Tijen Kaya Temiz

The effect of sildenafil on the altered thoracic aorta smooth muscle responses in rat pre-eclampsia model

The pathophysiology of pre-eclampsia is still unknown thus effective primary prevention is not possible at the stage. The present study was conducted to research the smooth muscle responses in the pre-eclampsia model with suramin treated rats and the effect of phosphodiesterase-5 (PDE5) inhibitor on these responses. Rats of three groups; control, suramin and suramin+sildenafil were given intraperitoneal injections of saline, suramin or sildenafil citrate. Suramin injections caused increased blood pressure, protein in urine and caused fetal growth retardation. The use of sildenafil citrate straightened significantly both blood pressure and average fetus weight, but did not reach to control values. At the end of pregnancy, thoracic aorta rings were exposed to contractile and relaxant agents. KCl contraction responses, sodium nitroprusside and papaverine relaxation responses were similar in three groups. Contraction responses of phenylephrine, increased significantly in suramin group. Relaxation responses of acethylcholine and bradykinin decreased in suramin group. The use of sildenafil citrate partially straightened both relaxation and contraction responses, but did not reach to control values. In all groups in the presence of L-nitromonomethylarginine (L-NAME), 1H-(1, 2, 4) oxadiazole (4, 3-a) guinoxalin-1-one (ODQ) and indomethacin decreased the relaxation responses of acetylcholine and bradykinin. The cyclic guanosine monophosphate (cGMP) content of thoracic aorta tissue was determined by radioimmunoassay technique. The content of cGMP in suramin group decreased and use of sildenafil citrate increased the cGMP content but did not reach to control values. We conclude that in pre-eclampsia, the increase of contraction responses, the decrease of relaxation responses and the decrease of cGMP content can depend on insufficiency about synthesis or release of relaxant factors which was released from the vessel endothelium. The results in this study show that in pre-eclampsia; PDE5 inhibitors enhance endothelial function and may be used for protection. Further studies are needed to clear the efficiency and safety of PDE5 inhibitors.

Effects of tyrosine kinase inhibitor E7080 and eNOS inhibitor L-NIO on colorectal cancer alone and in combination

OBJECTIVE To investigate the effects of E7080 and N (5)-(1-iminoethyl)-L-ornithine dihydrochloride (L-NIO) on colorectal cancer alone and in combination. METHODS HT29 colorectal cancer cell line from Sap Institute was used. Real-time cell analysis (xCELLigence system) was performed to determine the effects of E7080 and L-NIO on colorectal cell proliferation. While apoptosis was determined with Annexin V staining, and the effect of agents on angiogenesis was determined with chorioallantoic membrane (CAM) model. RESULTS We found that E7080 has a strong antiproliferative effect with an half maximum inhibition of concentration (IC50) value of 5.60×10(-8) mol/L. Also it has been observed that E7080 showed antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Antiangiogenic scores of E7080 were 1.2, 1.0 and 0.6 for 100, 10 and 1 nmol/L E7080 concentrations, respectively. Furthermore, apoptosis has been detected in 71% of HT29 colorectal cancer cells after administration of 100 nmol/L E7080 which may indicate strong apoptotic effect. Meanwhile administration of L-NIO alone did not show any effect, but the combination of E7080 with L-NIO increased the antiproliferative, antiangiogenic and apoptotic effects of E7080. CONCLUSIONS Results of this study indicate that E7080 may be a good choice in treatment of colorectal tumors. Furthermore the increased effects of E7080 when combined with L-NIO raise the possibility to use a lower dose of E7080 and therefore avoid/minimize the side effects observed with E7080.

