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Experimental growth retardation produced by transient period of uteroplacental ischemia in pregnant Sprague-Dawley rats
Fetus-Placenta-Newborn
Experimental growth retardation produced by transient period of uteroplacental ischemia in pregnant Sprague-Dawley rats Mamoru Tanaka, MD, Michiya Natori, MD, PhD, Hitoshi Ishimoto, MD, Toyohiko Miyazaki, MD, PhD, Toshifumi Kobayashi, MD, PhD, and Shiro N ozawa, MD, PhD
Tokyo, japan OBJECTIVE: Introduction of experimental growth retardation, which was based on the hypothesis of uteroplacental postischemic hypoperfusion, was attempted by a transient period of uteroplacental ischemia in dated-pregnant Sprague-Dawley rats. STUDY DESIGN: On day 17 of gestation right uterine horn Circulation was occluded for 5 to 60 minutes in 35 dams. The fetuses were delivered by cesarean section and studied on day 21 of gestation. For each experiment the fetuses in the right horn served as the ischemia group and those in the left horn were used as the control group. RESULTS: Statistical analysis by Wilcoxon signed-rank test demonstrated a significant decrease in the fetal weights and in the liver-to-body weight ratios, in contrast to an increase in the brain-to-body weight ratios in the 60-minute ischemia group, compared with those in the control group. This ischemia resulted in a 14% incidence of fetal deaths. CONCLUSION: Ischemia of a single uterine horn circulation in pregnant rat for 60 minutes should readily serve as a suitable model for asymmetric intrauterine growth retardation. (AM J OesTET GYNECOL 1994;171 :1231-4.)
Key words: Intrauterine growth retardation, uteroplacental circulation, postischemic hypoperfusion, animal model. Sprague-Dawley rat Intrauterine growth retardation (I VCR) is thought to be one of the major causes of perinatal mortality and morbidity.I-3 Many investigators believe that asymmetric growth retardation is frequently related to placental insufficiency of unknown cause and have sought to develop a small animal model to investigate this clinical problem! The most widely used system was developed by Wigglesworth 5 in 1964, and there have been numerous studies using this system. However, this system of completely ligating the uterine artery of one horn resulted in a high mortality rate, up to 80%.6 In the field of cerebral blood flow it is a well-established fact that a transient period of global ischemia abolishes the vascular responsiveness of the brain. DurFrom the Department of Obstetrics and Gynecology, Keio UnIVersity School of Medicine. Received for publication March 3, 1994; revised May 25, 1994; accepted June 15, 1994. Reprint requests: Mamoru Tanaka, MD, Department of Obstetrics and Gynecoloy, Keio UniverSity School of Medicme. 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan. Copyright © 1994 by Mosby-Year Book, Inc. 0002-9378/94 $3.00 + 0 6/1/58412
ing the recirculation period the cerebral blood flow after the transient phase of hyperemia drops to values below controls-a phenomenon called "postischemic hypoperfusion."7. 8 From this perspective we attempted to apply this phenomenon to uteroplacental circulation to create a new IVCR model, which resulted in a low mortality rate and favorable reproducibility.
Material and methods The study was approved by the local Ethical Committee for Animal Experimentation. A total of 35 dated pregnant Sprague-Dawley rats were purchased from a local breeder (Sankyo Labo Service, Tokyo). On day 17 of pregnancy a low abdominal midline incision was made with the animal under ether anesthesia. The uterine horns were inspected and the number of live fetuses in each horn was recorded. Two small artery clamps were used to occlude the uterine vessels near the lower and upper ends of the right horn (Fig. 1). The clamps were removed after 5, 10, 20, 30, 45, and 60 minutes of ischemia (average 3 dams per time duration), and then all animals received 1231
1232 Tanaka et al.
November 1994
Am J Obstet Gynecol
Artery clamps (15iJ";~\-Uterine
vessels
Fig. 1. Schematic diagram of transient period of uteroplacental ischemia.
