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Cardiovascular disease is part of the main causes of disability and even death throughout the world. Moreover, diabetes mellitus is often associated with complications of various organ systems, of especially microvascular dysfunction. Uncaria rhynchophylla, a traditional Chinese herb medicine, has long been used as an anti-hypertension drug in China for thousands of years. Our group has long devoted to extracting, synthesizing and evaluating indole alkaloids derived from Uncaria rhynchophylla. G2, one of the racemic analog of indole alkaloids we synthesized, exhibited significant vasodilation activity which has, even more, potential than Rhynchophylline in vitro rat thoracic aorta test. After further separation on a choral column, two enantiomers, G2-a and G2-b were obtained from G2. Based on the pharmaceutical preliminary studies on the relaxation of rat thoracic aorta, G2 and its stereoisomers have been chosen as the vascular relaxation agents to further investigate their functions and mechanisms on the treatment of microvascular dysfunction leading to diabetes.
Diabetic model in Sprague-Dawley rats was induced by intrapulmonary injection of 60 mg/kg streptozotocin (STZ) followed by a gavage of high-glucose solution. After 8 weeks of modeling, diabetes was established by confirming the blood glucose measuring. Then, the diabetic rats were addressed in 20 mg/kg G2 (gavage) for 2 weeks, and mesenteric arteries were taken. Then vessels were placed for vasodilation effects by myograph chambers, eNOS and iNOS levels by western blotting and immunohistochemical staining.
To determine whether G2 could restore endothelium function, phenylephrine-induced concentration-dependent contractions and acetylcholine-induced endothelium-dependent relaxations were performed. G2 (20mg/kg) gavage for a week improved EDRs and decreased Phenylephrine-induced concentration-dependent contractions. G2 could protect the vessel from eNOS loss induced by diabetes mellitus, which was vital for artery relaxation.
Diabetes as a pathological model of endothelium damage to investigate whether the chemicals could still trigger relaxant effects and again to illustrate that whether endothelium-dependent relaxation was involved. G2 could generate vasodilation effects with a right shift curve, indicating endothelium was involved in G2-incduced vasorelaxation.