Association of non-steroidal anti-inflammatory drug use with encephalopathy development: An analysis using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases.

Encephalopathy is the most severe complication of various common infections, including influenza and herpes, and it often results in death or severe neurological disability. The risk factors for viral encephalopathy include non-steroidal anti-inflammatory drug (NSAID) use; however, studies on NSAID-related encephalopathy are limited. In this study, we aimed to investigate the characteristics of NSAID-related encephalopathy. We investigated the incidence of NSAID-related encephalopathy using data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases containing reports on spontaneous adverse effects (AEs) published by the Pharmaceuticals and Medical Devices Agency. We used these databases to detect AEs based on reported odds ratios. By separating suspicious drugs, concomitant drugs, and drug interactions involving NSAIDs, we investigated the relationship between encephalopathy pathology and AEs of NSAIDs. Significant encephalopathy signals were detected for loxoprofen and etodolac in the FAERS database and loxoprofen in the JADER database. In the JADER database, significant encephalopathy signals in loxoprofen-treated patients were detected in 70-79-year-old, ≥80-year-old, influenza viral infection, and herpes virus infection groups. Significant encephalopathy signals in patients with herpes virus infection were detected in the ≥80-year-old and loxoprofen-treated groups. Regarding the involvement of loxoprofen in the development of encephalopathy, the JADER database listed loxoprofen as a suspect drug, without indicating any concomitant drug interactions. In conclusion, our findings suggest that loxoprofen and etodolac may be associated with viral encephalopathy. Accordingly, prudence is recommended when using loxoprofen in older individuals with viral infections.

Relationship between the administration of nicardipine hydrochloride and the development of delirium in patients on mechanical ventilation.

A history of hypertension is a known risk factor for delirium in patients in intensive care units, but the effect of antihypertensive agents on delirium development is unclear. Nicardipine, a calcium channel blocker, is widely used in ICU as a treatment agent for hypertensive emergency. This study investigated the relationship between the administration of nicardipine hydrochloride and delirium development in patients under mechanical ventilation. We conducted a medical chart review of 103 patients, who were divided into two groups according to the use of nicardipine hydrochloride. The prevalence of delirium was compared with respect to factors such as age, sex, laboratory data, and medical history, by multivariate analysis. 21 patients (20.4 %) were treated with nicardipine hydrochloride in 103 patients. The treatment and non-treatment groups differed significantly in age (72 vs. 65 years) and history of high blood pressure (57% vs. 11%). Multivariate analysis revealed that patients in the treatment group developed delirium significantly less often than those in the non-treatment group (19% vs. 48%). These results suggested that treatment of high blood pressure with nicardipine hydrochloride is a possible method for preventing the development of delirium.

Laparoscopic transabdominal preperitoneal approach for recurrent inguinal hernia: A randomized trial.

INTRODUCTION: The repair of the recurrent hernia is a daunting task because of already weakened tissues and distorted anatomy. Open posterior preperitoneal approach gives results far superior to those of the anterior approach. Laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair is an evolving technique associated with advantages of a minimally invasive approach. The present work aimed at comparing these three approaches for repair of recurrent inguinal hernia regarding complications and early recurrence. MATERIALS AND METHODS: A total of 180 patients were divided randomly into three equal groups: A, B, and C. Group A patients were subjected to open posterior preperitoneal approach , those of group B were subjected to transinguinal anterior tension-free repair and group C patients were subjected to TAPP. The primary end point was recurrence and the secondary end points were time off from work, postoperative pain, scrotal swelling, and wound infections. RESULTS: The mean hospital stay, the mean time to return to work and the mean time off from work were less in group C then A and B. Chronic postoperative pain was observed in eight patients in group A (13.33%), in 18 patients in group B (30%) and six patients in group C (10%). The overall complication rate was 19.7% in both groups A and C and 34.36% in group B. CONCLUSION: In recurrent inguinal hernia, the laparoscopic and open posterior approaches are equally effective in term of operative outcome. The open preperitoneal hernia repair is inexpensive, has a low recurrence rate. Postoperative recovery is short and postoperative pain is minimal. This approach gives results far superior to those of the commonly used anterior approach. However, while laparoscopic hernia repair requires a lengthy learning curve and is difficult to learn and perform, it has advantages of less post-operative pain, early recovery with minimal hospital stay, low post-operative complications and recurrence. TRIAL REGISTRATION: ACTRN12613001050741.

