decreased to 0.54 with indomethacin, whereas it decreased to 0.27 (p < 0.05) in those with pretreatment with vitamin A on the 19th and 20th d. In preterm fetuses on the 20th d without pretreatment with vitamin A, D/P decreased to 0.82 with indomethacin, whereas it decreased to 0.66 (p < 0.05) in those with pretreatment with vitamin A on the 19th d. It is concluded that maternally administered vitamin A accelerates maturation of the ductus arteriosus in fetal rats.

This study investigated the effect of acidosis on intracellular pH (pHi), intracellular calcium concentration ([Ca]i), and vascular contraction in the aorta of the newborn and adult rabbit. Isometric tension, pHi, and [Ca]i were measured in an isolated ring preparation. After the vascular contraction was induced with 50mM KC1, the effect of respiratory acidosis produced by elevation of PCO2 was studied. Respiratory acidosis caused a transient depression followed by a recovery of contractile tension. The decrease in developed tension was greater in the newborn than in the adult. The decrease in pHi during acidosis was similar in the two age groups. [Ca]i increased during acidosis and the increase was greater in the newborn than in the adult. These data show that the vasorelaxant effect of acidosis in the newborn aorta is greater than that in the adult aorta. The greater vasodilation in the newborn cannot be explained by the difference in pHi or [Ca]i.

This study investigated developmental changes in the contractile system of the mesenteric small arteries of the rabbit. Arteries about 1 mm in length and 100-250 microns in internal diameter were dissected out from the mesenteric bed of the fetus (29 d of gestation), newborn (3-5 d old), and adult rabbit. Vascular contraction was induced by high KCl concentration, and contractile force was measured using a tension transducer. The sensitivity of vascular contraction to high KCl was similar in the three age groups. To determine the role of Ca influx across the sarcolemma in vascular contraction, the vasorelaxant effect of diltiazem was studied in the artery precontracted with high KCl concentration. The vasorelaxant effect of diltiazem in the fetus and newborn was less than in the adult. To estimate the size of the intracellular Ca pool, caffeine-induced and noradrenaline-induced contraction were measured in the Ca- and Na-free solution. In the fetus and newborn, both the caffeine-induced contraction and noradrenaline-induced contraction were greater than in the adult. The ultrastructural study showed that the endoplasmic reticulum was abundant in the fetus and newborn, and it was scarce in the adult. These data indicate that the dependency of vascular contraction on Ca influx across the sarcolemma increases and the intracellular Ca store decreases with development in the mesenteric resistance arteries.

Background. Myocardial contractile dysfunction has been frequently observed in adolescents or adults with cyanotic congenital heart disease. Impaired energy metabolism may be present in such dysfunctional myocardium. Methods and Results. To evaluate the findings of myocardial free fatty acid metabolism, and its relations to ventricular wall motion and myocardial perfusion in cyanotic congenital heart disease, we performed a combined study of iodine 123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) scintigraphy, thallium scintigraphy, and contrast cineangiography in seven patients with single right or left ventricle. The results showed that wall motion was reduced in 17 of 35 ventricular segments (49%), which were mostly identical in location to decreased BMIPP uptake. The severity of BMIPP uptake deficit correlated positively with the degree of impairment of wall motion. On the other hand, thallium uptake was abnormal only in 5 of 35 segments (14%), and the severity of the perfusion defect did not correlate with the degree of wall motion abnormality. Conclusions. Contractile dysfunction in cyanotic heart disease was primarily linked to impaired free fatty acid metabolism rather than to myocardial scar as represented by perfusion defect on thallium imaging.