Investigation of the role of the NO-cGMP pathway on YC-1 and DEA/NO effects on thoracic aorta smooth muscle responses in a rat preeclampsia model

The present study was designed to investigate the effects of YC-1, a nitric oxide (NO)-independent soluble guanylate cyclase (sGC) activator, and DEA/NO, a NO donor, on smooth muscle responses in the preeclampsia model with suramin-treated rats and on the levels of cyclic guanosine monophosphate (cGMP) of thoracic aorta rings isolated from term-pregnant rats. Rats of 2 groups, control group and suramin group, were given intraperitoneal injection of saline or suramin, respectively. Suramin injection caused increased blood pressure, protein in urine, and fetal growth retardation. Thoracic aorta rings were exposed to contractile and relaxant agents. KCl contraction and papaverine relaxation responses were similar. Relaxation responses of YC-1 and DEA/NO decreased in suramin group. In both groups in the presence of ODQ, a sGC inhibitor, the relaxation responses of YC-1 and DEA/NO decreased. The cGMP content was determined by radioimmunoassay technique. The content of cGMP in the suramin group decreased. In the presence of YC-1 and DEA/NO in both groups, cGMP content increased, but in ODQ-added groups, there was a significant decrease. We conclude that in preeclampsia, the decrease of relaxation responses and the decrease of cGMP content could be due to the reduction in stimulation of sGC and the decrease in cGMP levels.

Investigation of Relaxant Effects of Propofol on Sheep Sphincter of Oddi

Background/Aims: Intravenous anesthetics are often used for conscious sedation in endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincter of Oddi (SO) manometry. This study was designed to investigate the effects of propofol on sheep SO. Methods: SO rings were mounted in a tissue bath and tested for changes in isometric tension in response to propofol (10^–8–10^–4M) in the presence or absence of L-NAME (3 × 10^–5M), a non-specific inhibitor of nitric oxide (NO) synthase; indomethacin (10^–5M), an inhibitor of cyclooxygenase; glibenclamide (10^–5M), an inhibitor of ATP-sensitive potassium channels; tetraethylammonium (3 × 10^–4M), inhibitors of calcium-activated potassium channels; 4-aminopyridine (10^–3M), a voltage-dependent potassium channel blocker. Furthermore, we investigated the Ca²⁺ antagonist feature of propofol in precontracted SO rings by CaCl₂. Results: Carbachol (10^–9–10^–5M) induced concentration-dependent contraction responses in the SO rings. Propofol (10^–8–10^–4M) produced concentration-dependent relaxation on isolated SO rings precontracted by carbachol (10^–6M). Preincubation of SO rings by L-NAME (3 × 10^–5M), indomethacin (10^–5M), glibenclamide (10^–5M), and 4-aminopyridine (10^–3M) did not produce a significant alteration on propofol-induced relaxation responses (p > 0.05), while preincubation by tetraethylammonium (3 × 10^–4M) significantly decreased the propofol-induced relaxation responses (p < 0.05). Propofol (10^–8–10^–4M) induced concentration-dependently relaxations in precontracted isolated SO rings by CaCl₂. Conclusion: The results suggest that propofol induced concentration-dependent relaxations in precontracted isolated SO rings. These relaxations are independent from NO, cyclooxygenase metabolites, and opened ATP-sensitive and voltage-dependent potassium channels. Opened Ca²⁺-sensitive K⁺ channels and inhibited L-type Ca²⁺ channels existing in smooth muscle by propofol can contribute to these relaxations. Propofol can be beneficial as alternative drugs for obtaining selective relaxation during SO manometry after controlled clinical studies.

Does topical isotretinoin exposure during pregnancy increase the risk of congenital malformations

Türkderm-Deri Hastalıkları ve Frengi Arşivi Dergisi, Galenos Yayınevi tarafından basılmıştır. Turkderm-Archives of the Turkish Dermatology and Venerology, published by Galenos Publishing. A 34-year-old patient who learned that she was 7 weeks pregnant while she was using topical isotretinoin + erythromycin gel for acne treatment was referred to İzmir Katip Çelebi University Teratology Information Service for information regarding the risk of teratogenicity. Systemic use of isotretinoin is well-known for its teratogenic effects and case reports suggesting possible teratogenic effects in case of topical exposure to retinoids in pregnancy exist in the literature. However, findings reported in four prospective controlled studies do not suggest an increased congenital malformation risk in case of inadvertent exposure during pregnancy. This manuscript aims to give a summary and evaluation of available data for counseling pregnant patients regarding the possible teratogenic risk of inadvertent topical isotretinoin exposure during pregnancy. It also aims to emphasize the importance of increasing communication between pregnant patients, clinicians and teratology information services for the benefit of mother and unborn. (Turkderm 2015; 49: 92-4)

