Deneysel hipertansiyon modelinde agomelatinin arteriyel kan basıncı ve kardiyak yeniden şekillenme üzerine etkisinin incelenmesi
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Date
2024
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Trakya Üniversitesi
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info:eu-repo/semantics/openAccess
Abstract
Giriş ve Amaç: Agomelatinin hipotansif etkilerinin altında yatan mekanizmalar ve kardiyak yeniden şekillenme üzerine etkileri tam olarak bilinmemektedir. Çalışmamızın amacı, NOS inhibisyonu ile oluşturulan deneysel hipertansiyon modelinde agomelatinin arteriyel kan basıncı ve kardiyak yeniden şekillenme üzerine olası etkisinde NO/cGMP, HSP90 ve antioksidan mekanizmaların rolünü araştırmaktır. Gereç ve Yöntemler: Spraque-Dawley türü 32 adet yetişkin erkek sıçan Kontrol (K), Agomelatin (AGO), Hipertansiyon (HT) ve Hipertansiyon+Agomelatin (HT+AGO) olmak üzere dört gruba ayrıldı. HT ve HT+AGO gruplarının içme suyuna 6 hafta boyunca L-NAME 400 mg/L eklendi. Deneyin son iki haftası AGO ve HT+AGO gruplarına agomelatin (40 mg/kg/gün) intraperitonal olarak verildi. Serum ve sol ventrikülde eNOS, cGMP ve HSP90 düzeyleri ELISA yöntemiyle, NO düzeyi spektrofotometrik yöntemle incelendi. Sol ventrikül dokusunda ERK1/2 ve p-ERK1/2 western blot ve immünohistokimyasal yöntemlerle, MDA ve GSH düzeyleri ise spektrofotometrik yöntemle incelendi. Ayrıca sol ventrikül kardiyomiyosit çapları Hematoksilen Eozin ile boyanarak belirlendi. Bulgular: Sistolik kan basıncı HT grubunda ilk haftadan itibaren K grubuna göre yükselirken (p<0,001), HT+AGO grubunda HT grubuna kıyasla azaldı (p<0,001). HT+AGO grubunda, serum eNOS, NO ve cGMP düzeyleri ile sol ventrikül GSH düzeyleri HT grubuna göre yüksek bulundu (tümü p<0,05). Serum HSP90 düzeyi ise HT+AGO grubunda K grubuna göre yüksek bulundu (p<0,05). Sol ventrikül dokusunda p-ERK1/2 / ERK1/2 oranı HT grubunda K grubuna göre yüksek (p<0,01) ancak HT+AGO grubunda HT grubuna göre düşük bulundu (p<0,05). Sol ventrikül kardiyomiyosit çapı HT ve HT+AGO gruplarında, K ve AGO gruplarına göre yüksekti (tümü p<0,01). Sonuç: Agomelatinin arteriyel kan basıncı üzerine azaltıcı etkisinde NO-cGMP yolağı ve HSP90 düzeyi artışı rol oynamaktadır. Agomelatin, kardiyak dokuda GSH düzeyinde yükselmeye neden olarak antioksidan etki ve ERK1/2 protein aktivasyonunu azaltarak antihipertrofik etki oluşturabilir. Ancak bu etkiler sol ventrikülde morfolojik düzeyde belirgin değişime neden olmamıştır.