After undergoing the Fontan procedure for congenital heart disease, 16 young patients performed a maximal treadmill test according to the Bruce protocol. The peak velocity of the blood flow in the ascending aorta, stroke index, and cardiac index were measured by continuous-wave Doppler echocardiography at rest and at each stage of the test. The results were compared with those from 18 normal children. The body surface area was similar in the two groups. The endurance time was 37% shorter in the Fontan group than in the control group. From the beginning of exercise until the sixth minute, the increase in stroke index was lower in the Fontan group (NS). After that point, the stroke index was maintained at a high level in the control group but decreased toward its original level in the Fontan group. The response of cardiac index to exercise in the two groups was comparable until the sixth minute, after which the Fontan group failed to maintain an ascending curve. All the hemodynamic values were significantly higher in the control group at maximal exercise; at this point the cardiac index had increased 79% in the Fontan group and 170% in the control group. The subnormal response of the stroke volume at submaximal exercise and the subsequent decrease at maximal exercise following the Fontan procedure are important hemodynamic findings.

This study was performed to determine the efficacy of balloon-expandable stents in the treatment of branch pulmonary artery-stenoses and conduit stenosis in children. A total of eight stainless steel stents were implanted in seven patients. Three patients had tetralogy of Fallot with pulmonary artery stenosis following total correction, one patient had conduit stenosis following correction of transposition of the great arteries, one patient had intra-cardiac conduit stenosis after septation for single left ventricle, and two patients had pulmonary artery stenosis after Fontan operation. Six stents were placed in the branch pulmonary arteries, one in the extracardiac conduit, and one in the intracardiac conduit. The mean age at implantation was 13 +/- 3 years and the mean weight 37 +/- 12 kg. Follow-up time ranged from 0.3-2 years. The diameter of pulmonary arteries with stenoses increased from 5.6 +/- 2.2 mm to 10.6 +/- 1.8 mm (n = 7). The systolic pressure gradient decreased from 56 +/- 26 mmHg to 22 +/- 16 mmHg (n = 5). No embolization or thrombotic event has been noted. One stent placed in the intracardiac conduit was compressed and fractured. These data indicate that balloon-expandable stents are useful in the treatment of pulmonary artery branch stenoses and extracardiac conduit stenosis in children. The use of stents for intracardiac stenosis may result in stent fracture.

In situ cross-sectional morphology of the ascending, descending, and abdominal aorta and the com- mon iliac arteries was studied after rapid, whole-body freezing of fetal and neonatal rats. In the fetus, the ascend- ing aorta was smaller than the descending aorta and the abdominal aorta was relatively large, continuing to the large right common iliac artery and the umbilical artery. After birth, the umbilical artery and the ductus arteriosus closed rapidly, and the size of the aorta changed within a few days. The ascending aorta became larger than the descending aorta in 2 d, and the abdominal aorta became smaller, especially at the infrarenal part. The right com- mon iliac artery, which continues to the umbilical artery in fetal life, became smaller, and its diameter was the same as that of the left common iliac artery 2 d after birth. (Pediatv Res 33: 302-306, 1993)

In situ cross-sectional morphology of the foramen ovale was studied after rapid whole-body freezing of the fetal and neonatal rat. In the fetus, the foramen ovale was open widely toward the left atrium with a thin, short primum septum. The opening area of the foramen ovale was 40% of the cross-section of the thoracic inferior vena cava, and the ratio of the long diameter to the short diameter was 2 to 1. After birth, the primum septum became longer, thicker, and straighter, with less leftward bowing. The opening of the foramen ovale diminished in the first 2 d and closed completely 3 d after birth. Postnatal thickening of the primum septum was very remarkable, increasing by 400% in the first 2 d, while only minimal change was noticed in the right and the left atrial walls. The length of the primum septum was short and was only 90% of the diameter of the fossa ovalis in the fetus. It increased and reached 97% and 111% of the diameter of the fossa ovalis 1 and 2 d after birth, respectively. The septum secundum also grew rapidly after birth, and its length and width increased by 40% and 29% after 1 and 2 d, respectively. These observations indicate a sudden, ex- plosive growth of the atrial septum in the early neonatal period in the rat. (Pediatr Res 32: 669-672, 1992)

