Palosuranın preeklemptik gebe sıçan ve yavruları üzerine etkisi
Küçük Resim Yok
Dosyalar
Tarih
2022
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Ege Üniversitesi, Tıp Fakültesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Preeklampsi, tüm dünyada gebeliklerin yaklaşık %5-7’sini etkilemektedir. Fetal ve maternal morbidite ve mortalitenin önemli nedenlerinden biridir. Preeklampsi; proteinüri,
uteroplasental disfonksiyon veya maternal organ disfonksiyonundan bir veya daha fazlasının eşlik ettiği 20. gebelik haftası ve sonrasında başlayan gestasyonel hipertansiyon olarak tanımlanmaktadır. Deney hayvanlarına N-Nitro L-Arjinin Metil Ester (L-NAME) uygulaması iyi bilinen bir deneysel hipertansiyon, kardiyovasküler ve böbrek hastalığı modelidir. Sıçanlarda nitrik oksit sentazın farklı gebelik evrelerinde L-NAME tarafından inhibisyonunun hipertansiyon, proteinüri ve IUGR gibi preeklampsi benzeri semptomlara yol açtığı gösterilmiştir. Ürotensin II (U-II), bugüne kadar tanımlanan en güçlü vazokonstriktör peptiddir. Gprotein ilişkili bir reseptör olan GPR14 aracılığıyla kalp ve arteriyel kan damarlarının düz kas hücreleri üzerinde vazokonstriktör etkisi bulunmaktadır. Kardiyovasküler sistem ve santral sinir sistemi başta olmak üzere böbrek, endokrin sistem ve plasenta gibi birçok dokuda U-II ve U-II reseptörü eksprese edilmektedir. Preeklamptik gebelerde yapılan çalışmalarda plazma UII seviyesi ve plasentada UTR düzeylerinin arttığı bulunmuştur. Preeklamptik gebelerde plazma ve plasenta U-II düzeyleri ile ortalama arteriyel basıncın korele olduğu gösterilmiştir. Palosuran peptid olmayan, selektif bir U-II reseptör antagonistidir. Hayvanlarda renal iskemi, nefrotoksisite ve pulmoner arteriyel hipertansiyon gibi hastalıklarda terapötik rolü çalışılmıştır. Çalışmamızda sıçanlar 4 gruba ayrılmıştır: Kontrol grubu (9. günden itibaren
intraperitoneal salin uygulananlar, n=10), Palosuran grubu (14. günden itibaren günde iki kez oral gavaj ile 75 mg/kg Palosuran uygulananlar, n=8) L-NAME grubu (9. günden itibaren 150 mg/kg/gün intraperitoneal L-NAME uygulananlar, n=8) ve Tedavi grubu (9. günden itibaren 150 mg/kg/gün intraperitoneal L-NAME ve 14. günden itibaren günde iki kez oral gavaj ile 75 mg/kg Palosuran uygulananlar, n=8). Tüm gruplardaki sıçanlar östrus siklusunun uygun zamanında çiftleştirilmiş ve gebe oldukları vajinal smearde sperm varlığı ile belirlenmiştir. Gebelik boyunca her sıçanın kuyruğundan kan basıncı ölçülmüş ve metabolik kafes ile 24 saatlik idrar örnekleri toplanmıştır. Bu işlemler üç farklı zaman noktasında tekrarlanmıştır. Sezaryen sonrasında serum kreatinin, BUN, AST, ALT, hemoglobin, hematokrit, trombosit, sFlt-1, PlGF ve U-II düzeyleri ölçülmüştür. Anne böbrek, karaciğer, plasenta ve umbilikal kordu ile yenidoğan beyninde histolojik incelemeler ve eNOS, iNOS, nNOS ve UTR ile immunohistokimyasal boyama yapılmıştır. L-NAME ile artan sistolik basınç, diyastolik basınç, ortalama arteriyel basınç ve proteinüri Palosuran tedavisi sonrası azalmıştır. Serum kreatinini ve ALT L-NAME grubunda artarken BUN, AST, hemoglobin, hematokrit, trombosit sayısı, sFlt-1, PlGF ve sFlt1/PLGF tüm gruplarda benzer bulunmuştur. Ürotensin II düzeyi L-NAME grubunda Kontrol ve Palosuran grubuna göre artarken, Tedavi grubunda azalmıştır. Gruplar arasında yavru sayısı, plasenta ağırlığı ve böbrek ağırlığı açısından anlamlı farklılık bulunmamıştır. L-NAME grubunda Kontrol ve Palosuran grubuna kıyasla yavru ağırlığı azalmıştır. Histolojik incelemelerde L-NAME grubunda böbrek, plasenta, karaciğer ve yavru beyninde histolojik yapının bozulduğu ancak Tedavi grubunda düzeldiği görülmüştür. İmmunohistokimyasal incelemelerde plasenta, böbrek ve karaciğerde eNOS ekspresyonunun L-NAME grubunda azaldığı ancak Palosuran uygulamasıyla arttığı görülmüştür. iNOS’un ise L-NAME ile arttığı ancak Palosuran’la azaldığı gösterilmiştir. Serebral korteks, hipokampus ve serebellumda L-NAME ile azalan nNOS ekspresyonu Tedavi grubunda artmıştır. Sonuç olarak Palosuranın preeklampside gebe ve yavru üzerinde olumlu etkileri olduğuna dair bulgular elde edilmiştir. Altta yatan mekanizmaların daha iyi anlaşılabilmesi ve preeklampside terapötik olarak kullanılması için ileri çalışmalar gerekmektedir.
