6-Gingerol alleviates exaggerated vasoconstriction in diabetic rat aorta through direct vasodilation and nitric oxide generation

Drug Design, Development and Therapy Dovepress open access to scientific and medical research Original Research Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 213.32.59.121 on 13-Jul-2018 For personal use only. Open Access Full Text Article 6-Gingerol alleviates exaggerated vasoconstriction in diabetic rat aorta through direct vasodilation and nitric oxide generation This article was published in the following Dove Press journal: Drug Design, Development and Therapy 9 November 2015 Number of times this article has been viewed Salah A Ghareib 1 Hany M El-Bassossy 1,2 Ahmed A Elberry 3,4 Ahmad Azhar 5 Malcolm L Watson 6 Zainy Mohammed Banjar 7 Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt; 3 Department of Clinical Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 4 Department of Pharmacology, Faculty of Medicine, Beni Suef University, Beni Suef, Egypt; 5Department of Pediatric Cardiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 6Department of Pharmacy and Pharmacology, University of Bath, Bath, UK; 7Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia 1 Abstract: The aim of the present study is to investigate the effect and potential mechanism of action of 6-gingerol on alterations of vascular reactivity in the isolated aorta from diabetic rats. Male Wistar rats were divided into two experimental groups, control and diabetics. Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg kg−1), and the rats were left for 10 weeks to develop vascular complications. The effect of in vitro incubation with 6-gingerol (0.3–3 µM) on the vasoconstrictor response of the isolated diabetic aortae to phenylephrine and the vasodilator response to acetylcholine was examined. Effect of 6-gingerol was also examined on aortae incubated with methylglyoxal as an advanced glycation end product (AGE). To investigate the mechanism of action of 6-gingerol, the nitric oxide synthase inhibitor Nω-nitrol-arginine methyl ester hydrochloride (100 µM), guanylate cyclase inhibitor methylene blue (5 µM), calcium-activated potassium channel blocker tetraethylammonium chloride (10 mM), and cyclooxygenase inhibitor indomethacin (5 µM) were added 30 minutes before assessing the direct vasorelaxant effect of 6-gingerol. Moreover, in vitro effects of 6-gingerol on NO release and the effect of 6-gingerol on AGE production were examined. Results showed that incubation of aortae with 6-gingerol (0.3–10 μM) alleviated the exaggerated vasoconstriction of diabetic aortae to phenylephrine in a concentration-dependent manner with no significant effect on the impaired relaxatory response to acetylcholine. Similar results were seen in the aortae exposed to methylglyoxal. In addition, 6-gingerol induced a direct vasodilation effect that was significantly inhibited by Nω-nitro-l-arginine methyl ester hydrochloride and methylene blue. Furthermore, 6-gingerol stimulated aortic NO generation but had no effect on AGE formation. In conclusion, 6-gingerol ameliorates enhanced vascular contraction in diabetic aortae, which may be partially attributed to its ability to increase the production of NO and stimulation of cyclic guanosine monophosphate. Keywords: diabetes, 6-gingerol, vasorelaxant, nitric oxide, advanced glycation end products, vascular complications Introduction Correspondence: Ahmed A Elberry Department of Clinical Pharmacy, Faculty of Pharmacy, King Abdul-Aziz University, University Street, Jeddah 21589, Saudi Arabia Tel +966 5 4343 0919 Fax +966 12 695 1696 Email 6019 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2015:9 6019–6026 Dovepress © 2015 Ghareib et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/DDDT.S94346 Powered by TCPDF (www.tcpdf.org) Diabetes mellitus (DM) is a common disease that affects almost 387 million people worldwide with a prevalence of 8.3% and an expected 205 million increase by 2035, according to the International Diabetes Federation.1 Despite significant improvements in controlling diabetes, vascular complications remain a major cause of morbidity and mortality in patients with DM.2 Macrovascular complications of DM include coronary artery disease,3 heart failure,4 and stroke.5 In addition, microvascular diseases of DM, including nephropathy6 and retinopathy,7 continue to cause morbidity and mortality. These vascular complications may be partially attributed to impairment of vasomotor function of smooth muscles.8,9 Dovepress Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 213.32.59.121 on 13-Jul-2018 For personal use only. Ghareib et al Ginger rhizome (Zingiber officinale), commonly known as ginger, is utilized worldwide as a spice and a flavoring agent, with a long history of medicinal use for diseases, including arthritis, pain, sore throat, constipation, indigestion, vomiting, dementia, fever, infectious diseases, and helminthiasis.10 Moreover, it is used in South Asia as a traditional medicine to treat cardiopathy and hypertension due to its vasodilator effect.11 Phytochemical reports showed that the main constituents of ginger are the gingerols, shogaols, zingerone, and paradol.12 6-Gingerol, one of the major elements of ginger, has been found to exhibit antiinflammatory,13 antihyperglycemic,14 antiangiogenic,15 and anticancer16 effects. In addition, antiplatelet aggregatory and vasorelaxatory effects of the constituents of ginger were reported by Liao et al.17 Hence, the current study is designed to investigate the effect and potential mechanism of action of 6-gingerol on alterations of vascular reactivity in the isolated aorta from diabetic rats. Materials and methods Drugs and chemicals 6-Gingerol, Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME), methylene blue (MB), tetraethylammonium chloride (TEA), indomethacin (INDO), aminoguanidine (AG), ribose, bovine serum albumin (BSA), acetylcholine (ACh), and phenylephrine (PE) were purchased from Sigma-Aldrich Co., St Louis, MO, USA, and 4-amino-5-methylamino-2′,7′difluorofluorescein (DAF-FM) diacetate was purchased from Molecular Probes, NY, USA. All chemicals (...truncated)