Pioglitazonun Metabolik Sendromlu Sıçan Kalp Fonksiyonuna Etkisinin Elektrofizyolojik Yöntemlerle İncelenmesi

Abstract

Objective: Metabolic syndrome (MetS), generally characterized with insulin-resistance, leads to severe cardiovascular disorders, however, the underlying mechanisms of this syndrome has not yet been fully determined. In addition, there are some controversies related with unti-diabetic agents used for treatment of MetS-induced complications, including their aggravating effects on the depressed cardiac function. Therefore, in this study, we first aimed to investigate the effects of pioglitazone, known as a insulinsensitizer, on MetS-induced heart dysfunction. Second, for a comparative study to determine whether MetS-induced heart dysfunction is due to increased oxidative stress, we used a known antioxidant (quercetin) to MetS rats for the same period. Material and Methods: Total 28 male Wistar rats (3 months) were grouped as control group, (Con), MetS group (MetS; added 32% sucrose to drinking water for 18-week), MetS group supplemented with pioglitazone (Piog; 30 mg/kg/day via gavage for 2-week, from 16th-week of MetS-group) and MetS with quercetin (Quer; 75 mg/kg/day via gavage for 2-weeks from 16th-week of MetS group). All rats were fed with standard rat-diet and tap water at standard condition. At the end of experimental period, the body weights and blood glucose levels, and total oxidative status (TOS) and total antioxidant status (TAS) in serum by using special kits were measured for all animals. By using Langendorff-isolated-organ system, left ventricle pressure changes (LVPC) were measured in isolated hearts. The basal level of intracellular free Ca2+ ([Ca2+]i) and Ca2+ transients under electrical-situmulation (under action-potential) were measured in freshly isolated cardiomyocytes by enzymatic-method (loaded with Ca2+-sensitive fluorescence dye, Fura-2AM). Results and Discussion: Either pioglitazone or quercetin application have positive effects on body weight and high blood sugar levels in MetS-group rats. Additionally, both agents caused a small but significant increase on serum TAS levels (p<0.05) while they could not affect the increased serum TOS levels, significantly. Furthermore, quercetin has no significant effect on depressed LVPC levels, while pioglitazone treatment caused even more depression on LVPC levels (p<0.05). Nonetheless, both treatments induced significant protection against MetS-induced alterations in calculated parameters of [Ca2+]i levels and the Ca2+ transients obtained under electrical stimulation (p<0.05). Under the light of our data, such as positive effects on cellular level including parameters of [Ca2+]i changes in isolated cardiomyocytes and no similar positive effects in isolated-organ level, we can assert that these two-agents may have no effects on MetS-induced marked generation of fibrosis in the heart with high sucrose diet in rats.

Keywords

• Diabetes
• Antioxidants
• Oxidative Stress
• Insulin-Resistance
• Tension
• Ca2+ - Homeostasis

Pioglitazonun Metabolik Sendromlu Sıçan Kalp Fonksiyonuna Etkisinin Elektrofizyolojik Yöntemlerle İncelenmesi

Abstract

Amaç: Metabolik sendrom (MetS), genellikle insülin-direnci ile karakterize, kardiyovasküler sistem sorunlarıyla seyreden, mekanizması henüz tam olarak anlașılamamıș bir hastalıktır. Diğer yandan, MetS-indüklü komplikasyonların tedavisinde kullanılan bazı ilaçların, kardiyovasküler sistem sorunlarına ek sorunlar getirebildiği tartıșılmaktadır. Bu çalıșmada, ilk olarak insülin-duyarlaștırıcı olarak bilinen pioglitazonun, MetSindüklü bozulan kalp fonksiyonu üzerindeki etkisini incelemeyi hedefledik. İkinci olarak, MetS-indüklü etkinin artan oksidatif stres üzerinden olup olmadığını göstermek amacıyla, bilinen bir antioksidan (kuersetin) uygulayarak sonuçları karșılaștırmalı olarak incelenmesi hedefledik. Materyal ve Metodlar: Toplam 28-adet erkek Wistar-türü sıçanlar (3 aylık), kontrol grubu (Kon), MetS grubu (MetS; 18-hafta içme suyuna %32 sükroz eklenerek olușturulmuștur), MetS-grubunun 16. haftasından itibaren 2-hafta süre ile ya pioglitazon uygulanmıș MetS-grubu (Piog; 30 mg/kg/gün), ya da kuersetin uygulanmıș MetS grubu (Kuer; 75 mg/kg/gün) olarak düzenlenmiștir. Tüm hayvanlar standart koșullarda normal sıçan yemi ile beslenmiștir. Çalıșma sonunda, hayvanların vücut ağırlıkları, kan șekeri ile serum toplam oksitatif stres (TOS) ve antioksidan (TAS) durumları özel kit ile ölçülmüștür. Langendorff-izole-organ-sisteminde sol ventrikül içi basınç değișimleri (SVBD) ile, enzimatik yöntemle kalbin ventrikülünden izole edilen kardiyomiyositlerde (Ca2+–duyarlı florofor Fura-2AM ile boyanmıș) hücre-içi bazal serbest-Ca2+ seviyesi ([Ca2+]i) ve elektriksel-uyarı altında (aksiyon-potansiyeli sırasında) geçici [Ca2+]i değișimleri incelenmiștir. Bulgular ve Sonuç: Pioglitazon veya kuersetin, MetS-grubunda kilo artıșı ve yüksek kan șekeri üzerinde pozitif etkiler gösterirken, her iki ajan artmıș olan serum TOS seviyelerini değiștirememiș, buna karșılık küçük fakat anlamlı seviyede TAS seviyesinin yükselmesine neden olmușlardır (p<0,05). Kuersetin, MetS-grubunda baskılanmıș olan SVBD’leri etkilemezken, pioglitazon daha da baskılanmasına neden olmuștur. Buna karșılık, MetS-grubunda, artmıș olan bazal [Ca2+]i seviyesi ile elektriksel uyarı altında ölçülen geçici [Ca2+]i değișimlerinin her iki ajan uygulaması ile normal seviyelere döndüğü görülmüștür. Her iki uygulamanın hücre düzeyinde özellikle [Ca2+]i değișimlerini benzer șekilde pozitif yönde etkilerken, organ düzeyinde aynı pozitif etkilerin gözlenememesinin nedeni, bu 2 ajanın MetS-indüklü kalp dokusunda gelișen fibröz olușumu üzerinde etkili olamamalarından kaynaklanabileceğini düșündürmektedir.

Keywords

• Diyabet
• Antioksidanlar
• Oksidatif Stres
• İnsülin-Direnci
• Kasılma Kuvveti
• Ca2+- Homeostazı

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