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Summary: Objectives: The objective of the study is to compare the efficacy of hypoglycaemic drugs for type 2 diabetes mellitus (T2DM) by network meta‐analysis of randomized controlled trials (RCTs). Methods: We compared 11 major oral hypoglycaemic drugs under five categories evaluated by RCTs as drug monotherapy for the patients with T2DM, measuring glycosylated haemoglobin (%) or fasting plasma glucose (mmol L−1) as outcomes. RCT quality was assessed with the Cochrane risk of bias tool. Network meta‐analysis estimated the mean differences and 95% credible intervals. Subgroup and sensitivity analyses were performed to determine the results robustness. The Grading of Recommendation, Assessment, Development, and Evaluation evidence strength was assessed. Results: Seventy‐five RCTs including 33,830 patients were identified. Their study quality was high. Regarding glycosylated haemoglobin, top three anti‐diabetics were repaglinide (mean differences −1.39 [95% credible intervals −1.75 to −1.03]), gliclazide (−1.37 [−2.04 to −0.71]) and metformin (−1.13 [−1.37 to −0.90]), against placebo. Regarding fasting plasma glucose, top three anti‐diabetics were repaglinide (−2.01 [−2.75 to −0.97]), metformin (−1.72 [−2.16 to −1.27]) and glipizide (−1.57 [−2.44 to −0.64]), against placebo. There was no difference between metformin and repaglinide. Subgroup and sensitivity analyses found the results to be robust. The evidence strength was moderate to high. Conclusion: This meta‐analysis showed that repaglinide and metformin would be the most efficacious oral drugs for first‐line monotherapy of T2DM. [ABSTRACT FROM AUTHOR]

Background and Purpose Kaempferol, a plant flavonoid present in normal human diet, can modulate vasomotor tone. The present study aimed to elucidate the signalling pathway through which this flavonoid enhanced relaxation of vascular smooth muscle. Experimental Approach The effect of kaempferol on the relaxation of porcine coronary arteries to endothelium-dependent (bradykinin) and -independent (sodium nitroprusside) relaxing agents was studied in an in vitro organ chamber setup. The whole-cell patch-clamp technique was used to determine the effect of kaempferol on potassium channels in porcine coronary artery smooth muscle cells ( PCASMCs). Key Results At a concentration without direct effect on vascular tone, kaempferol (3 × 10−6 M) enhanced relaxations produced by bradykinin and sodium nitroprusside. The potentiation by kaempferol of the bradykinin-induced relaxation was not affected by Nω-nitro- L-arginine methyl ester, an inhibitor of NO synthase (10−4 M) or TRAM-34 plus UCL 1684, inhibitors of intermediate- and small-conductance calcium-activated potassium channels, respectively (10−6 M each), but was abolished by tetraethylammonium chloride, a non-selective inhibitor of calcium-activated potassium channels (10−3 M), and iberiotoxin, a selective inhibitor of large-conductance calcium-activated potassium channel ( KCa1.1; 10−7 M). Iberiotoxin also inhibited the potentiation by kaempferol of sodium nitroprusside-induced relaxations. Kaempferol stimulated an outward-rectifying current in PCASMCs, which was abolished by iberiotoxin. Conclusions and Implications The present results suggest that, in smooth muscle cells of the porcine coronary artery, kaempferol enhanced relaxations caused by endothelium-derived and exogenous NO as well as those due to endothelium-dependent hyperpolarization. This vascular effect of kaempferol involved the activation of KCa1.1 channels. [ABSTRACT FROM AUTHOR]

Aims: To investigate the roles of cyclooxygenases (COX) and their metabolites in C57/BL6 mice with 5/6 nephrectomy, an animal model of chronic renal failure., Main Methods: C57/BL6 mice were grouped into sham-operated (2K), one kidney removal (1K) and 5/6 nephrectomy groups (5/6Nx). Renal resistive index was measured by ultrasonography. Blood, aortae, renal arteries and renal cortex were collected for measurement of kidney function, assessment of vascular responsiveness, Western blotting, immuohistochemistry and enzyme-linked immunosorbent assays., Key Findings: After four weeks, acetylcholine-induced relaxations were blunted in renal arteries of 1K and 5/6Nx mice; indomethacin, a non-selective COX inhibitor, improved the response in 5/6Nx, but not in 1K renal arteries. In 5/6Nx renal arteries, but not in 1K preparations, the protein presence of endothelial nitric oxide synthase (eNOS) was decreased, while that of COX-2 and its products [prostacyclin and thromboxane A 2 ] were increased. The renal resistive index was lower in 5/6Nx mice, suggesting a lower resistance in the renal microvasculature. In the renal cortex of 5/6Nx mice, eNOS protein presence was increased; while the presence of COX-2 was not detectable. The prostaglandin E 2 level was lower in the 5/6Nx cortex than in the other two groups., Significance: The early stage of renal mass removal is associated with increased renal arterial constriction and reduced microvascular resistance. The former is due to downregulation of eNOS and upregulation of COX-2, leading to an increased production of prostacyclin and thromboxane A 2 . A reduced production of PGE 2 in the renal cortex is important for maintaining normal renal function., (Copyright © 2017. Published by Elsevier Inc.)