an intraperitoneal injection of 50 mg of cefazolin sodium (Cefamezin, Fuzisawa Pharmaceutical, Osaka, Japan). On day 21 of gestation the live fetuses and placentas were delivered by cesarean section with the dam under ether anesthesia and were weighed to the nearest 0.001 gm. In the 60-minute ischemia group each fetal brain and liver were weighed to the nearest 0.001 gm for further study. The fetal death rate was determined by comparing the living fetuses on day 21 with those on day 17. For each experiment the fetuses in the right horn served as the ischemia group and those in the left horn as the control group. The right uterine horn was chosen in a random manner irrespective of the number of fetuses, and 12 dams were used in this 60-minute group. Statistical analysis was performed with the Wilcoxon signed-rank test, and a value of 5% was considered to be significant.
Results Fetal body and placental weight after various durations of ischemia are shown in Table 1. The only differences in fetal body and placental weights were noted after the 60-minute period of ischemia. In this group the mean body weight in the ischemia group was 89.9% of that of the nonischemia controls. The fetal death rate in the ischemia group was 14% at term, and no fetal death was found in the controls. Fetal brain and liver weights and the values, expressed as organ/body weight ratios. in the 60-minute ischemia group are shown in Table II. Both brain and liver of the ischemia group weighed significantly less than did those of the control nonischemia group. Although the brainlbody weight ratio of the ischemia
group significantly increased, the liverlbody weight ratio decreased significantly compared with controls. There was no effect on the placentalbody weight ratio.
Comment In this study transient uteroplacental ischemia and reperfusion caused fetal growth retardation, and the organ/body weight ratio revealed an asymmetric growth pattern. This system poses several strengths, including low fetal death rate, good reproducibility, and simplicity. Although this system is disadvantageous in that it subjects the fetuses and mothers to anesthesia for a long time, the mean body weights in the control group demonstrated small differences for ischemia. In addition, because we encountered a wide variation in the fetal weights between the dams in our preliminary studies, we used the opposite horns as controls. The average weights of brain, liver, and placenta in the 60-minute ischemia group were significantly lower than the average weights in the control groups. However, the organlbody weight ratios revealed an increase in brain, decrease in liver, and no significant change in placenta. The brain/weight ratio indicates a brainsparing effect accompanied by IUGR, and the placentalbody weight ratio indicates that the growth retardation might be related to placental insufficiency. Singh et al. 9 reported that 30 minutes of uteroplacental ischemia on day 14 of pregnancy caused histopathologic changes in the rat placenta on day 21 of gestation. This suggests that placental alteration might lead to fetal growth retardation in our model. 9 In addition, the fetal death rate in the 60-minute group was lower than that in the Wigglesworth model. 6 These results indicate that the postischemic placental insufficiency in our model is a milder form than that in the other models.
Tanaka et al.
Volume 171, Number 5 Am J Obstet Gynecol
1233
Table I. Fetal body and placental weights at term (day 21) after various durations of ischemia on day 17 Ischemic time 5mzn Total body (gm) Ischemia group (No. of fetuses) Nonischemia group (No. of fetuses) % of controls Placenta (gm) Ischemia group Nonischemia group
10 min
30 min
20 min
45 min
60 min
3.51 ± 0.07 (17) 4.09 ± 0.09 (22) 3.72 ± 0.06 (90) 4.25 ± 0.12 (17) 4.12 ± 0.12 (11) 3.36 ± 0.06 (79)* 3.57 ± 0.08 (17) 4.17 ± 0.09 (15) 3.87 ± 0.06 (69) 4.30 ± 0.09 (12) 4.25 ± 0.11 (13) 3.74 ± 0.05 (73)* 98.1
98.4
98.8
95.9
97.1
89.9
0.415 ± 0.018
0.417 ± 0.015
0.454 ± 0.008
0.448 ± 0.013
0.438 ± 0.010
0.424 ± 0.007*
0.420 ± 0.013
0.446 ± O.oJ5
0.459 ± 0.009
0.463 ± 0.011
0.455 ± 0.010
0.478 ± 0.007*
Values are mean ± SEM. *p < 0.001.