The Effects of Daily Repeated Magnetic Field on S-Nitroso-N-acetyl-DL penicillamine Induced Hyperalgesia

Abstract Aim. The treatment of pain has been one of the most important objectives of medicine. We aimed to investigate antinociceptive effects and mechanisms of magnetic field (MF) on the hyperalgesia produced by S-Nitroso N-acetyl penicillamine (SNAP). Method. Study has been made in two sections. In the first section, rats were divided four groups (six in each). The first group was determined as sham group and administrated 0.3 mL, 0.9% NaCl intraperitoneally (i.p) before assessing tail flick latencies (TFLs) (Sham group). In the second group, 2 mg/kg SNAP administrated i.p. and TFLs were assessed at the same time points with first group (SNAP group). In the third group, rats were repeatedly exposed to MF for 6 consecutive days (MF group). In the fourth group, SNAP was administrated i.p everyday shortly before MF exposure (SNAP+MF group). In the second section, animals divided to the same groups with the first section. Same procedures have been performed with the first section groups and blood samples were collected to determine plasma levels of β-endorphin and substance P. Results. SNAP (2 mg/kg) produced hyperalgesic effect with i.p. administration. MF application (5 mT and 165 min per day) produced a strong antinociception in Days 3 and 4. Tail flick values of SNAP+MF in Days 3 and 4 were found to be significantly low as compared to MF and Sham groups. In SNAP group, substance P levels were found to be significantly high. Plasma β-endorphin levels in MF and SNAP+MF groups were significantly high as compared to the Sham group. Conclusion. MF may be an alternative antinociceptive approach for pain treatment. There is need for further studies to overcome the tolerance to antinociceptive effects of MF. Keywords: Hyperalgesia, magnetic field, snap, substance p, β-endorphin, tail flick Ozet Amac. Agri tedavisi tibbin en onemli hedeflerinden biridir. Bu arastirmada manyetik alan uygulamasinin S-Nitroso N-acetyl penicillamine (SNAP) tarafindan olusturulan agri uzerindeki etkilerini ve etki mekanizmasini arastirmayi amacladik. Yontem. Calisma iki kisim olacak sekilde tasarlandi. Birindi kisimda hayvanlar her birinde alti hayvan olacak sekilde 4 gruba bolundu. Birinci grup sham grubu olarak belirlendi ve bu hayvanlara 0,3 mL %0,9 NaCl tail flick latensleri olculmeden once uygulandi. Ikinci gruba (SNAP grubu) 2 mg/kg SNAP i.p. olarak enjekte edildi ve sham grubu ile ayni zaman noktalarinda tail flick olcumleri yapildi. Ucuncu grup (MF grubu) tekrarlayan alti gun boyunca manyetik alana maruz birakildi. Dorduncu grupta (SNAP+MF) hayvanlara manyetik alan uygulamasi yapilmadan hemen once 2 mg/kg SNAP i.p. olarak uygulandi. Calismanin ikinci kisminda ratlardan kan ornekleri alinarak kanlarinda supstance p ve B-endorfin seviyelerine ELISA yontemi ile bakildi. Bulgular. SNAP (2 mg/kg) anlamli bir hiperaljezi meydana getirerek tail flick latenleslerini kisaltti. Manyeteik alan uygulamasi (5 mT ve 165 dakika/gun) ozellikle 3. ve 4. gunlerde anlamli bir analjezi meydana getirdi. SNAP grubunda substance p seviyeleri yuksek bulunurken, manyetik alan grubunda B-endorfin seviyelerinin yuksek oldugu tespit edildi . Sonuc . Bu sonuclar manyetik alan uygulamasinin agri tedavisinde alternatif bir yaklasim olabilecegini gostermektedir. Fakat bu yontemin kullanilabilmesi icin gelisen toleransin ustesinden gelmenin yollarinin bulunmasi ve bunun icinde ileri arastirmalara gereksinim vardir. Anahtar sozcukler: Hiperaljezi, manyetik alan, snap, p maddesi, β-endorfin, tail flick