Nine cases of imperforate tricuspid valve associated with dysplasia of the right ventricular myocardium, pulmonary valve, and right coronary artery are described. The mean frontal QRS axis of the electrocardiograms did not indicate left axis deviation in seven of the nine. Two-dimensional echocardiograms showed an imperforate tricuspid valve, normally aligned atrioventricular septum, and an irregular-shaped right ventricular cavity with a thin wall. In three cases with absence of the pulmonary valve, pulsed Doppler echocardiograms of the right ventricular outflow tract revealed antegrade flow during systole and retrograde flow during diastole, and selective angiography through a persistent ductus arteriosus showed retrograde filling of the blind-ended right ventricular cavity via the main pulmonary artery. Necropsy examinations showed an imperforate tricuspid valve with a thin-walled aneurysmal right ventricle in all six cases examined. Pulmonary atresia was observed in two cases, and the absence of the pulmonary valve in four. The right coronary artery was hypoplastic in four cases and absent in two. A shunt operation should be carried out in early infancy to prevent hypoxia after closure of the ductus arteriosus.

Background: Sulfonylureas (tolbutamide = Rastinon, glibenclamide = glyburide, glimepiride = Amaryl) inhibit KATP channels and induce release of insulin. In in-vitro studies, glibenclamide constricts the ductus arteriosus. Placental transport of sulfonylureas is variable; high with tolbutamide, and low with glibenclamide, respectively. Purpose: To clarify the in-vivo ductus constrictive effects of various sulfonylureas. Methods: Sulfonylureas were administered orogastrically to pregnant near-term (21FD) or preterm (19FD) Wistar rats. Fetal ductus arteriosus was studied 2, 4, 8 and 24 hours later, with a rapid whole-body freezing method and measurement of the inner diameter of the ductus. Results: Tolbutamide constricted the fetal ductus dose-dependently. With clinical dose (10 and 30 mg/kg), the near-term fetal ductus constricted moderately, and the ductal diameter decreased to 0.8 and 0.5 compared to the control four hours later. With a large dose (100 mg/kg), the fetal ductus constricted severely, and the diameter decreased to 0.2 compared to the control four hours later. Tolbutamide constricted the pre-term ductus comparatively less. Glimepiride with a large dose of 10 mg/kg constricted the near-term fetal ductus only mildly. With a large dose of glibenclamide (10 mg/kg), it did not constrict the near-term or the preterm ductus arteriosus, reflecting poor placental transport. Conclusion: Clinical doses of tolbutamide constrict the fetal ductus moderately. With a 10 times larger dose, the ductus closes completely. Experimental comparison suggests tolbutamide is more potent constrictor of the fetal ductus than indomethacin, and can be used to close a premature PDA in the rat model. FD = Fetal Days.

We studied the effects of prostaglandins and their precursors in animal models. Rabbit ductus arteriosus constricted rapidly after delivery. PGE1, and PGE2, and arachidonic acid injected SC dilated the ductus over 60 min. Orogastrically administered PGE2 dilated the ductus for 3 hr. PGF2a and arachidonic acid showed weak ductus-dilating effects. Response of the ductus to PGE1 was most prominent in the first hr after birth. Pretreatment with indomethacin blocked the ductus-dilating effect of arachidonic acid.

Morphology of the cardiac chambers and great vessels of fetal and neonatal rats was studied using the whole body freezing technique and by sectioning through the short axis of the heart with a freezing microtome. Compared to the fetal heart, the neonatal heart showed rapid change 2 to 8 days after birth. The ventricular sinus septum was straight in the fetus and became concave to the left ventricle after birth. The right ventricular wall was as thick as the left in the fetus and became thinner rapidly after birth. At the same time, the right ventricular cavity dilated. The right and left pulmonary arteries and pulmonary veins were small in the fetus and enlarged soon after birth. At the same time, the foramen ovale was closed and the diameters of the inferior vena cava and descending aorta were diminished. One-half-mm thick sections were cut serially and then photographed. Ventricular volumes and masses were calculated from summation of the areas of each chambers. Left ventricular mass per body weight increased rapidly after birth, whereas right ventricular mass per body weight remained constant from 0 to 8 days after birth.