Table II. Fetal organ weights and body weight ratios for 60-minute ischemia group and controls Ischemia group (n = 79) Brain weight (gm) Liver weight (gm) Brain weightlbody weight (%) Liver weightlbody weight (%) Placental weightlbody weight (%)
0.173 0.180 5.25 5.30 12.8
± 0.001 ± 0.001 ± 0.08 ± 0.07 ± 0.2
Nonzschemia group (n = 73) 0.183 0.215 4.95 5.73 12.9
± 0.001
± 0.004
± 0.06 ± 0.06 ± 0.2
Ischemza grouplnonischemza group (%) 94.5 83.7 106 92.4 99.1
Significance*
p = 0.0001 P = 0.0001 P = 0.0140
P=
0.0001
P = 0.4508
Values are mean ± SEM. *Calculated by Wilcoxon signed-rank test.
Gilbert and Leturque lO demonstrated that a relationship exists between fetal weight and placental blood flow in the Wigglesworth model with the radioactive microsphere method and suggested that fetal growth might be limited by the rate of placental flow. This implies that postischemic placental hypoperfusion might leaad to fetal growth retardation in our model. However, we did not measure placental blood flow in this study, and a further study should be performed to confirm whether postischemic hypoperfusion truly occurs in this model. In the field of cerebrovascular disease the ultimate degree of brain damage sustained after a cerebral ischemic-anoxic insult is not thought to be entirely related to the initial insult, but some postischemic pathophysiologic changes occur that may be amenable to therapy.7 Although the mechanism of this phenomenon remains unclarified, both intravascular factors and structural and biochemical components of the vascular endothelium are thought to influence postischemic hypoperfusion. II The relationship between the severity of fetal growth retardation and the degree of placental infarction has been demonstrated. '2 -'4 Placental infarct usually represents a lobular distribution and is thought to indicate
quite extensive placental ischemia resulting from spiral artery occlusion. 13 Salafia et al. 14 reported that multiple types of placental lesions were significantly frequent in growth-retarded infants, and they suggested that placental infarction would likely be associated with regional changes in blood flow in the placenta. Thus we assume that spontaneous reperfusion should occur in some lobules similar to cerebral ischemia and coronary artery disease and might playa role in fetal growth retardation. Our model appears to be a completely new one based on ischemia and reperfusion injury hypothesis; it should be useful in understanding pathophysiologic features and in seeking treatment of IUGR. Further study is required, however, to support this hypothesis applicable to IUGR. REFERENCES 1. Battaglia FC. Intrauterine gro-wth retardation. A'll"] OBSTET GYNECOL 1970;106:1103-14. 2. Seeds ]W. Impaired fetal growth: definition and clinical diagnosis. Obstet Gynecol 1984;64:303-10. 3. Pollack RN, Divon MY. Intrauterine growth retardation: definition, classification and etiology. Clin Obstet Gynecol 1992;35:99-107. 4. Evans MI. MukheJjee AB, Shulman ]D. Alllmal models of intrauterine growth retardation. Obstet Gynecol Surv 1983;38: 183-92.
Walker, Moore, and Brace
5. Wigglesworth JS. Experimental growth retardation in the foetal rat. J Pathol Bacteriol 1964;88:1-13. 6. Hayashi IT, Dorko ME. A rat model for the study of intrauterine growth retardation. AM J OBSTET GVNECOL 1988; 158: 1203-7. 7. Nemoto EM, Snyder Jv, Carrol RG, Morita H. Global ischemia in dogs: cerebrovascular CO 2 reactivity and autoregulation. Stroke 1975;6:425-31. 8. Hossmann KA, Lechtape-Griiter H, Hossmann V. The role of cerebral blood flow for the recovery of the brain after prolonged ischemia. Z Neurol 1973;204:281-99. 9. Singh S. Sensharma GC, Chinara PK. Placental changes in rat following experimental ischaemic hypoxia. Indian J Med Res 1983;77:144-9. 10. Gilbert M, Leturque A. Fetal weight and its relationship to
November 1994
Am J Obstet Gynecol
11. 12. 13. 14.