Klonidin, deksmedetomidin ve midazolamın normal ve peritonitli sıçan kolon peristaltik hareketleri üzerine olan inhibitör etkilerinin karşılaştırılması

Ozet Amac. Bu deneysel calismada, genellikle yogun bakimda sedasyon amaci ile kullanilan deksmedetomidin, midazolam ve klonidinin normal ve peritonitli sican kalin barsak motilitesi uzerindeki inhibitor etkileri arastirilmistir. Yontem. Calismamizda her grupta 8 adet rat olan 2 grup olusturuldu. Kontrol grubuna sham operasyonu, peritonit grubuna ise cekum ligasyonu ve perforasyonu operasyonu yapildi. Operasyonlardan 24 saat sonra her iki gruptaki sicanlar oldurulerek proksimal kolon ve distal kolon dokulari alinip Krebs Bikarbonat solusyonu icinde 1 cm’lik preparatlar halinde organ banyosuna asilarak KCl ile kastirildiktan sonra, spontan kasilma yanitlari ve spontan kasilmalar uzerine deksmedetomidin, midazolam ve klonidin’in inhibitor etkilerine bakildi. Bulgular. Calismamizda KCl yanitlari arasinda fark yoktu. Proksimal kolonun spontan kasilmalari distal kolona gore daha fazlaydi ve peritonitli grupta kontrol grubuna gore spontan kasilmalar daha fazlaydi. Ilaclarin ucu de her iki grupta konsantrasyona bagli olarak spontan kasilmalarda inhibisyon yapti. Bu inhibitor etkiler kontrol grubunda peritonitli gruba gore daha fazlaydi. Her grup ve her dokuda da bu 3 ilacin spontan kasilmalar uzerinde inhibitor etki bakimindan en guclusu deksmedetomidin ve distal kolon peritonitli grup haric en zayifi da klonidin’di. Sonuc. Bu sonuclar bize spontan aktiviteleri azaltma ve onleme acisindan ozellikle kontrol gruplarinda deksmedetomidinin digerlerine gore daha etkili oldugunu ve yogun bakimdaki ishalli hastalarda (peritonit veya degil) bu 3 ilacin da kullanilabilecegi ama deksmedetomidinin digerlerine gore daha faydali olabilecegini dusundurmektedir. Anahtar sozcukler: Deksmedetomidin, midazolam, klonidin, peritonit, spontan kasilmalar, yogun bakim Abstract Aims. In this experimental study, the inhibitor effects of dexmedetomidine, midazolam and clonidine, generally used for sedation in intensive care units, on rat colon motility in control and peritonitis groups were investigated. Methods. Sixteen rats were allocated into two groups (eight in each). The first sham group underwent the same surgical procesure with the peritonitis group. Rats in the second group underwent cecal puncture and ligation. At the second laparotomy, 24 h later the rats were killed. The abdomen was opened and proximal and distal colon were removed and placed in Krebs-bicarbonate solution. Proximal and distal colon segments with 1 cm thickness were placed in circular direction in tissue baths, filled with Krebs Bicarbonate solution (KBS). By this way, after KCl contraction responses, spontaneous contraction responses and inhibitor effects of dexmedetomidine, midazolam and clonidine on spontaneous contractions were evaluated. Results. In our study, contractions induced by KCl were not significantly different between the peritonitis group and the control group. The amplitude of spontaneous contractions of proximal colon was higher than distal colon. Also the amplitude of spontaneous contractions of peritonitis group was higher than control group. Dexmedetomidine, midazolam and clonidine inhibited spontaneous contractions of colon strips in both peritonitis and control groups. This inhibitor effect was prominent in control group. In case of inhibitor effect on colon motility, in all groups and tissues, although the most potent drug was dexmedetomidine, the less was clonidine except in distal colon. The inhibitor effects of midazolam and colonidine was similar in distal colon. Conclusion. These results suggest that Dexmedetomidine is more effective that other drugs in inhibition of spontaneous contractions, especially in control groups and these drugs, especially dexmedetomidine, may be used for the patients with diarrhea in intensive care units. Keywords: Dexmedetomidine, midazolam, clonidine, peritonitis, spontaneous contractions, intensive care unit.