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AIMS Several studies suggest increased mortality postcoronary angioplasty in patients on sulphonylureas. However, a theoretical reduction in cardiac risk has been suggested with the newer sulphonylurea agents, which differ from the first-generation agents. In the present study, we investigated whether a third generation of sulphonylurea, glimepiride, might stimulate nitric oxide (NO) production and thereby inhibit cytokine-induced nuclear factor (NF)-kappaB activation in endothelial cells compared with the classical sulphonylurea glibenclamide. METHODS AND RESULTS We demonstrated that glimepiride, but not glibenclamide, induces NO production in human umbilical vein endothelial cells (HUVEC). A significant increase in endothelial NO synthase (eNOS) activity, measured in terms of citrulline production, was observed with glimepiride treatment. Akt phosphorylation followed by phosphorylation of eNOS (Ser1177) was observed with glimepiride treatment in HUVEC. Moreover, two phosphoinoside 3-kinase inhibitors, wortmannin and LY294002, significantly inhibited glimepiride-induced NO production. We also demonstrated inhibition of tumour necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation in HUVEC treated with glimepiride, which was attenuated by pretreatment with N(omega)-nitro-L-arginine methyl ester. We also demonstrated a marked increase in p65 in nuclear extracts from untreated HUVEC following stimulation with TNFalpha, which was dose dependently inhibited by glimepiride, but not by glibenclimide in association with NF-kappaB levels. CONCLUSION These data suggest that glimepiride might be a preferable sulphonylurea agent in the setting of type 2 diabetes and vascular disease because it may have protective effects on vascular endothelial cells.

BACKGROUND Although neuroendocrine (NE) cells in prostate cancer have been speculated to accelerate the growth and progression of surrounding cancer cells, the evidence is as yet inconclusive. We investigated the effect of an NE allograft (NE-10) and its cell line, NE-CS, which were established from the prostate of the LPB-Tag 12T-10 transgenic mouse, on human prostate cancer cell line LNCaP. METHODS The proliferation and pulmonary metastasis of LNCaP xenografts in athymic mice with and without NE-10 allografts were evaluated. Boyden chamber assay and microarray analysis were performed to investigate changes in invasion/migration and mRNA of LNCaP cells under the influence of the NE cells, respectively. RESULTS NE-10 did not influence the proliferation of LNCaP. The pulmonary metastasis of LNCaP with NE-10 significantly increased compared to mice without it. The NE-CS cells accelerated the in vitro invasion/migration of adenocarcinoma cells. Increased expression of mRNA of gelsolin was observed in LNCaP cells incubated with the supernatant of NE-CS cells. CONCLUSIONS The NE-10 allograft promotes pulmonary metastasis of subcutaneously inoculated LNCaP cells by facilitating cell invasion. Secretions from NE cells upregulate the expression of gelsolin, which is an actin-binding protein, resulting in acceleration of the migration of LNCaP cells. © 2005 Wiley-Liss, Inc.

1 In the oesophageal muscularis mucosae, we examined the effects of endothelin-1 (ET-1), endothelin-2 (ET-2), endothelin-3 (ET-3) and sarafotoxin S6c (SX6c) as agonists, and FR139317, BQ-123 and RES-701-1 as endothelin receptor antagonists. 2 All of the endothelins produced tonic contractions which were frequently superimposed on rhythmic motility in a concentration-dependent manner. The order of potency (−log EC50) was ET-1 (8.61)=SX6c (8.65)>ET-2 (8.40)>ET-3 (8.18). 3 FR139317 (1–3 μM) and BQ-123 (1 μM) caused parallel rightward shifts of the concentration-response curve to ET-1, but at higher concentrations caused no further shift. RES-701-1 (3 μM) caused a rightward shift of the concentration-response curve to ET-1, while RES-701-1 (10 μM) had no additional effect. RES-701-1 (0.1–1 μM) concentration-dependently caused a rightward shift of the concentration-response curve to SX6c. The contraction to ET-1 (10 nM) in preparations desensitized to the actions of SX6c was greatly inhibited by pretreatment with FR139317 (10 μM). 4 Modulation of the Ca2+ concentration in the Krebs solution caused the concentration-response curve to ET-1 or SX6c to shift to the right and downward as external Ca2+ concentrations decreased. Verapamil (30 μM) abolished rhythmic motility induced by ET-1 or SX6c. Ni2+ (0.1 mM) weakly inhibited ET-1- or SX6c-induced tonic contraction. SK&F 96365 (60 μM) completely inhibited ET-1-induced contractions. 5 We conclude that there are two types of ET-receptors, excitatory ETA- and ETB-receptors in the oesophageal muscularis mucosae. These receptors mediate tonic contractions predominantly by opening receptor-operated Ca2+ channels (ROCs) and partly by opening T-type Ca2+ channels, and mediate rhythmic motility by opening L-type Ca2+ channels. British Journal of Pharmacology (1998) 125, 849–857; doi:10.1038/sj.bjp.0702140