Preeclampsia affects approximately 5-7% of all pregnancies worldwide. It is a major cause of maternal and perinatal mortality and morbidity. Preeclampsia is defined as new onset gestational hypertension with proteinuria, maternal organ dysfunction or uteroplacental dysfunction after 20 weeks’ gestation. The administration of N-nitro-L-arginine-methyl ester (L-NAME) to laboratory animals is a well known experimental hypertension, cardiovascular and kidney disease model. It has been show that inhibition of NOS in rats by L-NAME at different gestational stages led to preeclampsia-like symptoms such as hypertension, proteinuria and IUGR. Urotensin II (U-II) is currently the most potent vasoconstrictor identified. It is mainly affecting myocardial and arterial smooth muscle cells through a G-protein coupled receptor named GPR14. U-II and its receptor are mostly expressed in the cardiovascular and central nervous systems, but also in the endocrine system, placenta and the kidneys. In some studies on preeclamptic women, it has been demonstrated that U-II levels in plasma and UTR levels in placenta were increased. It has been shown that plasma and placenta U-II levels and mean arterial pressure are positively correlated in preeclamptic women. Palosuran is a non-peptide, selective U-II receptor antagonist. Its therapeutic role in diseases such as nephrotoxicity, renal ischemia and pulmonary arterial hypertension has been studied in animals. In our study, rats were divided into 4 groups: Control group (rats treated with intraperitoneal saline starting from gestational day 9 GD9, n=10), Palosuran group (rats treated with Palosuran 75 mg/kg/twice a day starting from GD14, n=8), L-NAME group (rats treated with intraperitoneal L-NAME 150 mg/kg starting from GD9, n=8), Treatment group (rats treated with intraperitoneal L-NAME 150 mg/kg starting from GD9 and Palosuran 75 mg/kg/twice a day starting from GD14, n=8). All rats were mated at the appropriate time of the estrous cycle and pregnancy was determined by the presence of sperm in the vaginal smear. Throughout pregnancy, maternal blood pressure was measured by noninvasive tail cuff methode and urine samples were collected by metabolic cage. Both processes were repeated three times. After cesarean, maternal serum creatinine, BUN, AST, ALT, hemoglobin, hematocrit, platelet, sFlt-1, PlGF and U-II levels were measured. Histological and immunohistochemical (eNOS, iNOS, nNOS and UTR) examinations were performed on the maternal kidney, liver, placenta, umbilical cord and offspring brain. Administration of palosuran improved L-NAME induced hypertension and proteinuria. Serum creatinine and ALT increased in the L-NAME group. BUN, AST, hemoglobin, hematocrit, platelet count, sFlt-1, PlGF and sFlt1/PLGF were similar in all groups. Urotensin II level increased in the L-NAME, but decreased in the Treatment group. There were no significant differences between the groups in terms of the number of offspring, placental weight and kidney weight. Pup weight decreased in the L-NAME group compared to the Control and Palosuran groups. In histological examinations, it was observed that the histological structure was impaired in the kidney, placenta, liver and pup brain in the L-NAME group, but improved in the Treatment group. In immunohistochemical analysis, eNOS expression in the placenta, kidney and liver decreased in the L-NAME group, but increased with Palosuran administration. It has been shown that iNOS expression increased with L-NAME but decreased with Palosuran. nNOS expression decreased with L-NAME in the cerebral cortex, hippocampus and cerebellum but increased in the Treatment group. As a result, findings have been obtained that Palosuran has positive effects on pregnant women and offspring in preeclampsia. Further studies are needed to better understand the underlying mechanisms and to use Palosuran therapeutically in preeclampsia.