placental blood flow and placental weight in experimental intrauterine growth retardation in the rat. J Dev Physiol 1982;4:237 -46. Schmidt-Kastner R, Hossmann KA, Grosse-Ophoff B. Pial artery pressure after one hour of global ischemia. J Cereb Blood Flow Metabol 1987;7:109-17. Fox H. White infarcts of the placenta. J Obstet Gynaecol Br Commonw 1963;70:980-91. WigglesworthJS. Vascular anatomy of the human placenta and its significance for placental pathology. J Obstet Gynaecol Br Commonw 1969;76:979-89. Salafia CM, Vintzileos AM, Silberman L, Bantham KF, Vogel CA. Placental pathology of idiopathic intrauterine growth retardation at term. Am J Perinatol 1992;9: 179-84.
Indomethacin and arginine vasopressin interaction in the fetal kidney: A mechanism of oliguria Martin P.R. Walker, BM, BS, Thomas R. Moore, MD, and Robert A. Brace, PhD San Diego, California OBJECTIVE: Indomethacin has been shown to cause fetal oliguria in humans and animals. This study was designed to test the hypothesis that indomethacin-induced fetal oliguria is mediated through the renal action of arginine vasopressin. STUDY DESIGN: Twenty-seven late-gestation (129 ± 4 days [mean ± SED chronically catheterized fetal sheep were studied. After a 1-hour control period fetal responses to indomethacin, 0.05 mg/kg given intravenously, followed by a 4-hour maintenance infUsion (n = 9), were compared with an identical indomethacin infusion plus an arginine vasopressin V2-receptor antagonist (d[CH2]'s, D-Phe 2, lIe4 ,Arg8 ,Ala9)-VP (n = 8) or vehicle alone (n = 10). Fetal arterial and venous pressures, heart rate, and urinary flow were measured continuously. RESULTS: Fetal urinary flow rate (p < 0.0001) and free water clearance (p = 0.004) fell in response to indomethacin alone, but the addition of the arginine vasopressin V2-receptor antagonist blocked indomethacin's oliguric and free water effect. Urinary osmolality and sodium increased in both indomethacin and indomethacin + arginine vasopressin V2-receptor antagonist groups compared with vehicle (p < 0.05). Fetal arterial pressure increased in response to indomethacin, and the addition of the arginine vasopressin V2-receptor antagonist potentiated this response (p = 0.007). CONCLUSIONS: These results suggest that (1) fetal oliguria secondary to indomethacin is mediated through the stimulation of the renal arginine vasopressin V2-receptor and (2) prostaglandin synthesis inhibition may playa role in renal tubular sodium handling. In addition, the arginine vasopressin V2-receptor plays a role in ameliorating the hypertensive response to indomethacin. We speculate that indomethacin stimulates circulating arginine vasopressin levels and enhances peripheral arginine vasopressin effects in the fetus, resulting in oliguria and hypertension. (AM J QBSTET GYNECOL 1994;171 :1234-41.)
Key words: Prostaglandins, urinary flow, arginine vasopressin, heart rate, arterial pH
From the Division of Perinatal Medicine, Department of Reproductive Medicine, UnIVersity of Californio, San Diego. Supported by National Institutes of Health grants No. HD23724 and No. HD20299 from the National Institute of Child Health and Human Development and by the McLaughlm Fellow5hlp Foundatzon. Presented at the Fortieth Annual Meeting of the SOCIety for Gynecologzc Investlgatzan, Toronto, Ontano, Canada, March 31-April 3, 1993.