Open preperitoneal versus anterior approach for recurrent inguinal hernia: a randomized study.

BACKGROUND: Inguinal herniorrhaphy remains one of the most common general surgical operations, with approximately 15% performed for recurrence. The repair of the resulting recurrent hernia is a daunting task because of already weakened tissues and obscured and distorted anatomy. The aim of this study is to compare the posterior preperitoneal versus anterior tension-free approach for repair of unilateral recurrent inguinal hernia regarding complications and early recurrence. METHODS: 120 Patients in this study were divided randomly into 2 main groups; Group A patients were subjected to posterior preperitoneal approach and those of group B were subjected to conventional anterior tension-free repair. The primary end point was recurrence and the secondary end points were time off from work, postoperative pain, scrotal swelling and wound infections. RESULTS: The mean hospital stay was 1.2 days and 4.7, the mean time to return work was 8.2 and 11.2 days and the mean time off from work was 9.4 and 15.9 days in group A and B respectively. The maximum follow-up period was 48 months and the minimum was 14 months with a mean value as 37.11 ± 5.14 months. Only 2 recurrences (3.3%) in group A and 4 cases (6.25%) in group B were seen. The final pain score per patient and the overall complication rate were higher in group B. CONCLUSIONS: The open preperitoneal repair offers the advantages of low recurrence rate and allows covering all potential defects with one piece of mesh and is far superior to the anterior approach. TRIAL REGISTRATION: ACTRN12611000337976.

A Proposed Phonography-Based Measurement of Fetal Breathing Movement Using Segmented Structures with Frequency Splitting.

This paper proposes a detection method of fetal breathing movement (FBM) as an important data of fetal well-being. To analyze the chaotic nature of the individual episodes, the frequency band has been split into single test frequencies in order to find its starting point (SP) as a signal free (quiet) zone. Computing some features of the signal the sound will be distinguishable from the disturbing signals as hiccups, body's rotation and limb movements or even additional noises of maternal heart beats. The SPs of the episodes are characterized by an approximation process in order to select the real ones.Clinical relevance- The method is an irradiation free measurement, carried out on the maternal abdomen. Furthermore, connected with the fetal phonocardiographic (fPCG) monitoring the method offers a non-invasive way for FBM detection applicable also at home. More than 50 pregnancies were examined with the proposed method for at least for 20-min with synchronous measurements by the proposed phonographic device and a 3D ultrasound machine in the third trimester.

Imagery of movements immediately following performance allows learning of motor skills that interfere.

Motor imagery, that is the mental rehearsal of a motor skill, can lead to improvements when performing the same skill. Here we show a powerful and complementary role, in which motor imagery of different movements after actually performing a skill allows learning that is not possible without imagery. We leverage a well-studied motor learning task in which subjects reach in the presence of a dynamic (force-field) perturbation. When two opposing perturbations are presented alternately for the same physical movement, there is substantial interference, preventing any learning. However, when the same physical movement is associated with follow-through movements that differ for each perturbation, both skills can be learned. Here we show that when subjects perform the skill and only imagine the follow-through, substantial learning occurs. In contrast, without such motor imagery there was no learning. Therefore, motor imagery can have a profound effect on skill acquisition even when the imagery is not of the skill itself. Our results suggest that motor imagery may evoke different neural states for the same physical state, thereby enhancing learning.

Adrenomedullin facilitates reinnervation of phenol-injured perivascular nerves in the rat mesenteric resistance artery.

Our previous report showed that innervation of calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-containing nerves in rat mesenteric resistance arteries was markedly reduced by topical application of phenol, and that nerve growth factor (NGF) facilitates the reinnervation of both nerves. We also demonstrated that a CGRP superfamily peptide, adrenomedullin, is distributed in perivascular nerves of rat mesenteric resistance arteries. In the present study, we investigated the influence of adrenomedullin on the reinnervation of mesenteric perivascular nerves following topical phenol treatment. Under pentobarbital-Na anesthesia, 8-week-old Wistar rats underwent in vivo topical application of phenol (10% phenol in 90% ethanol) to the superior mesenteric artery proximal to the bifurcation of the abdominal aorta. After the treatment, the animals were subjected to immunohistochemistry of the third branch of small arteries proximal to the intestine and to vascular responsiveness testing on day 7. Topical phenol treatment caused marked reduction of the density of NPY-like immunoreactive (LI)- and CGRP-LI nerve fibers in the arteries. Adrenomedullin (360 or 1000 ng/h) or NGF (250 ng/h), which was administered intraperitoneally for 7 days using an osmotic mini-pump immediately after topical phenol treatment, significantly increased the density of CGRP-LI- and NPY-LI nerve fibers compared with saline. Treatment with adrenomedullin (1000 ng/h) or NGF restored adrenergic nerve-mediated vasoconstriction and CGRP nerve-mediated vasodilation in the perfused mesenteric artery treated topically with phenol. These results suggest that adrenomedullin, like NGF, has a facilitatory effect on the reinnervation of perivascular nerves.