Background and Aim: The mechanisms underlying the hypotensive effects of agomelatine and its effects on cardiac remodeling are not fully known. The aim of our study was to investigate the role of NO/cGMP, HSP90 and antioxidant mechanisms in the possible effects of agomelatine on arterial blood pressure and cardiac remodeling in an experimental hypertension model induced by NOS inhibition. Material and Methods: Thirty-two adult male Spraque-Dawley rats were divided into four groups as Control (C), Agomelatine (AGO), Hypertension (HT) and Hypertension+Agomelatine (HT+AGO). L-NAME 400 mg/L was added to the drinking water of HT and HT+AGO groups for 6 weeks. In the last two weeks of the experiment, agomelatine (40 mg/kg/day) was administered intraperitoneally to AGO and HT+AGO groups. Serum and left ventricular eNOS, cGMP and HSP90 levels were analyzed by ELISA and NO levels were analyzed by spectrophotometric method. In left ventricular tissue, ERK1/2 and p-ERK1/2 were analyzed by western blot and immunohistochemical methods, and MDA and GSH levels were analyzed by spectrophotometric method. In addition, left ventricular cardiomyocyte diameters were determined by Hematoxylin and Eosin staining. Results: Systolic blood pressure increased in the HT group compared to the K group from the first week (p<0.001) and decreased in the HT+AGO group compared to the HT group (p<0.001). Serum eNOS, NO and cGMP levels and left ventricular GSH levels were higher in the HT+AGO group compared to the HT group (all p<0.05). Serum HSP90 level was higher in the HT+AGO group compared to the K group (p<0.05). The p-ERK1/2/ERK1/2 ratio in left ventricular tissue was higher in the HT group compared to the K group (p<0.01), but lower in the HT+AGO group compared to the HT group (p<0.05). Left ventricular cardiomyocyte diameters were higher in HT and HT+AGO groups compared to K and AGO groups (all p<0.01). Conclusion: NO-cGMP pathway and increased HSP90 level play a role in the decreasing effect of agomelatine on arterial blood pressure. Agomelatine may produce antioxidant effect by increasing GSH level in cardiac tissue and antihypertrophic effect by decreasing ERK1/2 protein activation. However, these effects did not cause significant morphological changes in the left ventricle.
Background and Aim: The mechanisms underlying the hypotensive effects of agomelatine and its effects on cardiac remodeling are not fully known. The aim of our study was to investigate the role of NO/cGMP, HSP90 and antioxidant mechanisms in the possible effects of agomelatine on arterial blood pressure and cardiac remodeling in an experimental hypertension model induced by NOS inhibition. Material and Methods: Thirty-two adult male Spraque-Dawley rats were divided into four groups as Control (C), Agomelatine (AGO), Hypertension (HT) and Hypertension+Agomelatine (HT+AGO). L-NAME 400 mg/L was added to the drinking water of HT and HT+AGO groups for 6 weeks. In the last two weeks of the experiment, agomelatine (40 mg/kg/day) was administered intraperitoneally to AGO and HT+AGO groups. Serum and left ventricular eNOS, cGMP and HSP90 levels were analyzed by ELISA and NO levels were analyzed by spectrophotometric method. In left ventricular tissue, ERK1/2 and p-ERK1/2 were analyzed by western blot and immunohistochemical methods, and MDA and GSH levels were analyzed by spectrophotometric method. In addition, left ventricular cardiomyocyte diameters were determined by Hematoxylin and Eosin staining. Results: Systolic blood pressure increased in the HT group compared to the K group from the first week (p<0.001) and decreased in the HT+AGO group compared to the HT group (p<0.001). Serum eNOS, NO and cGMP levels and left ventricular GSH levels were higher in the HT+AGO group compared to the HT group (all p<0.05). Serum HSP90 level was higher in the HT+AGO group compared to the K group (p<0.05). The p-ERK1/2/ERK1/2 ratio in left ventricular tissue was higher in the HT group compared to the K group (p<0.01), but lower in the HT+AGO group compared to the HT group (p<0.05). Left ventricular cardiomyocyte diameters were higher in HT and HT+AGO groups compared to K and AGO groups (all p<0.01). Conclusion: NO-cGMP pathway and increased HSP90 level play a role in the decreasing effect of agomelatine on arterial blood pressure. Agomelatine may produce antioxidant effect by increasing GSH level in cardiac tissue and antihypertrophic effect by decreasing ERK1/2 protein activation. However, these effects did not cause significant morphological changes in the left ventricle.
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Fizyoloji, Physiology