1234
ReceIVed for publication January 14, 1994; revised May 16, 1994; accepted Mav 31, 1994. Reprznt requests: Martm Walker, BM, BS, Room 1 U3, BC Women's Hospital, 4490 Oak St., Vancouver, British Columbia V6H 3V5, Canada. Copyright © 1994 by Mosby-Year Book, Inc. 0002-9378/94 $3.00 + 0 6/1/58062
Experimental growth retardation produced by transient period of uteroplacental ischemia in pregnant Sprague-Dawley rats Mamoru Tanaka, MD, Michiya Natori, MD, PhD, Hitoshi Ishimoto, MD, Toyohiko Miyazaki, MD, PhD, Toshifumi Kobayashi, MD, PhD, and Shiro N ozawa, MD, PhD
Tokyo, japan OBJECTIVE: Introduction of experimental growth retardation, which was based on the hypothesis of uteroplacental postischemic hypoperfusion, was attempted by a transient period of uteroplacental ischemia in dated-pregnant Sprague-Dawley rats. STUDY DESIGN: On day 17 of gestation right uterine horn Circulation was occluded for 5 to 60 minutes in 35 dams. The fetuses were delivered by cesarean section and studied on day 21 of gestation. For each experiment the fetuses in the right horn served as the ischemia group and those in the left horn were used as the control group. RESULTS: Statistical analysis by Wilcoxon signed-rank test demonstrated a significant decrease in the fetal weights and in the liver-to-body weight ratios, in contrast to an increase in the brain-to-body weight ratios in the 60-minute ischemia group, compared with those in the control group. This ischemia resulted in a 14% incidence of fetal deaths. CONCLUSION: Ischemia of a single uterine horn circulation in pregnant rat for 60 minutes should readily serve as a suitable model for asymmetric intrauterine growth retardation. (AM J OesTET GYNECOL 1994;171 :1231-4.)
Key words: Intrauterine growth retardation, uteroplacental circulation, postischemic hypoperfusion, animal model. Sprague-Dawley rat Intrauterine growth retardation (I VCR) is thought to be one of the major causes of perinatal mortality and morbidity.I-3 Many investigators believe that asymmetric growth retardation is frequently related to placental insufficiency of unknown cause and have sought to develop a small animal model to investigate this clinical problem! The most widely used system was developed by Wigglesworth 5 in 1964, and there have been numerous studies using this system. However, this system of completely ligating the uterine artery of one horn resulted in a high mortality rate, up to 80%.6 In the field of cerebral blood flow it is a well-established fact that a transient period of global ischemia abolishes the vascular responsiveness of the brain. DurFrom the Department of Obstetrics and Gynecology, Keio UnIVersity School of Medicine. Received for publication March 3, 1994; revised May 25, 1994; accepted June 15, 1994. Reprint requests: Mamoru Tanaka, MD, Department of Obstetrics and Gynecoloy, Keio UniverSity School of Medicme. 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan. Copyright © 1994 by Mosby-Year Book, Inc. 0002-9378/94 $3.00 + 0 6/1/58412
ing the recirculation period the cerebral blood flow after the transient phase of hyperemia drops to values below controls-a phenomenon called "postischemic hypoperfusion."7. 8 From this perspective we attempted to apply this phenomenon to uteroplacental circulation to create a new IVCR model, which resulted in a low mortality rate and favorable reproducibility.
Material and methods The study was approved by the local Ethical Committee for Animal Experimentation. A total of 35 dated pregnant Sprague-Dawley rats were purchased from a local breeder (Sankyo Labo Service, Tokyo). On day 17 of pregnancy a low abdominal midline incision was made with the animal under ether anesthesia. The uterine horns were inspected and the number of live fetuses in each horn was recorded. Two small artery clamps were used to occlude the uterine vessels near the lower and upper ends of the right horn (Fig. 1). The clamps were removed after 5, 10, 20, 30, 45, and 60 minutes of ischemia (average 3 dams per time duration), and then all animals received 1231
1232 Tanaka et al.
November 1994
Am J Obstet Gynecol
Artery clamps (15iJ";~\-Uterine
vessels
Fig. 1. Schematic diagram of transient period of uteroplacental ischemia.