Angiotensin II type 2 receptors facilitate reinnervation of phenol-lesioned vascular calcitonin gene-related peptide-containing nerves in rat mesenteric arteries.

The present study was designed to investigate involvement of angiotensin II (Ang II) type 2 receptors (AT2 receptors) in restoration of perivascular nerve innervation injured by topical phenol treatment. Male Wistar rats underwent in vivo topical application of 10% phenol around the superior mesenteric artery. After phenol treatment, animals were subjected to immunohistochemistry of the third branch of small arteries, Western blot analysis of AT2 receptor protein expression in dorsal root ganglia (DRG) and studies of mesenteric neurogenic vasoresponsiveness. Ang II (750 ng/kg/day), nerve growth factor (NGF; 20 microg/kg/day) and PD123,319 (AT2 receptor antagonist; 10 mg/kg/day) were intraperitoneally administered for 7 days using osmotic mini-pumps immediately after topical phenol treatment. Losartan (AT1 receptor antagonist) was administered in drinking water (0.025%). Phenol treatment markedly reduced densities of both calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) and neuropeptide Y (NPY)-LI-containing fibers. NGF restored densities of both nerve fibers to the sham control level. Coadministration of Ang II and losartan significantly increased the density of CGRP-LI-fibers but not NPY-LI-fibers compared with saline control. The increase of the density of CGRP-LI-fibers by coadministration of Ang II and losartan was suppressed by adding PD123,319. Coadministration of Ang II and losartan ameliorated reduction of CGRP nerve-mediated vasodilation of perfused mesenteric arteries caused by phenol treatment. The AT2 receptor protein expression detected in DRG was markedly increased by NGF. These results suggest that selective stimulation of AT2 receptors by Ang II facilitates reinnervation of mesenteric perivascular CGRP-containing nerves injured by topical phenol application in the rat.

Life-style activities in systemic lupus erythematosus.

OBJECTIVE: We evaluated the life-style activities of outpatients with SLE and factors that reduce their social activities. SUBJECTS: SLE group = 60 patients, Control 1 = 30 healthy subjects and Control 2 = 30 patients with other autoimmune diseases. The Frenchay Activity Index (FAI), Zung's self-rating depression scale (SDS), and the Japanese version of the Philadelphia Geriatric Center morale scale-revised (MS) were compared between groups. Relation between FAI and age, disease duration, steroid dose, SDS, and MS were examined in the SLE group, Control 1, and Control 2. RESULTS: Total scores by FAI was 28.1 +/-8.0 points in Control 1, whereas it was 26.5 +/- 5.8 points in Control 2 and 24.5 +/- 7.7 points in the SLE group. While there was no statistical difference between the SLE group and Control 2, the scores were significantly lower in the SLE group than in Control 1 (P < 0.05). In SLE patients, age, the duration of the disease, and the steroid dose had no correlation, but MS had a positive correlation (P < 0.05) and SDS had a negative correlation (P < 0.05). In Control 2, age, the duration of the disease, the steroid dose, MS and SDS had no correlation whereas there was significant negative relation between FAI and SDS in Control 1 (r= -0.516, P<0.005). CONCLUSION: The significant relation between life-style activities and subjective well-being, and depression in SLE suggests that detection and treatment of mental status is important in improving the life-style activities of SLE patients.

Overlapping free bone graft with galea-pericranium in reconstruction of the anterior skull base to prevent CSF leak and sequestrum formation.

