S-1投与ラットにおける味覚障害の想定される末梢メカニズム

BACKGROUND: Taste disorders are frequently observed in cancer patients undergoing chemotherapy and are serious adverse events which impair the quality of life (QoL) of the cancer patient. Nevertheless, taste disorder mechanisms in cancer patients undergoing chemotherapy have not yet been fully elucidated. The aim of this study was to reveal taste disorder-related peripheral mechanisms using the two-bottle preference test (TBPT) and histological examination of tongues by hematoxylin-eosin staining and immunohistochemistry with protein-gene product 9.5. METHODS: In the TBPT, one bottle was filled with the 0.01 mM quinine hydrochloride (quinine), as a bitter compound, and the other was filled with water. Doses of 50 and 100 mg kg-1 day-1 S-1 (tegafur/gimeracil/oteracil potassium) are lethal to Wistar rats. Therefore, doses ranging from 2-20 mg kg-1 day-1 were administered to the rats for 3 weeks. The S-1 dose of 2 mg kg-1 day-1 corresponds to the clinical dose administered to cancer patients. The part of the tongue containing the circumvallate papillae was excised the following TBPT. RESULTS: The rate of increase in terms of the average preference rate for the quinine vs. all intake (quinine plus water) was significant from the initial S-1 period to the final one, compared with that in control rats, suggesting the possibility of a worsening sensation for the bitter taste. In S-1 rats, the area of taste nerve fibers were significantly decreased and the rate of degeneration of intra-tongue ganglionic nerve cells was significantly increased. These changes were significantly correlated with the rate of increase in average preference rate of the quinine. CONCLUSION: Neuropathy of the gustatory nerve at the periphery may be involved in taste disorders induced by an anticancer drug.博士（医学）・乙1329号・平成26年3月17

Electrical behavior of myenteric neurons induced by mesenteric nerve stimulation in the guinea pig ileum.

Effects of mesenteric nerve (MN) stimulation on the electrophysiological behavior of myenteric neurons in the guinea pig ileum were investigated with intracellular recording techniques in the myenteric flaps innervated with mesenteric nerves. MN stimulation at 0.11-6 Hz evoked fast excitatory postsynaptic potentials (EPSPs) in 6 myenteric neurons (2 Type 2/AH, 3 NS and 1 Type 1/S cells) and rarely evoked antidromic soma spike potentials in 3 myenteric neurons. Fast EPSPs were abolished by hexamethonium. Slow EPSPs evoked by MN stimulation (Takaki and Nakayama (1988) Brain Res., 442, 351-353) were also obtained in 5 Type 2/AH neurons and were irreversibly abolished by superfusion with capsaicin 10 microM. It is, therefore, likely that fast EPSPs mediated by nicotinic cholinergic receptors are due to stimulation of the vagus nerve and slow EPSPs are mediated by a release of substance P at axosomatic synapses due to antidromic activation of the capsaicin-sensitive sensory nerves.</p

Effect of motilin on the sphincter of Oddi in the dog.

To investigate the action of motilin on the sphincter of Oddi, the flow rate of the perfusate (FRP) discharged into the duodenal lumen through the orifice of the common bile duct was measured by means of an electric drop counter in decerebrated dogs. Motilin in doses above 0.5 micrograms/kg i.v. reduced or stopped the FRP. The fifty percent recovery time of FRP was 20 min and full recovery time was 30 min. The reduction of FRP induced by motilin was unaffected by denervation and atropinization. These results suggest that motilin caused an increase in tone of the sphincter of Oddi by acting on the sphincter muscle.</p

Mechanism of rectal contraction mediated by sympathetic efferents from rectoanal pelvic afferents in guinea pigs.

In guinea pigs whose pelvic nerves were bilaterally sectioned, afferent stimulation of rectoanal branches of the pelvic nerve (PAS) could produce an intense contraction in the rectum similar to propulsive contractions elicited during defecation. The mechanism of this reflex was analyzed. Rectal contraction by PAS was abolished after transecting the spinal cord at T13 or sectioning the lumbar splanchnic nerves (LSN) or lumbar colonic nerves (LCN), but was unaffected by severing the intermesenteric and hypogastric nerves. Rectal contraction induced by PAS was abolished peripherally by atropine, guanethidine or yohimbine, while propranolol had no affect. Yohimbine antagonized the inhibitory effect of LSN or LCN stimulation on atropine-sensitive rectal contractions. It may, therefore, be concluded that PAS blocks the inhibition, by LCN efferents acting through alpha-adrenoreceptors, of cholinergic neurons in the myenteric plexus, thus facilitating recto-rectal propulsive contractions initiated by the defecation reflex.</p

Opiate-like inhibitory effect of trimebutine on the twitch response of the isolated guinea pig ileum.

Trimebutine at low concentrations (6 X 10(-9)-1.4 X 10(-8) M) slightly enhanced the twitch response of isolated guinea pig ileum induced by transmural stimulation. At high concentrations (2 X 10(-8)-2 X 10(-7) M), however, it inhibited the twitch response in a dose dependent manner. This inhibitory effect of trimebutine was reversed by naloxone (8.1 X 10(-9) M). These results suggest that trimebutine has an opiate-like action on the myenteric plexus.</p

Functional role of lumbar sympathetic nerves and supraspinal mechanism in the defecation reflex of the cat.

