Objective: Nebivolol is a highly selective beta-1 adrenergic receptor blocker with additional vasorelaxant properties. The vasorelaxant effect of nebivolol has been mainly attributed to endothelium-dependent mechanisms including beta-adrenergic receptors. However, the involvement of ATP-sensitive potassium (KATP) channels, another potential mechanism for vasorelaxant effect, in the vasorelaxant response to nebivolol remains unclear. Therefore, this study was aimed to investigate the role of KATP channels in the nebivolol-induced vasorelaxation in the isolated rat aorta Methods: The rat thoracic aortic rings isolated from Sprague-Dawley rats were mounted in organ bath chambers containing Krebs-Henseleit solution at 37 o C continuously bubbled with 95% O2 and 5% CO2. After an equilibration period, the presence of endothelium was confirmed by the response (more than 50%) to acetylcholine (10 μM) in aortic rings precontracted with phenylephrine (1 μM). After washout, in control group, the endothelium-intact aortic rings were contracted by potassium chloride (30 mM) before the cumulative addition of nebivolol (0.0001-100 μM). In some experiments, the relaxant response to nebivolol (0.0001-100 μM) was also obtained in the presence of glibenclamide (KATP channel blocker, 10 μM) or Nω-Nitro-L-arginine methyl ester (L-NAME: eNOS inhibitor, 100 μM) in the endothelium-intact aortic rings precontracted with potassium chloride (30 mM). Data were presented as means±SEM. Multiple comparisons of groups were performed by using ANOVA followed by post-hoc Bonferroni test. Results: Nebivolol elicited a concentration dependent vasorelaxant effect in the endothelium-intact aortic rings. Relaxant response to nebivolol was significantly inhibited by the presence of glibenclamide or L-NAME (p< 0.05). Although Emax values were not found significantly different among groups, pD2 values of nebivolol were reduced in the endothelium-intact aortic rings incubated with glibenclamide or L-NAME. Conclusion: These results demonstrate for the first time the involvement of KATP channels in the nebivololinduced vasorelaxation in the endothelium-intact aorta precontracted with potassium chloride.

Amaç; Böbrek nakli ya da cerrahi girişimler sırasında gelişebilen iskemi ve reperfüzyon hasarı etkisini hücrelerdeki enerji metabolizmasının bozulması ve oksidatif stresin artmasına yol açarak gösterir. Popüler sporcu destek ürünü olan kreatin monohidrat endojen bir bileşiktir. Hücrelerin enerji metabolizmasını etkileyerek oksidatif stresi azalttığı ve antioksidan etki gösterdiği bilinmektedir. Böbrekte deneysel olarak oluşturulan iskemi reperfüzyon hasarı sonrasında artan oksidatif strese ve yapısal düzeyde izlenen hasara karşı kreatin monohidratın olası etkisinin değerlendirilmesi hedeflenmiştir. Gereç ve Yöntem: Çalışmada Sprague dawley (250-300gr) türü 24 adet erkek sıçan kullanıldı. Sıçanlar rastgele dört gruba ayrıldı: Grup 1: Saf kontrol grubu (n=5), Grup 2: İskemi/ Reperfüzyon Grubu (n=7), Grup 3: İskemi/ Reperfüzyon +Kreatin monohidrat (Kreatin 2 g/kg/gün) (n=7), Grup 4: Kreatin monohidrat (2 g/kg/gün) (n=5) olarak düzenlendi. Grup 2 ve Grup 3’deki sıçanlara intraperitoneal anestezi sonrası 45 dakika boyunca sol renal arterin klemplenmesiyle renal iskemi oluşturuldu ve 45. dk’nın sonunda klemp uzaklaştırıldıktan sonra sol böbreğin parlak kırmızı renge ulaşması reperfüzyonun sağlanması olarak kabul edilerek karın ön duvarı kapatıldı. Grup 3 ve Grup 4’deki sıçanlara 3 gün süresince kreatin monohidrat (2g/kg/gün) distile su içinde çözülerek gavaj yoluyla uygulandı. Reperfüzyondan 72 saat sonra genel anestezi altında kardiyak kan, sol böbrek dokuları alındıktan sonra sakrifiye edildiler. Böbrek dokuları ışık mikroskobik ve elektron mikroskobik olarak değerlendirilirken, plazma örneklerinde total oksidan ve antioksidan stres parametreleri ölçümlendi. Bulgular: İskemi ve reperfüzyon modelinde ince yapı düzeyinde glomerüler kapillerlerdeki belirgin eritrosit stazı saptandı. Bunun yanında glomerüller endotelin ve podositlerin hücre bütünlüğünün korunamadığı izlenirken proksimal tübüllerdeki hücrelerde de şişme sonucu tübül lümenin tıkandığı görüldü. Kreatin uygulanan gruplarda total antioksidan seviyesinin istatistiksel olarak anlamlı ölçüde artması yeniden yapılanma sürecinin pozitif yönde ilerlediğinin göstergesi olarak yorumlandı. Sonuç: Sonuç olarak uygulanan yöntemden kaynaklandığı düşünülen eritrosit stazı nedeniyle dolaşımın tam olarak sağlanamadığı ve buna bağlı olarak kreatin monohidrat desteğinin yapısal düzeyde belirgin olumlu etki gösteremediği düşünüldü.