Background. Reconstruction of the skull base after resection of a tumour is important to prevent postoperative complications such as infectionsand cerebrospinal fluid (CSF) leakage. Several reconstructive methods of the anterior skull base have been reported but, their long-term results are not clear. Methods. We describe a technique used after removal of an olfactory neuroblastoma with infiltration of the skull base. The reconstructed dura was covered with a galeal patch, a replicated galeal-pericranial flap, a graft from the inner table of skull, and a vascularised galeal-pericranial flap placed on the skull base defect. All layers were fixed with fibrin glue. Conclusion. Three dimensional computed tomography (3D-CT) at bone window settings demonstrated the bone graft covered the bone defect and was not absorbed and after 11 years there have been no signs of tumour regrowth or complications.

Innervation and functional changes in mesenteric perivascular calcitonin gene-related peptide- and neuropeptide Y-containing nerves following topical phenol treatment.

We have previously shown that age-related reduction of innervation and function in mesenteric perivascular calcitonin gene-related peptide-containing vasodilator nerves takes place in spontaneously hypertensive rats. The present study was performed to investigate innervation and functional changes in perivascular calcitonin gene-related peptide- and adrenergic neuropeptide Y-containing nerves after topical treatment with phenol, which damages nerve fibers, around the rat superior mesenteric artery. Under pentobarbital-Na anesthesia, 8-week-old Wistar rats underwent in vivo topical application of phenol (10% phenol in 90% ethanol) or saline (sham rats) to the superior mesenteric artery proximal to the bifurcation of the abdominal aorta. After the treatment, the animals were subjected to immunohistochemistry of the 3rd branch of small arteries proximal to the intestine and to vascular responsiveness testing on day 3 through day 14. The innervation levels of calcitonin gene-related peptide-like immunoreactivity containing fibers and neuropeptide Y-like immunoreactivity containing fibers were markedly reduced on day 3 to day 14 and on day 5 to day 14 after the treatment, compared with those in sham-operated rats, respectively. In perfused mesenteric vascular beds isolated from phenol-treated rats, adrenergic nerve-mediated vasoconstriction and calcitonin gene-related peptide nerve-mediated vasodilation in response to periarterial nerve stimulation (2-12 Hz) were significantly decreased on day 3 and day 7. Neurogenic release of norepinephrine in phenol-treated rats on day 7 was significantly smaller that that in sham-operated rats. Nerve growth factor content in the mesenteric arteries of phenol-treated rats was significantly lower than that in sham-operated rats. Administration of nerve growth factor using osmotic mini-pumps for 7 days after the phenol treatment resulted in greater density of calcitonin gene-related peptide- and neuropeptide Y-like immunoreactivity fibers than in phenol-treated rats and restored decreased vascular responses to periarterial nerve stimulation. These results suggest that topical phenol-treatment of the mesenteric artery effectively induces functional denervation of perivascular nerves, which can be prevented or reversed by nerve growth factor treatment.

The catalytic mechanism of amidase also involves nitrile hydrolysis.

The amidase from Rhodococcus rhodochrous J1, which hydrolyzes an amide to an acid and ammonium, was surprisingly found to catalyze the hydrolytic cleavage of the C-N triple bond in a nitrile to form an acid and ammonium stoichiometrically. The amidase exhibited a Km of 3.26 mM for benzonitrile in contrast to that of 0.15 mM for benzamide as the original substrate, but the Vmax for benzonitrile was about 116000 of that for benzamide. A mutant amidase containing alanine instead of Ser195, which is essential for amidase catalytic activity, showed no nitrilase activity, demonstrating that this residue plays a crucial role in the hydrolysis of nitriles as well as amides.

Eradication of Helicobacter pylori has no effect on gastric acidity in duodenal ulcer patients--evaluation of 24-h pH monitoring.

It is accepted that eradication of Helicobacter pylori leads to healing of chronic active gastritis facilitates ulcer healing and prevents ulcer recurrence in duodenal ulcer (DU) patients. However, it is not entirely known whether the eradication of the bacteria normalizes gastric acid secretion and abolishes dyspeptic symptoms after ulcer healing. This study was aimed to evaluate the intragastric acidity and dyspeptic complaints before, and 3 months after, eradication in 18 endoscopically proven H. pylori positive DU patients. Gastric pH was measured by 24-h continuous intraluminal recording, serum gastrin measurements and Congo-red tests were also performed. Dyspeptic complaints and antacid consumptions were recorded in diary cards, antisecretory therapy was not allowed after the cessation of eradication therapy. Endoscopy, H. pylori status and Congo-red tests were controlled at the 6th and 12th week, while pH measurements and serum gastrin tests were performed at inclusion and 3 months later. Three patients dropped out and in 14 out of the remaining subjects healing of DUs and successful eradication was achieved by the 6th and 12th week controls. The 24-h median pH and the percentage of 24-h pH readings under pH 3 were not changing significantly by the 3-month controls (from 1.9+/-0.5 to 1.8+/-0.4 and from 52.6+/-5.5% to 58.6+/-5%, respectively). Similarly, no significant changes were observed in serum gastrin levels and dyspeptic symptom scores (from 72+/-7 pg/ml to 56.7+/-8 pg/ml and from 2.69+/-0.4 to 1.26+/-0.3, respectively). The antacid consumption was almost stable when compared with the pre- and post-eradication periods. It was concluded that despite successful H. pylori eradication and healing of DU, intragastric acidity does not change significantly at least 3 months after the therapy. The persisting dyspeptic symptoms and the need for antacid consumption suggest that some healed ulcer patients require antisecretory therapy in the post-eradication period.

