Metabolik sendromda erektil yanıtlar h2s ile değişiyor mu?
Do erectile responses change in the presence of H2S in the metabolic sydrome?
Yazar: EZGİ DAYAR
Danışman: DOÇ. DR. NERGİZ MURAT
Dokuz Eylül Üniversitesi / Sağlık Bilimleri Enstitüsü / Farmakoloji Ana Bilim Dalı
Derece: Yüksek Lisans, 2016
Konu: Eczacılık ve Farmakoloji = Pharmacy and Pharmacology
Dizin: Cinsel işlev bozukluğu-fizyolojik = Sexual dysfunction-physiological ; Erektil disfonksiyon = Erectile dysfunction ; Fruktoz = Fructose ; Hidrojen sülfür = Hydrogen sulfide ; Metabolik sendrom = Metabolic syndrome

Özet:
Bu proje ile metabolik sendrom (MetS) modeli oluşturulan deney hayvanlarında, hidrojen sülfürün (H₂S) erektil yanıtlar üzerine etkisi değerlendirilerek ve penil dokudaki H₂S miktarı saptanarak, MetS'da H₂S'in erektil fonksiyonlar üzerine olası etkisinin değerlendirilmesi amaçlanmaktadır.
Projemizde Wistar sıçanlarda (200-250 gram) yüksek fruktoz diyeti (10hafta boyunca %60 oranında fruktoz) ile MetS modeli oluşturulacaktır. 10 hafta sonunda kontrol ve MetS gruplarında biyokimyasal analizler, in vivo kavernöz basınç yanıtları ve penil dokuda yapılacak H2S ölçümleri ile birlikte kontrol ve MetS grupları karşılaştırılarak MetS'de gelişen ED ve buna bağlı olarak penil dokuda değişen H2S düzeyleri değerlendirilecektir.
Kardiyovasküler hastalıklara neden olan risk faktörlerinin (hipertansiyon, obezite, insülin rezistansı) birkaçının bir arada bulunması olarak tanımlanan MetS'nin dünyada görülme sıklığı giderek artmaktadır. Seksüel birleşme için yeterli ereksiyona ulaşamama veya yeterli sürede ereksiyonu sürdürememe olarak tanımlanan ED ise MetS'nin ilk bulgusu olarak bilinmektedir. MetS-ED ilişkisi daha sıklıkla klinik çalışmalarla araştırılmıştır. Projemizde bu ilişki daha önce araştırılmamış olan bir mekanizma üzerinden değerlendirilecktir ve ortaya konulan mekanizma ile alternatif tedavi yöntemlerini araştıran çalışmalara ışık tutulacaktır. Memeli hücrelerinde endojen olarak sentezlenen H2S'in ise nöromodulasyon, hipertansiyon, ödem, insülin sekresyonu, miyokardiyal kontraktilite ve vasküler tonusun düzenlenmesi gibi çeşitli fizyolojik ve patofizyolojik olaylarda rol oynadığı ortaya konmuştur. Bu çalışma ile H2S-MetS aracılı ED arasındaki ilişki ilk kez araştırılacaktır. H2S'in MetS hastalarında ED'nu iyileştirici etkisi olabileceği düşünülmektedir. Elde edilen sonuçlara göre H2S'in klinik uygulamalarda kullanılabilirliği değerlendirilecektir.

Abstract:
Metabolic syndrome (MetS) is a progressive disease which is manifested by combination of hypertension, abdominal obesity, insulin resistance, hyperglycemia, dyslipidemia, glucose intolerance and at various clinical conditions associated with type 2 diabetes and vascular pathologies. Most epidemiologic studies clearly show that the prevalence of MetS in the world is increasing rapidly. It is shown that the recent studies have linked MetS with erectile dysfunction. Erectile dysfunction (ED), defined as the consistent inability to achieve or maintain an erection sufficient for satisfactory intercourse, is known as first symptom of MetS. The relationship between MetS and ED has been generally demonstrated in clinical studies. With this project, evaluation of an uninvestigated mechanism of MetS-dependent ED was highlight to future studies that explore alternative treatments. Hydrogen sulfide (H2S) is known as the third member of gastotransmitter family, which are synthesized endogenously in mammalian cells have been revealed to involving in numerous physiological and pathophysiological processes, such as neuromodulation, hypertension, insulin secretion, myocardial contractility, regulation of vascular tone especially erectile physiology. In this study, the relationship between H2S-MetS mediated ED was investigated for the first time. H2S is thought to be therapeutic effect on ED in patients with MetS. According to the results obtained, clinical applications  of H2S was evaluated in MetS-dependent ED.
The aim of this project is to examine the effect of hydrogen sulfide (H2S) on erectile functions MetS model by evaluating the effect of H2S on erectile responses and determining the levels of H₂S in the penile tissues. 
The MetS model was established by high fructose diet (60% fructose) in male Wistar rats (200-250g). MetS group (n=21) were fed a high-fructose diet for 10 weeks. The control group (n=21) were fed a standard diet for 10 weeks. At the end of 10 weeks, in control and MetS groups biochemical analyzes, in vivo intracavernosal pressure responses and H2S measurements in the penile tissue was performed. MetS-dependent  ED and the role of H2S was assessed by the comparison of two groups parameters.
The rats were anesthetized with an intraperitoneal injection of urethane (1200mg/kg). The erectile function was evaluated by in vivo ratio mean arterial blood pressure to intracavernous pressure (ICP/MAP) and area under the curve (EAA).
The fasting serum glucose, triglycerides, uric acid and insulin levels and HOMA-IR parameters were assessed at control and MetS groups. Body weight and waist circumference ratio to tibial length was used for the evaluation of abdominal obesity.
Data are represented as mean±standard error of mean (SEM). Statistical analysis was done by Student's t test by using GraphPad Prism5 Software. P<0,05 was considered as significant.
MetS group triglycerides and insulin levels were significantly higher than the control group (respectively **p=0,0029; ***p<0,0001). Also the average HOMA-IR (insulin resistance measurement test) value of MetS group was significantly higher than the control group (p<0,0001). There were no significant differences in glucose and uric acid levels between the groups (respectively p=0,1259; p=0,5127).
Significant inreases were observed in body weight and waist circumference/tibia percent between control and MetS group at the end of the 10 weeks (respectively ***p<0,0001; ***p<0,0001).
In the MetS group ICP/MAP ratio is reduced compared to the control group (***p<0,0001). Accordingly, MetS group compared with control group, the AUC are decreased significantly (**p=0,0089). Also, compared to the control group blood pressure in the MetS is increased significantly (p=0,0011). In the MetS group, intracavernous administration of NaHS caused a significant increase in intracavernous pressure (*p=0,0436). There were no significant differences in control group (p=0,0744).
In the penil tissue, there was a significant diminished H2S levels at the MetS group (***p=0,0003).
In the MetS group compared to the control group, triglycerides and insulin levels, weight and waist circumference/tibia percent and blood pressure increased respectively. No changes were observed in glucose and uric acid levels. However, due to the increase in HOMA-IR index insulin resistance was improved. Also in the MetS group, it has been shown to deteriorate the erectile response and H2S administration has improved the erectile response.
In conclusion, H2S could be a new therapeutic target for MetS-dependent ED treatment.