Objective: The present study aimed to investigate the protective effect of nebivolol in the bladder isolated from rats exposed to ischemia-reperfusion (IR) injury. Methods: Sprague-Dawley rats were divided into control, IR, and nebivolol+IR groups. In the nebivolol+IR group, nebivolol was administered (0.4 mg/kg, subcutaneous) in rats prior to IR insult. At the end of the experimental protocol, the urinary bladder was rapidly isolated and bladder strips were mounted in an organ bath. After the equilibration period, potassium chloride (KCl, 20-100 mM) or carbachol (0.01-10 μM) was cumulatively added to the organ bath to generate cumulative concentration-response curves (CCRCs). Oxidative stress and interleukin 6 (IL-6) levels were also evaluated in the bladder tissue. Results: The CCRCs of KCl and carbachol were significantly reduced in the IR group compared to those of the control, and this inhibition was reversed by the pretreatment of rats with nebivolol (P < .05). The IR group's total antioxidant status was significantly lower with a concomitant increase in IL-6 levels than that of the control and nebivolol+IR groups (P < .05). Conclusions: The present study indicates that pretreatment of rats with nebivolol (0.4 mg/kg) could improve bladder contractile dysfunction caused by IR injury through suppression of increased oxidative stress and IL-6 levels.

Objective: One of the proposed mechanism mediating the vasorelaxant effect of nebivolol is based on its agonistic activity on beta-2 and/or beta-3 adrenergic receptors. These receptors are also involved in the relaxation of urinary bladder. The aim of this study was to explore the ability of nebivolol to induce relaxation of the isolated rat bladder strip precontracted with cholinergic stimuli using carbachol or non-cholinergic stimuli using potassium chloride (KCl). Methods: The isolated bladder strips were mounted in organ bath and contracted by KCl (40 μM) or carbachol (1mM) before the cumulative addition of nebivolol (0.0001-100 μM). To investigate the role of beta-adrenergic receptors in the nebivolol-induced relaxant response, some bladder strips were incubated with propranolol (1 μM) for 30 min. Statistical significance was tested by Student's t-test. p<0.05 was considered to be statistically significant. Results: Nebivolol elicited concentration-dependent relaxant response in the bladder strips precontracted with KCl or carbachol. Although the relaxant response to nebivolol in the bladder strips precontracted with carbachol was significantly inhibited by propranolol (p<0.05), the nebivolol-induced relaxation failed to be inhibited by propranolol in the bladder strips precontracted with KCl. The maximum relaxation in response to nebivolol was found to be significantly higher in the bladder strips precontracted with carbachol compared to that of KCl (p<0.05). Conclusion: The findings of the present study indicate that beta-adrenergic receptors play role in the relaxant response of nebivolol in the isolated rat bladder strip precontracted with carbachol.

Experimental evidence exists that cardiac action of dobutamine is mediated by alfa-1 and betaadrenergic receptors. However, uncertainty remains regarding the vascular effect of dobutamine and contribution of beta-adrenergic receptors to this effect. The aim of the present study was to investigate the direct effect of dobutamine in the rat aorta and the role of beta-adrenergic receptors in this effect. Materials and methods: The isolated thoracic aortic rings were mounted in organ bath containing Krebs-Henseleit solution. After an equilibiration period, endothelial integrity was then checked by the response to acetylcholine (10 μM) in aortic rings pre-contracted with phenylephrine (1 μM). After washout, dobutamine (0.001-10 μM) was added to generate cumulative concentration-response curves (CCRCs). To investigate the role of alfa-and beta-adrenergic receptors in the dobutamine-induced vascular response, prazosin (0.0003 µM) or propranolol (1 µM) was added to the bath medium 30 min before the addition of dobutamine in some experiments. Results: Dobutamine produced concentration-dependent contraction in the endothelium-intact isolated rat aorta. This effect was significantly inhibited by either propranolol or prazosin (p<0.05). Prazosin also significantly supressed the maximum vascular response obtained by dobutamine (p<0.05). Conclusion: The results, to the best of my knowledge, demonstrates for the first time that beta-adrenergic receptors are involved in the vasoconstrictor effect of dobutamine in the endothelium-intact rat aorta.