an intraperitoneal injection of 50 mg of cefazolin sodium (Cefamezin, Fuzisawa Pharmaceutical, Osaka, Japan). On day 21 of gestation the live fetuses and placentas were delivered by cesarean section with the dam under ether anesthesia and were weighed to the nearest 0.001 gm. In the 60-minute ischemia group each fetal brain and liver were weighed to the nearest 0.001 gm for further study. The fetal death rate was determined by comparing the living fetuses on day 21 with those on day 17. For each experiment the fetuses in the right horn served as the ischemia group and those in the left horn as the control group. The right uterine horn was chosen in a random manner irrespective of the number of fetuses, and 12 dams were used in this 60-minute group. Statistical analysis was performed with the Wilcoxon signed-rank test, and a value of 5% was considered to be significant.
Results Fetal body and placental weight after various durations of ischemia are shown in Table 1. The only differences in fetal body and placental weights were noted after the 60-minute period of ischemia. In this group the mean body weight in the ischemia group was 89.9% of that of the nonischemia controls. The fetal death rate in the ischemia group was 14% at term, and no fetal death was found in the controls. Fetal brain and liver weights and the values, expressed as organ/body weight ratios. in the 60-minute ischemia group are shown in Table II. Both brain and liver of the ischemia group weighed significantly less than did those of the control nonischemia group. Although the brainlbody weight ratio of the ischemia
group significantly increased, the liverlbody weight ratio decreased significantly compared with controls. There was no effect on the placentalbody weight ratio.
Comment In this study transient uteroplacental ischemia and reperfusion caused fetal growth retardation, and the organ/body weight ratio revealed an asymmetric growth pattern. This system poses several strengths, including low fetal death rate, good reproducibility, and simplicity. Although this system is disadvantageous in that it subjects the fetuses and mothers to anesthesia for a long time, the mean body weights in the control group demonstrated small differences for ischemia. In addition, because we encountered a wide variation in the fetal weights between the dams in our preliminary studies, we used the opposite horns as controls. The average weights of brain, liver, and placenta in the 60-minute ischemia group were significantly lower than the average weights in the control groups. However, the organlbody weight ratios revealed an increase in brain, decrease in liver, and no significant change in placenta. The brain/weight ratio indicates a brainsparing effect accompanied by IUGR, and the placentalbody weight ratio indicates that the growth retardation might be related to placental insufficiency. Singh et al. 9 reported that 30 minutes of uteroplacental ischemia on day 14 of pregnancy caused histopathologic changes in the rat placenta on day 21 of gestation. This suggests that placental alteration might lead to fetal growth retardation in our model. 9 In addition, the fetal death rate in the 60-minute group was lower than that in the Wigglesworth model. 6 These results indicate that the postischemic placental insufficiency in our model is a milder form than that in the other models.
Tanaka et al.
Volume 171, Number 5 Am J Obstet Gynecol
1233
Table I. Fetal body and placental weights at term (day 21) after various durations of ischemia on day 17 Ischemic time 5mzn Total body (gm) Ischemia group (No. of fetuses) Nonischemia group (No. of fetuses) % of controls Placenta (gm) Ischemia group Nonischemia group
10 min
30 min
20 min
45 min
60 min
3.51 ± 0.07 (17) 4.09 ± 0.09 (22) 3.72 ± 0.06 (90) 4.25 ± 0.12 (17) 4.12 ± 0.12 (11) 3.36 ± 0.06 (79)* 3.57 ± 0.08 (17) 4.17 ± 0.09 (15) 3.87 ± 0.06 (69) 4.30 ± 0.09 (12) 4.25 ± 0.11 (13) 3.74 ± 0.05 (73)* 98.1
98.4
98.8
95.9
97.1
89.9
0.415 ± 0.018
0.417 ± 0.015
0.454 ± 0.008
0.448 ± 0.013
0.438 ± 0.010
0.424 ± 0.007*
0.420 ± 0.013
0.446 ± O.oJ5
0.459 ± 0.009
0.463 ± 0.011
0.455 ± 0.010
0.478 ± 0.007*
Values are mean ± SEM. *p < 0.001.
