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2 results on '"Sevin, Gülnur"'

1. The Effects of Novel Triazolopyrimidine Derivatives on H2S Production in Lung and Vascular Tonus in Aorta.

Author

Ozbek, Emine Nur, Istanbullu, Huseyin, Kızrak, Umran, Alan Albayrak, Elif, Sevin, Gülnur, and Yetik-Anacak, Gunay

Subjects
RESVERATROL, HYDROGEN sulfide, AORTA, CHRONIC obstructive pulmonary disease, LUNGS, OXIDATIVE stress, PULMONARY hypertension
Abstract

Introduction: Hydrogen sulfide (H2S), known as a third gasotransmitter, is a signaling molecule that plays a regulatory role in physiological and pathophysiological processes. Decreased H2S levels were reported in inflammatory respiratory diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary hypertension. H2S donors or drugs that increase H2S have emerged as novel treatments for inflammatory respiratory diseases. We previously showed that resveratrol (RVT) causes vascular relaxation and antioxidant effects by inducing H2S production. In the current study, we synthesized a new molecule Cpd2, as an RVT analog. We examined the effect of Cpd2 and its precursor chalcone compound (Cpd1) on H2S formation under both healthy and oxidative stress conditions in the lung, as well as vascular relaxation in the aorta. Methods: Cpd2 synthesized from Cpd1 with microwaved in basic conditions. H2S formation was measured by H2S biosensor in the mice lungs under both healthy and pyrogallol-induced oxidative stress conditions in the presence/absence of H2S synthesis inhibitor aminooxyacetic acid (AOAA). The effect of compounds on vascular tonus is investigated in mice aorta by DMT myograph. Results: RVT and Cpd2 significantly increased l-cysteine (l-cys) induced-H2S formation in the lung homogenates of healthy mice, but Cpd1 did not. Superoxide anion generator pyrogallol caused a decrease in H2S levels in mice lungs and Cpd2 restored it. Inhibition of Cpd2-induced H2S formation by AOAA confirmed that Cpd2 increases endogenous H2S formation in both healthy and oxidative stress conditions. Furthermore, we found that both Cpd1 and Cpd2 (10−8–10−4 M) caused vascular relaxation in mice aorta. Discussion and Conclusion: We found that Cpd2, a newly synthesized RVT analog, is an H2S-inducing molecule and vasorelaxant similar to RVT. Since H2S has antioxidant and anti-inflammatory effects, Cpd2 has a potential for the treatment of respiratory diseases where oxidative stress and decreased H2S levels are present. [ABSTRACT FROM AUTHOR]

Published
2023
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2. Pulmoner arter hipertansiyonunda hidrojen sülfürün rolü var mı?

Author

Turhan, Kumru, Sevin, Gülnur, Farmakoloji Anabilim Dalı, and Sağlık Bilimleri Enstitüsü

Subjects
Pulmonary Arterial Hypertension, Hidrojen Sülfit, Sistein, Vasodilator Agents, Wistar, Hypertrophy, Pulmoner Arteriyel Hipertansiyon, Hipertrofi, Rats, Wistar Sıçan, Pharmacy and Pharmacology, Vazodilatör Ajanlar, Hydrogen Sulfide, Cysteine, Eczacılık ve Farmakoloji
Abstract