We present a case of squamous cell carcinoma of the testis that metastasized from lung cancer. The patient, who had received left pneumonectomy 2 years earlier for squamous cell carcinoma (SCC) of the lung, developed pulmonary metastasis, which was treated with chemotherapy. Although the recurrence regressed after treatment, the testicular tumor progressed gradually. Left radical orchiectomy was performed. Pathological examination revealed metastatic SCC. Testicular metastasis from lung cancer is a very rare disease.

1 The submucous plexus-longitudinal muscularis mucosae preparation of the guinea-pig oesophagus was used to study the actions of catecholamines on the twitch responses to electrical stimulation.2 When the preparation was stimulated coaxially (0.1 Hz, 0.5 ms, supramaximal voltage), stable twitch-like contractions were obtained. These were abolished by tetrodotoxin (0.1 muM) and atropine (0.1 muM), potentiated by physostigmine (0.1 muM), and were mediated presumably by stimulation of intramural cholinergic nerves.3 The twitch contractions of the muscularis mucosae were inhibited by catecholamines, in a concentration-dependent manner. The order of potency was isoprenaline > adrenaline > noradrenaline > dopamine.4 The inhibitory actions of noradrenaline (1 muM) and adrenaline (1 muM) were partly reversed by phentolamine (1 muM) or by propranolol (1 muM), and completely abolished by both antagonists together. The inhibitory effect of dopamine (300 muM) was largely reversed by phentolamine (1 muM), but not by propranolol (1 muM), while the inhibitory action of isoprenaline was competitively antagonized only by propranolol (pA(2) of 7.6).5 The contraction of the muscularis mucosae to exogenously applied acetylcholine (ACh, 20 nM) which was comparable in magnitude with that to electrical stimulation was also inhibited by isoprenaline (0.1 muM), adrenaline (1 muM) and noradrenaline (1 muM), but not by dopamine (300 muM). In the presence of propranolol (1 muM), noradrenaline, adrenaline and dopamine potentiated the ACh-induced contraction, while the effect of isoprenaline was mainly antagonized. The potentiating effects were antagonized by further treatment with phentolamine (1 muM).6 Adrenaline, noradrenaline and dopamine but not isoprenaline, produced a weak contraction of the longitudinal muscularis mucosae in the presence of propranolol (3 muM). The contractile responses were completely inhibited by phentolamine (3 muM). Tone in the muscularis mucosae induced by carbachol (3 muM) in the presence of phentolamine (10 muM) was inhibited by catecholamines, in a concentration-dependent manner, an effect that was competitively antagonized by propranolol.7 In the submucous plexus-longitudinal muscularis mucosae preparation of the guinea-pig oesophagus there are three types of adrenoceptor, inhibitory prejunctional alpha-adrenoceptors, excitatory postjunctional alpha-adrenoceptors and inhibitory postjunctional beta-adrenoceptors, and cholinergic neurotransmission is inhibited by catecholamines acting at both prejunctional alpha- and postjunctional beta-adrenoceptors.