Table II. Fetal organ weights and body weight ratios for 60-minute ischemia group and controls Ischemia group (n = 79) Brain weight (gm) Liver weight (gm) Brain weightlbody weight (%) Liver weightlbody weight (%) Placental weightlbody weight (%)
0.173 0.180 5.25 5.30 12.8
± 0.001 ± 0.001 ± 0.08 ± 0.07 ± 0.2
Nonzschemia group (n = 73) 0.183 0.215 4.95 5.73 12.9
± 0.001
± 0.004
± 0.06 ± 0.06 ± 0.2
Ischemza grouplnonischemza group (%) 94.5 83.7 106 92.4 99.1
Significance*
p = 0.0001 P = 0.0001 P = 0.0140
P=
0.0001
P = 0.4508
Values are mean ± SEM. *Calculated by Wilcoxon signed-rank test.
Gilbert and Leturque lO demonstrated that a relationship exists between fetal weight and placental blood flow in the Wigglesworth model with the radioactive microsphere method and suggested that fetal growth might be limited by the rate of placental flow. This implies that postischemic placental hypoperfusion might leaad to fetal growth retardation in our model. However, we did not measure placental blood flow in this study, and a further study should be performed to confirm whether postischemic hypoperfusion truly occurs in this model. In the field of cerebrovascular disease the ultimate degree of brain damage sustained after a cerebral ischemic-anoxic insult is not thought to be entirely related to the initial insult, but some postischemic pathophysiologic changes occur that may be amenable to therapy.7 Although the mechanism of this phenomenon remains unclarified, both intravascular factors and structural and biochemical components of the vascular endothelium are thought to influence postischemic hypoperfusion. II The relationship between the severity of fetal growth retardation and the degree of placental infarction has been demonstrated. '2 -'4 Placental infarct usually represents a lobular distribution and is thought to indicate
quite extensive placental ischemia resulting from spiral artery occlusion. 13 Salafia et al. 14 reported that multiple types of placental lesions were significantly frequent in growth-retarded infants, and they suggested that placental infarction would likely be associated with regional changes in blood flow in the placenta. Thus we assume that spontaneous reperfusion should occur in some lobules similar to cerebral ischemia and coronary artery disease and might playa role in fetal growth retardation. Our model appears to be a completely new one based on ischemia and reperfusion injury hypothesis; it should be useful in understanding pathophysiologic features and in seeking treatment of IUGR. Further study is required, however, to support this hypothesis applicable to IUGR. REFERENCES 1. Battaglia FC. Intrauterine gro-wth retardation. A'll"] OBSTET GYNECOL 1970;106:1103-14. 2. Seeds ]W. Impaired fetal growth: definition and clinical diagnosis. Obstet Gynecol 1984;64:303-10. 3. Pollack RN, Divon MY. Intrauterine growth retardation: definition, classification and etiology. Clin Obstet Gynecol 1992;35:99-107. 4. Evans MI. MukheJjee AB, Shulman ]D. Alllmal models of intrauterine growth retardation. Obstet Gynecol Surv 1983;38: 183-92.
Walker, Moore, and Brace
5. Wigglesworth JS. Experimental growth retardation in the foetal rat. J Pathol Bacteriol 1964;88:1-13. 6. Hayashi IT, Dorko ME. A rat model for the study of intrauterine growth retardation. AM J OBSTET GVNECOL 1988; 158: 1203-7. 7. Nemoto EM, Snyder Jv, Carrol RG, Morita H. Global ischemia in dogs: cerebrovascular CO 2 reactivity and autoregulation. Stroke 1975;6:425-31. 8. Hossmann KA, Lechtape-Griiter H, Hossmann V. The role of cerebral blood flow for the recovery of the brain after prolonged ischemia. Z Neurol 1973;204:281-99. 9. Singh S. Sensharma GC, Chinara PK. Placental changes in rat following experimental ischaemic hypoxia. Indian J Med Res 1983;77:144-9. 10. Gilbert M, Leturque A. Fetal weight and its relationship to
November 1994
Am J Obstet Gynecol
11. 12. 13. 14.
