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The aim of this study was to examine whether metformin, a biguanide anti-hyperglycemic drug, dilates retinal blood vessels in rats. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo and diameters of retinal blood vessels were measured. Both systemic blood pressure and heart rate were continuously recorded. Metformin (0.01-0.3mg/kg/min) increased diameters of retinal blood vessels in a dose-dependent manner. This retinal vasodilator effect of metformin was abolished by compound C, an inhibitor of AMP-activated protein kinase (AMPK), and NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide (NO) synthase. Similar results were obtained with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleoside (AICAR, 0.01-1mg/kg/min). Neither metformin nor AICAR exerted significant effect on mean blood pressure and heart rate. However, a significant pressor response to AICAR was observed upon inhibition of NO synthase. These results suggest that metformin dilates retinal blood vessels through activation of AMPK, and NO plays an important role in the retinal vasodilator response following AMPK activation.

Intra-arterial high-dose cisplatin chemoradiation (CRT-IA) with sodium thiosulfate (STS) causes relatively less severe cisplatin ototoxicity than intravenous cisplatin chemoradiation without STS (CRT-IV). The results of this study also suggest that early detection of ototoxicity is possible by testing the hearing loss at ultra-high frequencies.To investigate protective effects of STS against cisplatin ototoxicity.Between 2011 and 2013, 18 patients with head and neck carcinomas were treated with intra-arterial infusions of high-dose cisplatin (range 100-180 mg/body, mean 111 mg/body; range 2-5 courses, mean 3.6 courses) and systemic administration of cisplatin (range 66-185 mg/body, mean 130 mg/body; range 1-3 courses, mean 2.6 courses) and concurrent radiation therapy (range 60-70 Gy, mean 69 Gy). Cisplatin was neutralized by STS in CRT-IA but not in CRT-IV.Intra-arterial infusion in the high-dose cisplatin group caused significant hearing loss at ultra-high frequencies of 10 and 12 kHz (p = 0.028, 0.039, respectively), whereas the group receiving systemic administration of cisplatin had significant hearing loss at high frequencies of 8 and 10 kHz (p = 0.016, 0.027, respectively).

Transient receptor potential cation channel subfamily V member 1 (TRPV1) plays a role in esophageal function. However, the distribution of TRPV1 nerve fibers in the esophagus is currently not well understood. In the present study, we investigated the distribution of TRPV1 and neurotransmitters released from TRPV1 nerve fibers in the mouse lower esophagus. Furthermore, we investigated changes in the presence of TRPV1 in the mouse model of esophagitis. Numerous TRPV1-immunoreactive nerve fibers were seen in both the submucosal layer and myenteric plexus of the lower esophagus and colocalized with calcitonin gene-related peptide (CGRP). TRPV1 colocalized with substance P in axons in the submucosal layer and myenteric plexus. TRPV1 colocalized with neuronal nitric oxide synthase in the myenteric plexus. We observed some colocalization of CGRP with the vesicular acetylcholine (ACh) transporter, packaging of ACh into synaptic vesicles after its synthesis in terminal cytoplasm, in the submucosal layer and myenteric plexus. In the esophagitis model, the number of the TRPV1 nerve fibers did not change, but their immunoreactive intensity increased compared with sham-operated mice. Inhibitory effect of exogenous capsaicin on electrically stimulated twitch contraction significantly increased in esophagitis model compared with the effect in sham-operated mice. Overall, these results suggest that TRPV1 nerve fibers projecting to both the submucosal and muscle layer of the esophagus are extrinsic spinal and vagal afferent neurons. Furthermore, TRPV1 nerve fibers contain CGRP, substance P, nitric oxide, and ACh. Therefore, acid influx-mediated TRPV1 activation may play a role in regulating esophageal relaxation.