Ten patients with total and one with partial anomalous pulmonary venous connection were studied by two-dimensional Doppler color flow-mapping echocardiography. In cases of anomalous pulmonary venous drainage into the innominate vein through the vertical vein, flow away from the transducer was detected in the echo space behind the atria in the subxiphoid four-chamber approach. In the suprasternal approach, flow toward the transducer was detected at the junction of the vertical and innominate veins. In the case of an anomalous pulmonary vein connecting directly into the superior vena cava, an area of flow toward the transducer, which was triangular in shape, was detected in the dilated superior vena cava. In the two cases in which the pulmonary vein drained into the coronary sinus, the flow toward the transducer was observed at the ostium of the coronary sinus in the subxiphoid four-chamber view, and it appeared as if the blood flow was emerging from this point. In a case of the paracardiac type of total anomalous pulmonary venous connection with drainage into the posterior wall of the right atrium, the flow toward the transducer occurred higher in the right atrium than in the cases with drainage into the coronary sinus. In a case with the infradiaphragmatic type of total anomalous pulmonary venous connection, continuous flow toward the transducer, which passed through the diaphragm in an anomalous vessel, was detected from the subxiphoid area. The downward flow in the anomalous vessel changed to an upward flow at the site of drainage into the hepatic vein. We conclude that the site of drainage in patients with total and partial anomalous pulmonary venous connection can be detected easily and without fail using two-dimensional Doppler color flow mapping.

Indomethacin 10 mg/kg was administered to the maternal rat on the 21st day of pregnancy, and the fetal and neonatal ductus arteriosus were studied using the rapid whole-body freezing technique. The sagittal section of the frozen thorax disclosed characteristic localized constriction at the aortic end of the fetal ductus at 24 h after administration of indomethacin. Proximal dilatation of that fetal ductus persisted for more than 4 h after birth, and disappeared gradually. Shortening of the ductal length was associated with both intrauterine constriction by indomethacin in experimental rats and neonatal physiologic constriction of control rats, but significantly greater shortening was seen with intrauterine constriction.

Herein we report age differences of in vivo constriction of the fetal ductus arteriosus by nonsteroidal antiinflammatory drugs in near-term and preterm rats. Two potent nonsteroidal antiinflammatory drugs, indomethacin and flurbiprofen, were studied in preterm (19th and 20th day) and near-term (21st day) rats, whose gestational period was 21.5 days. The time course of fetal ductus constriction was studied on the 20th (preterm fetus) and the 21st (near-term fetus) days of gestation with indomethacin (1 mg/kg, 10 mg/kg) and flurbiprofen (10 mg/kg). In addition, 5 mg/kg of indomethacin was used on the 21st day. Maximal ductal constriction was noticed 8 h after administration. Constriction of the ductus was significantly weaker on the 20th day than on the 21st day in all three studies including indomethacin 1 mg/kg, 10 mg/kg, and flurbiprofen, 10 mg/kg. Dose-response curves were studied at 4 h following administration of indomethacin on the 19th, 20th, and 21st days, and flurbiprofen on the 20th and 21st days. With both drugs, the ductus constricted more vigorously on the 21st day than on the 20th or 19th day. These studies showed a weaker constrictive response of the ductus to nonsteroidal antiinflammatory drugs in the preterm fetus than in the near-term fetus. Twenty-four h after administration of indomethacin on the 20th day, the fetal ductus was dilated, although its plasma indomethacin concentration was high and comparable with that obtained 4 h after administration. These results show that the response of the fetal ductus to indomethacin decreased further at 24 h after administration to preterm rats.

A morphological study using the rapid whole-body freezing technique revealed in utero development of hypertrophy and diminished cavity of the right ventricle caused by fetal ductal constriction.