Çalışmamızın amacı, MCT ile indüklenen PAH modelinde H2S'in rolünü, hem H2S üretimi hem de H2S aracılı yanıtlar üzerinden araştırmaktır. Erişkin erkek Wistar sıçanlar (250-300 g), kontrol, MCT, MCT+Na2S ve Na2S olmak üzere dört gruba ayrıldılar. Deneysel PAH modelini oluşturmak için, MCT (60 mg/kg, i.p.) sıçanlara tek doz olarak uygulandı. Kontrol ve MCT gruplarına fizyolojik salin çözeltisi; MCT+Na2S ve Na2S gruplarına ise Na2S (2.5 mg/kg, i.p.) 21 gün boyunca verildi. 60 mg/kg ketamin-5 mg/kg ksilazin anestezisi altında sağ ventriküle 23 G branül ile girilerek sağ ventrikül basıncı ölçüldü. Sağ ventrikül hipertrofisini belirlemek için [sağ ventrikül/(sol ventrikül+septum)] oranı hesaplandı. İzole organ banyosu deneylerinde ana pulmoner arterler kullanıldı. KCl ön kastırma sonrası tek doz ACh ve fenilefrin ön kastırma sonrası kümülatif ACh gevşeme yanıtları alındı. H2S’in rolünü değerlendirmek için fenilefrin ön kastırma sonrasında kümülatif L-sistein gevşeme yanıtları (AOAA varlığında/yokluğunda) ile kümülatif Na2S gevşeme yanıtları alındı. Bazal veya L-cys ile uyarılmış akciğer ve pulmoner arter homojenatlarında H2S düzeylerini ölçmek için MBA yapıldı. Sağ ventrikül basıncı ve [sağ ventrikül/(sol ventrikül+septum)] oranı, kontrol grubuna kıyasla MCT grubunda istatistiksel olarak anlamlı artarken MCT+Na2S grubunda ise anlamlı olarak azalmıştır. KCl kasılma yanıtları kontrol grubuna göre MCT grubunda azalırken, bu azalma MCT+Na2S grubunda istatistiksel olarak anlamlı düzeyde normalize olmuştur. KCl ön kastırması ve fenilefrin ön kastırması sonrası alınan ACh gevşeme yanıtı kontrol grubuna göre MCT grubunda istatistiksel olarak anlamlı düzeyde azalmıştır. Gevşemedeki bu azalma MCT+Na2S grubunda istatistiksel olarak anlamlı düzeyde normalize olmuştur. L-sistein gevşeme yanıtları, kontrol grubuna kıyasla MCT grubunda anlamlı düzeyde azalmış ve bu gevşemeler MCT+Na2S grubunda istatistiksel olarak anlamlı düzeyde artmıştır. Gevşemedeki bu artış AOAA ile tersine çevrilmemiştir. Na2S ile indüklenen gevşeme yanıtları, kontrol grubuna kıyasla MCT grubunda istatistiksel olarak anlamlı düzeyde azalmış ve bu gevşemeler MCT+Na2S grubunda istatistiksel olarak anlamlı düzeyde artmıştır. Akciğer dokusunda bazal H2S düzeylerinde gruplar arasında anlamlı bir değişiklik gözlenmemiştir. L-sistein ile uyarılmış akciğer dokusunda kontrol grubuna kıyasla MCT grubunda H2S düzeylerinde anlamlı bir azalma görülmüş, bu azalma MCT+Na2S grubunda bir miktar düzelmiş ancak istatistiksel olarak anlamlı düzeyde artmamıştır. Pulmoner arterlerde bazal H2S düzeyinde gruplar arasında anlamlı bir fark görülmezken; L-sistein varlığında, kontrol grubuna kıyasla MCT grubunda H2S düzeyi anlamlı düzeyde azalmış ve MCT+Na2S grubunda MCT grubuna kıyasla anlamlı düzeyde artmıştır. İn vivo Na2S tedavisi, PAH’da PAB, sağ ventrikül hipertrofisi ve endotel disfonksiyonunu düzeltmektedir. Pulmoner arterlerde azalan H2S seviyelerini ve L-sistein gevşemelerini arttırmaktadır. L-sistein gevşemelerindeki bu artış AOAA varlığında geri dönmediğinden bu etki, CSE/CBS aracılı endojen H2S üretiminden bağımsızdır. Oluşan bu yararlı etkiler, endojen H2S üretiminin diğer sorumlu enzimi olan 3-MST’den ya da Na2S'in H2S donörü gibi davranmasından kaynaklanabilir. PAH varlığında azalan eksojen Na2S gevşemelerinin in vivo tedavi sonrasında düzelmesi, aynı zamanda H2S kaynaklı alt mekanizmaların da PAH'dan etkilendiğini göstermektedir. Sonuçlarımız, PAH’da H2S düzeylerinin ve H2S aracılı yanıtların bozulduğunu, in vivo Na2S tedavisinin H2S’i arttırarak terapötik etkinlik gösterebileceğini ve H2S hedefli tedavilerin PAH’daki önemini işaret etmektedir., The aim of our study was to examine the role of H2S in the model of MCT-induced PAH in rats through both H2S production and H2S-mediated responses. Adult male Wistar rats (250-300 g) were divided into four groups: control, MCT, MCT+Na2S and Na2S. MCT (60 mg/kg, i.p.) was administered as a single dose to induce the experimental PAH model. Physiological saline was given to control and MCT groups; MCT+Na2S and Na2S groups were administered Na2S (2.5 mg/kg, i.p.) for 21 days. Under 60 mg/kg ketamine-5 mg/kg xylazine anaesthesia, a 23 G needle placed into the RV and RVP was measured. The ratio of [RV/(LV+S)] was calculated to determine the index of RV hypertrophy. The main PAs were used for vascular reactivity. First, PAs were pre-contracted with KCl and relaxed with a single dose of ACh. To investigate endothelial dysfunction, cumulative ACh relaxations were taken in the presence of Phe. In order to investigate the vasodilatory effect of H2S; the vasorelaxant responses to L-cysteine (L-cys) were obtained by using myograph in the presence/absence of AOAA (30 min., 2 mM). Cumulative Na2S vasorelaxations were also taken. To measure H2S levels in PA and lung homogenates, MBA was applied in the basal or L-cyst induced conditions. While RVP and RV/(LV+S) ratio was significantly increased in MCT group compared to control group, there was a significantly decrease in MCT+Na2S group. KCl contraction were reduced significantly in MCT group compared to control group. This decrease was normalized in MCT+Na2S group. ACh relaxations after KCl and Phe pre-contractions were reduced in MCT group compared to the control group but improved in MCT+Na2S group. Relaxation to L-cys significantly reduced in MCT group compared to the control group. These relaxations increased in MCT+Na2S group. AOAA did not reversed these relaxations. Na2S-induced relaxations decreased significantly in MCT group compared to the control group but increased in MCT+ Na2S group. There was a significant difference on H2S levels in lung tissues in the presence of L-cys, but no in basal condition. There was also no difference in the basal H2S level of the PAs. However, H2S formation was significantly decreased in MCT group compared to control group in the presence of L-cys and this decrease was reversed in MCT+Na2S group. In vivo Na2S treatment improved PAP, right ventricular hypertrophy and endothelial dysfunction in PAH. It increased H2S levels and L-cysteine relaxation in pulmonary arteries. This effect is independent of CSE/CBS-mediated endogenous H2S production as this increase in L-cysteine relaxations did not return in the presence of AOAA. These beneficial effects can be caused either by the 3-MST which was the other enzyme of endogenous H2S production, or by its acting as H2S donor. The reduction of exogenous Na2S relaxations in the presence of PAH showed that the sub-mechanisms of H2S are also affected by PAH. Our results suggest that H2S levels and H2S-mediated responses are impaired in PAH. In vivo Na2S therapy may have therapeutic efficacy by increasing H2S and shows the importance of H2S-targeted therapies in PAH.

Published
2020

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