placental blood flow and placental weight in experimental intrauterine growth retardation in the rat. J Dev Physiol 1982;4:237 -46. Schmidt-Kastner R, Hossmann KA, Grosse-Ophoff B. Pial artery pressure after one hour of global ischemia. J Cereb Blood Flow Metabol 1987;7:109-17. Fox H. White infarcts of the placenta. J Obstet Gynaecol Br Commonw 1963;70:980-91. WigglesworthJS. Vascular anatomy of the human placenta and its significance for placental pathology. J Obstet Gynaecol Br Commonw 1969;76:979-89. Salafia CM, Vintzileos AM, Silberman L, Bantham KF, Vogel CA. Placental pathology of idiopathic intrauterine growth retardation at term. Am J Perinatol 1992;9: 179-84.
Indomethacin and arginine vasopressin interaction in the fetal kidney: A mechanism of oliguria Martin P.R. Walker, BM, BS, Thomas R. Moore, MD, and Robert A. Brace, PhD San Diego, California OBJECTIVE: Indomethacin has been shown to cause fetal oliguria in humans and animals. This study was designed to test the hypothesis that indomethacin-induced fetal oliguria is mediated through the renal action of arginine vasopressin. STUDY DESIGN: Twenty-seven late-gestation (129 ± 4 days [mean ± SED chronically catheterized fetal sheep were studied. After a 1-hour control period fetal responses to indomethacin, 0.05 mg/kg given intravenously, followed by a 4-hour maintenance infUsion (n = 9), were compared with an identical indomethacin infusion plus an arginine vasopressin V2-receptor antagonist (d[CH2]'s, D-Phe 2, lIe4 ,Arg8 ,Ala9)-VP (n = 8) or vehicle alone (n = 10). Fetal arterial and venous pressures, heart rate, and urinary flow were measured continuously. RESULTS: Fetal urinary flow rate (p < 0.0001) and free water clearance (p = 0.004) fell in response to indomethacin alone, but the addition of the arginine vasopressin V2-receptor antagonist blocked indomethacin's oliguric and free water effect. Urinary osmolality and sodium increased in both indomethacin and indomethacin + arginine vasopressin V2-receptor antagonist groups compared with vehicle (p < 0.05). Fetal arterial pressure increased in response to indomethacin, and the addition of the arginine vasopressin V2-receptor antagonist potentiated this response (p = 0.007). CONCLUSIONS: These results suggest that (1) fetal oliguria secondary to indomethacin is mediated through the stimulation of the renal arginine vasopressin V2-receptor and (2) prostaglandin synthesis inhibition may playa role in renal tubular sodium handling. In addition, the arginine vasopressin V2-receptor plays a role in ameliorating the hypertensive response to indomethacin. We speculate that indomethacin stimulates circulating arginine vasopressin levels and enhances peripheral arginine vasopressin effects in the fetus, resulting in oliguria and hypertension. (AM J QBSTET GYNECOL 1994;171 :1234-41.)
Key words: Prostaglandins, urinary flow, arginine vasopressin, heart rate, arterial pH
From the Division of Perinatal Medicine, Department of Reproductive Medicine, UnIVersity of Californio, San Diego. Supported by National Institutes of Health grants No. HD23724 and No. HD20299 from the National Institute of Child Health and Human Development and by the McLaughlm Fellow5hlp Foundatzon. Presented at the Fortieth Annual Meeting of the SOCIety for Gynecologzc Investlgatzan, Toronto, Ontano, Canada, March 31-April 3, 1993.
1234
ReceIVed for publication January 14, 1994; revised May 16, 1994; accepted Mav 31, 1994. Reprznt requests: Martm Walker, BM, BS, Room 1 U3, BC Women's Hospital, 4490 Oak St., Vancouver, British Columbia V6H 3V5, Canada. Copyright © 1994 by Mosby-Year Book, Inc. 0002-9378/94 $3.00 + 0 6/1/58062