The Blue Coloration of the Common Surgeonfish, Paracanthurus hepatus-II. Color Revelation and Color Changes.

Measurements of spectral reflectance from the sky-blue portion of skin from the common surgeonfish, Paracanthurus hepatus, showed a relatively steep peak at around 490 nm. We consider that a multilayer thin-film interference phenomenon of the non-ideal type, which occurs in stacks of very thin light-reflecting platelets in iridophores of that region, is primarily responsible for the revelation of that hue. The structural organization of the iridophore closely resembles that of bluish damselfish species, although one difference is the presence of iridophores in a monolayer in the damselfish compared to the double layer of iridophores in the uppermost part of the dermis of surgeonfish. If compared with the vivid cobalt blue tone of the damselfish, the purity of the blue hue of the surgeonfish is rather low. This may be ascribable mainly to the double layer of iridophores in the latter since incident lightrays are complicatedly reflected and scattered in the strata. The dark-blue hue of the characteristic scissors-shaped pattern on the trunk of surgeonfish is mainly due to the dense population of melanophores, because iridophores are only present there in a scattered fashion. Photographic and spectral reflectance studies in vivo, as well as photomicrographic, photo-electric, and spectrometric examinations of the state of chromatophores in skin specimens in vitro, indicate that both melanophores and iridophores are motile. Physiological analyses disclosed that melanophores are under the control of the sympathetic nervous and the endocrine systems, while iridophores are regulated mainly by nerves. The body color of surgeonfish shows circadian changes, and becomes paler at night; this effect may be mediated by the pineal hormone, melatonin, which aggregates pigment in melanophores.

Retro-odontoid soft tissue mass associated with atlantoaxial subluxation in an elderly patient: a case report.

BACKGROUND: We present the case of an elderly patient with a retro-odontoid soft tissue mass associated with atlanto-axial subluxation. CASE DESCRIPTION: A 74-year-old man was admitted to our hospital with progressive motor weakness in his right arm and neck pain. Radiological examinations revealed atlantoaxial subluxation and diffuse degenerative changes. Cervical MRI revealed a syrinx at the C1 level and a retro-odontoid soft tissue mass that severely compressed the spinal cord. The mass was of low signal intensity on both T1- and T2-weighted images. Conservative therapy could not stop the progression of his symptoms, so posterior decompression via a laminectomy of C1 and occipitocervical fixation was performed. These procedures resulted in an improvement of his neurological condition and in reduction of the mass and the compression of the spinal cord. CONCLUSION: The patient lacked any specific conditions that might have caused chronic atlantoaxial subluxation. The degenerative changes alone might have provoked chronic atlantoaxial subluxation and a subsequent retro-odontoid soft tissue mass. In patients with this condition, posterior fixation without direct removal of the mass should be the first choice for surgical intervention.

[Morphologic and clinical aspects of chronic gastric erosions]. / A chronicus gastricus erosiók morphologiai és klinikai jellemzöi.

Chronic erosions of the stomach are mostly papular lesions of the gastric mucosa with large base, 0.5-1 cm in diameter, often with superficial central depression covered with fibrin, less frequently without it. The typical site of lesion is the antrum the chronic erosions are here manifold, solitary forms are infrequent. In the course of 5694 gastroduodenoscopies the authors observed in 198 patients (5.2%) typical endoscopic picture of chronic erosions. In biopsy samples volcano-type lesions of the mucous membrane characteristic of the disease were found. According to the results the chronic erosions of the stomach are lesions of aspecific symptomatology, the disturbance of the mucosal barrier cannot be made probable. It is important to know the morphological characteristics of the rather frequent independent entity also for separating it from adenomas. Malignant transformation was not found in the material of the authors.