Preeclampsia affects approximately 5-7% of all pregnancies worldwide. It is a major cause of maternal and perinatal mortality and morbidity. Preeclampsia is defined as new onset gestational hypertension with proteinuria, maternal organ dysfunction or uteroplacental dysfunction after 20 weeks’ gestation. The administration of N-nitro-L-arginine-methyl ester (L-NAME) to laboratory animals is a well known experimental hypertension, cardiovascular and kidney disease model. It has been show that inhibition of NOS in rats by L-NAME at different gestational stages led to preeclampsia-like symptoms such as hypertension, proteinuria and IUGR. Urotensin II (U-II) is currently the most potent vasoconstrictor identified. It is mainly affecting myocardial and arterial smooth muscle cells through a G-protein coupled receptor named GPR14. U-II and its receptor are mostly expressed in the cardiovascular and central nervous systems, but also in the endocrine system, placenta and the kidneys. In some studies on preeclamptic women, it has been demonstrated that U-II levels in plasma and UTR levels in placenta were increased. It has been shown that plasma and placenta U-II levels and mean arterial pressure are positively correlated in preeclamptic women. Palosuran is a non-peptide, selective U-II receptor antagonist. Its therapeutic role in diseases such as nephrotoxicity, renal ischemia and pulmonary arterial hypertension has been studied in animals. In our study, rats were divided into 4 groups: Control group (rats treated with intraperitoneal saline starting from gestational day 9 GD9, n=10), Palosuran group (rats treated with Palosuran 75 mg/kg/twice a day starting from GD14, n=8), L-NAME group (rats treated with intraperitoneal L-NAME 150 mg/kg starting from GD9, n=8), Treatment group (rats treated with intraperitoneal L-NAME 150 mg/kg starting from GD9 and Palosuran 75 mg/kg/twice a day starting from GD14, n=8). All rats were mated at the appropriate time of the estrous cycle and pregnancy was determined by the presence of sperm in the vaginal smear. Throughout pregnancy, maternal blood pressure was measured by noninvasive tail cuff methode and urine samples were collected by metabolic cage. Both processes were repeated three times. After cesarean, maternal serum creatinine, BUN, AST, ALT, hemoglobin, hematocrit, platelet, sFlt-1, PlGF and U-II levels were measured. Histological and immunohistochemical (eNOS, iNOS, nNOS and UTR) examinations were performed on the maternal kidney, liver, placenta, umbilical cord and offspring brain. Administration of palosuran improved L-NAME induced hypertension and proteinuria. Serum creatinine and ALT increased in the L-NAME group. BUN, AST, hemoglobin, hematocrit, platelet count, sFlt-1, PlGF and sFlt1/PLGF were similar in all groups. Urotensin II level increased in the L-NAME, but decreased in the Treatment group. There were no significant differences between the groups in terms of the number of offspring, placental weight and kidney weight. Pup weight decreased in the L-NAME group compared to the Control and Palosuran groups. In histological examinations, it was observed that the histological structure was impaired in the kidney, placenta, liver and pup brain in the L-NAME group, but improved in the Treatment group. In immunohistochemical analysis, eNOS expression in the placenta, kidney and liver decreased in the L-NAME group, but increased with Palosuran administration. It has been shown that iNOS expression increased with L-NAME but decreased with Palosuran. nNOS expression decreased with L-NAME in the cerebral cortex, hippocampus and cerebellum but increased in the Treatment group. As a result, findings have been obtained that Palosuran has positive effects on pregnant women and offspring in preeclampsia. Further studies are needed to better understand the underlying mechanisms and to use Palosuran therapeutically in preeclampsia.
Açıklama
Anahtar Kelimeler
Preeklampsi, L-NAME, Ürotensin, Palosuran, Preeclampsia, L-NAME, Urotensin, Palosuran