The role of the lumbar sympathetic nerves and supraspinal mechanism in the defecation reflex was investigated in 30 adult cats and 6 kittens. One or two propulsive contractions, whose mean pressure evoked was more than about 90 cmH2O (adult cats) and 50 cmH2O (kittens), were induced in the rectum of all animals by rectal distension. These propulsive contractions could be generated at the descending and the transverse colons. The removal of the supraspinal influence by spinal transection at T13 or removal of pelvic afferents to the supraspinal center by spinal transection at L abolished the propulsive contractions. Successive lumbar sympathectomy restored the contractions. Lumbar sympathectomy and the successive removal of the supraspinal influence did not affect the propulsive contractions. In both cases, the final exclusion of the sacral segments by pithing of the spinal cord abolished the propulsive contractions. These results suggest that the sacral excitatory reflex mediated via pelvic nerves and the lumbar inhibitory reflex mediated via lumbar sympathetic nerves can function during rectal distension in spinal cats and that the lumbar inhibitory reflex is suppressed by the supraspinal sympathetic inhibitory reflex activated by pelvic afferents in intact cats, as in guinea pigs, resulting in propulsive contractions.</p

SERCA2a過剰発現ラットにおけるイソプロテレノール持続投与誘導肥大心の左室力学的エネルギー学的性質の変化

Overexpression of cardiac sarcoplasmic reticulum Ca2 +-ATPase (SERCA2a) has been suggested as a strategic intervention for cardiac failure. However, its benefit in wild-type (WT) rats with normal SERCA2a levels seems to be small. To investigate whether it would be beneficial in a cardiac failure model with down-regulated SERCA2a levels, we made a cardiac hypertrophy model using isoproterenol infusion (1.2 mg kg− 1 day− 1 for 1 or 4 weeks; TG-ISO1w and TG-ISO4w, respectively) in SERCA2a transgenic (TG) rats and compared these rats with littermate WT rats that underwent the same treatments (WT-ISO1w and WT-ISO4w). We analyzed the left ventricular (LV) mechanoenergetics in the excised heart using our original cross-circulation system. The downward shift of curvilinear LV end-systolic pressure–volume relations (ESPVRs) observed in WT-ISO4w rats was abolished in TG-ISO4w rats. The slope and VO2 intercept of the VO2 (myocardial oxygen consumption per beat)–PVA (systolic pressure–volume area: total mechanical energy per beat) linear relation did not differ in any of the groups. The most important finding was a significantly smaller O2 cost of LV contractility in the TG-ISO4w group, which means that less O2 is needed to exert the same LV contractility, compared with the other groups. The increased ratio of SERCA2a/phospholamban returned to the level of the WT-control group only in the TG-ISO4w group. Longer-term up-regulation of mitochondrial transcription factor A for genes of mitochondrial enzymes producing ATP was observed in TG rats. In conclusion, longer-term overexpression of SERCA2a will be beneficial in the present cardiac failure model with down-regulated SERCA2a levels.博士（医学）・甲619号・平成26年3月17

SERCA2aの持続的過剰発現は、生理的条件下では膀胱機能に影響を及ぼすが、膀胱出口部閉塞亜急性期の病的条件下では膀胱機能に影響しない

A functional impairment of the bladder and heart in a decompensated state caused by a pressure overload is accompanied by a decrease in the sarcoplasmic reticulum Ca2+-ATPase (SERCA2). The beneficial effects of SERCA2 overexpression in preserving cardiac functions have been previously reported. The aim of the present study was to investigate the effects of overexpressed SERCA2 on bladder functions under physiological and pathological conditions using partial bladder outlet obstruction (BOO) in SERCA2a transgenic Wistar rats (TG). Bladder cystometry and western blot analysis were performed using the wild-type Wistar rats (WT), TG, and BOO models (WTBOO and TGBOO). Persistent overexpression of SERCA2 induces reduced bladder compliance without hypertrophy in TG. BOO induces reduced bladder compliance and hypertrophy in WT and TG in the sub-acute phase, but persistent overexpression of SERCA2a in TG does not aggravate the bladder compliance and hypertrophy. In conclusion, SERCA2a overexpression affects bladder functions under physiological conditions, but not in BOO-induced sub-acute pathological conditions.博士（医学）・甲第623号・平成26年5月28

Effects of capsaicin on the circular muscle motility of the isolated guinea-pig ileum.

Effects of capsaicin on the circular muscle motility of the isolated guinea-pig ileum were investigated. Capsaicin produced a contraction followed by a relaxation of the circular muscle. Both responses were easily desensitized. As the late relaxation response was not sufficiently intense to be analyzed, the inhibitory effect of capsaicin on substance P-induced contractions was explored. Capsaicin abolished the substance P-induced contractions. This inhibitory effect was not affected by tetrodotoxin, and the effect was desensitized. Therefore, all effects of capsaicin on circular muscle motility seem to be due to the release of sensory neuropeptides, similarly to those elicited in the longitudinal muscle.</p

Polar innervation of enteric non-cholinergic and non-adrenergic neurons in the isolated guinea-pig ileum.

To study the polarity of the efferent pathway of the myenteric plexus, recordings were made of the mechanical activity of the longitudinal muscle of isolated guinea-pig ileal segments upon stimulation with an electrical field around the myenteric plexus contained within strips of longitudinal muscle (LM-MP) continuous with each end of ileal segment. The amplitude of the contractile response to stimulation of the anal LM-MP was always larger than that to the oral LM-MP. After cholinergic and adrenergic transmission was suppressed by atropine (10 microM) and guanethidine (1 microM), and the tone of the segment was enhanced by histamine (1 microM), the LM-MP stimulation produced non-cholinergic, non-adrenergic (NCNA) ascending contraction and NCNA descending relaxation. The NCNA contraction, but not the NCNA relaxation, was abolished or reduced by desensitization to substance P. The present results suggest that the NCNA innervation of the myenteric plexus participates in the polar effects observed in the guinea-pig ileum, that the NCNA excitatory response may be mediated at least in part by myenteric substance P neurons, and that the NCNA inhibitory response is mediated by non-adrenergic neurons.</p