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Byline: Hidetaka Izumi, Yasuo Makino, Hidehito Mohtai, Koichi Shirakawa, R.E. Garfield Keywords: Histamine; endothelium-derived relaxing factor; nitric oxide; prostacyclin; human umbilical artery; pregnancy Abstract: OBJECTIVE: We intended to compare the relative importance of nitric oxide and prostacyclin as endothelium-derived vasorelaxing factors released by histamine in human umbilical artery at the midstage (18 to 22 weeks) of gestation. STUDY DESIGN: By use of very thin muscle strips, which allows rapid diffusional access of applied drugs (in a few seconds), isometric tensions were recorded in response to histamine. The histamine-induced contractions and the relaxing effect of histamine on the potassium chloride (39 mmol/L) contractions were studied in relation to the existence of endothelium, L-N.sup.G-nitro arginine, and indomethacin. The relaxing effects of glyceryl trinitrate and prostacyclin on the potassium chloride contractions were also examined. RESULTS: The contractile responses to histamine were more sensitive and the relation tensions of histamine contractions, compared with the 39 mmol/L K.sup.+-induced contractions, were larger in endothelium-denuded strips than in endothelium-intact strips. Histamine contractions were enhanced in endothelium-intact strips in the presence of 10 [mu]mol/L L-N.sup.G-nitro arginine (competitive inhibitor of nitric oxide synthase) but not in the presence of 10 [mu]mol/L indomethacin (cyclooxygenase inhibitor). Histamine produced a concentration-dependent relaxation during the maintained contraction induced by 39 mmol/L K.sup.+. These histamine-induced relaxations were completely blocked by L-N.sup.G-nitro arginine but not by indomethacin. Glyceryl trinitrate and prostacyclin relaxed the sustained contractions induced by 39 mmol/L K.sup.+ in a dose-dependent manner; however, the degree of relaxation by glyceryl trinitrate was more prominent than that by prostacyclin. CONCLUSION: These results suggest that nitric oxide is more potent than prostacyclin as a vasorelaxing substance released from the endothelium and that nitric oxide has an important role for controlling fetoplacental circulation at midgestation. (Am J Obstet Gynecol 1996;175:375-81.) Author Affiliation: Fukuoka, Japan, and Galveston, Texas Article History: Received 7 June 1995; Revised 22 January 1996; Accepted 28 February 1996 Article Note: (footnote) [star] From the Department of Obstetrics and Gynecology, Fukuoka University School of Medicine,a and the Department of Obstetrics and Gynecology, University of Texas Medical Branch. b , [star][star] Reprint requests: Hidetaka Izumi, MD, Department of Obstetrics and Gynecology, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka 814-01, Japan., a 0002-9378/96 $5.00 + 0 6/1/73373

The chemical histamine may induce relaxation of the human umbilical artery in the middle of pregnancy rather than at the end. Researchers studied how histamine affects dilation of the umbilical artery by using thin strips of umbilical muscle from fetuses in the middle of pregnancy. Endothelium-derived relaxing factor (EDRF) responded more strongly to histamine in mid-pregnancy than at term. EDRF is thought to be nitric oxide. Nitric oxide caused relaxation and dilation of the umbilical artery. Contractions are caused by the release of calcium ions from various storage sites. Histamine antagonists are given to pregnant women with asthma or allergies. The findings of this study may indicate that this practice decreases umbilical blood flow.

Background. To elucidate the relationship between the epithelial and mesenchymal elements of malignant mixed Mullerian tumors (MMMT), the authors examined the biologic properties of two clones of different cell types (designated as FU-MMT-2-CL and FU-MMT-2-S1) established from a uterine MMMT cell line (FU-MMT-2), which they previously have reported. Methods and Results. By morphologic and immunocytochemical analyses, FU-MMT-2-C1 exhibited features of adenocarcinoma cells, whereas FU-MMT-2-S1 showed characteristics of sarcoma cells with myogenic differentiation. Some FU-MMT-2-C1 cells at confluence differentiated spontaneously into myogenic mesenchymal cells in vitro. In addition, transitional-type cells between epithelial cells and sarcomatous cells were observed in the areas of mesenchymal differentiation in FU-MMT-2-C1 by light and electron microscopic study. Ultrastructurally, the transitional-type cells represented biphasic morphologic characteristics consisting of epithelial and myogenic features, which proved to coexpress epithelial, mesenchymal, and muscle markers by double immunoenzymatic staining. However, no epithelial differentiations were apparent in the sarcoma clone FU-MMT-2-S1. FU-MMT-2-C1 produced tumor in nude mice, the histologic study of which showed a mixture of adenocarcinoma and myogenic sarcomatous elements that resembled the original tumor. Cytogenetic studies demonstrated that these two clones were monocional in origin because of the presence of common karyotypic abnormalities in both cells. In addition, the amplified (approximately fourfold to eightfold) c-myc oncogene was found in the cloned cells and the original tumor cells. Conclusions. The current results strongly support the theory of single cell origin in uterine MMMT and suggest that the mesenchymal elements originated from primitive Mullerian epithelial cells capable of differentiating into epithelial, mesenchymal, or both elements. Cancer 1993; 71:3065-75.

To clarify the cellular origin and characteristics of malignant mixed mullerian tumor (MMMT), the authors investigated two cell lines (designated as FU-MMT-1 and FU-MMT-2) established from two patients with heterologous MMMT of the uterus. Both cell lines propagated continuously for 83 and 55 serial passages over 1.5 years, respectively. Morphologically, FU-MMT-2 was a mixture of carcinoma cells and sarcoma cells with predominance of carcinoma cells; FU-MMT-1 only had a sarcomatous element with distinct rhabdomyoblastic differentiation. Immunocytochemically, the sarcoma cells of each cell line expressed, not only myogenic and mesenchymal antigens (desmin, myoglobin, and vimentin), but also epithelial antigens, including epithelial membrane antigen and keratin. The carcinoma cells in FU-MMT-2 were positive for the epithelial antigens and vimentin and negative for desmin and myoglobin. Both lines had abnormal karyo-types; the modal chromosome numbers of FU-MMT-1 and FU-MMT-2 were 47 and 80, respectively. In addition, FU-MMT-1 had trisomy 8, and FU-MMT-2 had complex structural abnormalities. When transplanted into nude mice, FU-MMT-1 reproduced and maintained the characteristics of the original tumor. These cell lines and xenografts appear to provide a useful system for studying the biologic behavior, cytogenetic features, and histogenesis of MMMT. In conclusion, the presence of epithelial antigens in the sarcomatous and carcinomatous elements seemed to support the hypothesis that both elements are derived from a common stem cell. Cancer 1992; 69: 1759-1768.