Teneligliptin for the treatment of type 2 diabetes.

Teneligliptin, characterized by a "J-shaped" structure formed by five consecutive rings, is a novel dipeptidyl peptidase 4 (DPP IV) inhibitor for the treatment of type 2 diabetes. Teneligliptin is eliminated via excretion with a half-life of 24.2 hours in human plasma from the kidney and metabolism involving certain enzymes. Hence, dose adjustment is not required in patients with renal impairment. A pharmacokinetic/pharmacodynamic study revealed that teneligliptin inhibits DPP IV activity over 24 hours, with elevation of activated glucagon-like peptide 1 (GLP-1) levels and the resulting suppression of postprandial hyperglycemia at all three daily meals. Monotherapy for 12 weeks significantly decreased hemoglobin A1c (HbA1c), fasting blood glucose, and 2-hour postprandial blood glucose levels in patients with type 2 diabetes. The therapeutic efficacy of teneligliptin over 52 weeks was confirmed not only as monotherapy but also as add-on therapy in patients with inadequately controlled blood glucose levels with sulfonylureas or thiazolidinediones. The incidence of adverse drug reactions was approximately 10% in all clinical studies of patients with type 2 diabetes conducted in Japan. The incidence of hypoglycemia was comparable in patients receiving teneligliptin or placebo, and no serious hypoglycemia was observed. Thus, teneligliptin is a novel antihyperglycemic agent with a preferable profile in terms of long-term efficacy and safety in patients with type 2 diabetes.

Incidence, patterns, and factors predicting mortality of abdominal injuries in trauma patients.

BACKGROUND: Abdominal trauma is a major public health problem for all nations and all socioeconomic strata. AIM: This study was designed to determine the incidence and patterns of abdominal injuries in trauma patients. MATERIALS AND METHODS: We classified and identified the incidence and subtype of abdominal injuries and associated trauma, and identified variables related to morbidity and mortality. RESULTS: Abdominal trauma was present in 248 of 300 cases; 172 patients with blunt abdominal trauma and 76 with penetrating. The most frequent type of abdominal trauma was blunt trauma; its most common cause was motor vehicle accident. Among patients with penetrating abdominal trauma, the most common cause was stabbing. Most abdominal trauma patients presented with other injuries, especially patients with blunt abdominal trauma. Mortality was higher among penetrating abdominal trauma patients. CONCLUSIONS: Type of abdominal trauma, associated injuries, and Revised Trauma Score are independent risk factors for mortality in abdominal trauma patients.

Paracrine control of mesenteric perivascular axo-axonal interaction.

Immunohistochemical study of rat mesenteric arteries showed dense innervation of adrenergic nerves, calcitonin gene-related peptide (CGRP)-containing nerves (CGRPergic nerves), nitric oxide-containing nerves (nitrergic nerves). Double-immunostaining revealed that most CGRPergic or nitrergic nerves were in close contact with adrenergic nerves. CGRPergic and transient receptor potential vanilloid-1 (TRPV1)-immunopositive nerves appeared in the same neurone. In rat perfused mesenteric vascular beds without endothelium and with active tone, perfusion of nicotine, or bolus injection of capsaicin and acetylcholine and periarterial nerve stimulation (PNS) lowered pH levels of out flowed perfusate concomitant with vasodilation. Cold-storage denervation of preparations abolished pH lowering induced by nicotine and PNS. Guanethidine inhibited PNS- and nicotine-, but not acetylcholine- and capsaicin-, induced pH lowering. Pharmacological analysis showed that protons were released not only from adrenergic nerves but also from CGRPergic nerves. A study using a fluorescent pH indicator demonstrated that nicotine, acetylcholine and capsaicin applied outside small mesenteric artery lowered perivascular pH levels, which were not observed in Ca(2+) free medium. Exogenously injected hydrochloric acid in denuded preparations induced pH lowering and vasodilation, which was inhibited by denervation, TRPV1 antagonists and capsaicin without affecting pH lowering. These results suggest that excitement of adrenergic nerves releases protons to activate TRPV1 in CGRPergic nerves and thereby induce vasodilation. It is also suggested that CGRPergic nerves release protons with exocytosis to facilitate neurotransmission via a positive feedback mechanism.