Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme.

Angiotensin II receptor blockers (ARBs) are widely used for the treatment of hypertension. It is believed that treatment with an ARB increases the level of plasma angiotensin II (Ang II) because of a lack of negative feedback on renin activity. However, Ichikawa (Hypertens Res 2001; 24: 641-646) reported that long-term treatment of hypertensive patients with olmesartan resulted in a reduction in plasma Ang II level, though the mechanism was not determined. It has been reported that angiotensin 1-7 (Ang-(1-7)) potentiates the effect of bradykinin and acts as an angiotensin-converting enzyme (ACE) inhibitor. It is known that ACE2, which was discovered as a novel ACE-related carboxypeptidase in 2000, hydrolyzes Ang I to Ang-(1-9) and also Ang II to Ang-(1-7). It has recently been reported that olmesartan increases plasma Ang-(1-7) through an increase in ACE2 expression in rats with myocardial infarction. We hypothesized that over-expression of ACE2 may be related to a reduction in Ang II level and the cardioprotective effect of olmesartan. Administration of 0.5 mg/kg/day of olmesartan for 4 weeks to 12-week-old stroke-prone spontaneously hypertensive rats (SHRSP) significantly reduced blood pressure and left ventricular weight compared to those in SHRSP given a vehicle. Co-administration of olmesartan and (D-Ala7)-Ang-(1-7), a selective Ang-(1-7) antagonist, partially inhibited the effect of olmesartan on blood pressure and left ventricular weight. Interestingly, co-administration of (D-Ala7)-Ang-(1-7) with olmesartan significantly increased the plasma Ang II level (453.2+/-113.8 pg/ml) compared to olmesartan alone (144.9+/-27.0 pg/ml, p<0.05). Moreover, olmesartan significantly increased the cardiac ACE2 expression level compared to that in Wistar Kyoto rats and SHRSP treated with a vehicle. Olmesartan significantly improved cardiovascular remodeling and cardiac nitrite/ nitrate content, but co-administration of olmesartan and (D-Ala7)-Ang-(1-7) partially reversed this anti-remodeling effect and the increase in nitrite/nitrate. These findings suggest that olmesartan may exhibit an ACE inhibitory action in addition to an Ang II receptor blocking action, prevent an increase in Ang II level, and protect cardiovascular remodeling through an increase in cardiac nitric oxide production and endogenous Ang-(1-7) via over-expression of ACE2.     

Analysis of variance study of the rat cortical layer 4 barrel and layer 5b neurones

Unique formation of rodent cortical barrels by layer 4 neurones attracts study of the sensory function of cortical input stage neurones (layer 4) compared with that of output stage neurones (layer 5). We have recorded extracellular responses from rat somatosensory cortical neurones to deflections of contralateral vibrissae. Thirty-two layer 4 barrel neurones and 29 layer 5b neurones were studied. Whisker stimulations were ramp-and-hold deflections with one of six different ramp velocities (100–2.5 mm s⁻¹) and one of four different plateau amplitudes (2000–200 μm). Twenty-four (6 × 4) different stimulus forms were applied to the tip of a whisker trimmed to 10 mm in a predetermined order in stimulus cycles of 20–50 repetitions. Spike counts for a period of 2560 ms in 10 ms bins were summed to construct a matrix of 24 peristimulus histograms for each neurone. Twenty-four amplitude and 24 velocity values were computed from counts during the plateau and ramp phases, respectively. To determine the amplitude- and velocity dependence of a neurone, an amplitude F value (the ratio of variations among-/within-amplitude of the amplitude value) and a velocity F value (ratio of variations among-/within-velocity of the velocity value) were derived by analysis of variance. The amplitude F value of the layer 4 barrel neurones was greater than that of the layer 5b neurones ( P < 0.0001). The velocity F value of the barrel neurones was smaller than that of the layer 5b neurones ( P = 0.0226). The results suggests that barrel neurones and layer 5b neurones tend to detect amplitude and velocity components of whisker deflection, respectively.     

Case of acute zonal occult outer retinopathy (AZOOR): a 15 years' mislabeling as retrobulbar optic neuritis]

A 30-year-old woman was admitted to Mie University Hospital for recurrence of sudden visual field defect with photopsia in the right eye. She had experienced the same episodes at the age of 15, 20, 25 and 28 years old. A diagnosis of retrobulbar optic neuritis had been made at each episode, but corticosteroid therapy failed to resolve the symptoms. Neurologic examination on admission was unremarkable except for the visual field defect of the right eye. Brain MRIs with and without gadolinium enhancement were normal. On ophthalmologic examination, visual acuity was normal, but the Mariotte blind spot of the right eye was expanded. Ophthalmoscopic examination, visual evoked potential, flicker electro-oculogram and Hess test were normal. Multifocal electroretinogram (ERG) revealed reduction in the inferior temporal response of the right eye that corresponded to the expansion of the Mariotte blind spot These findings were consistent with conditions of acute zonal occult outer retinopathy (AZOOR). The visual symptoms of AZOOR thus resemble those of retrobulbar optic neuritis and findings of multifocal ERG were useful to differentiate them. AZOOR is a newly established condition, and it is necessary to pay more attention to AZOOR on the differential diagnoses of acute-onset mono ocular visual disturbances.     

Fractalkine and inflammatory diseases]

The migration of leukocytes into inflamed peripheral tissues and lymphoid organs involves a cascade of molecular events finely regulated by cell adhesion molecules and chemokines. Fractalkine/CX3CL1 is a membrane-bound chemokine that functions not only as a chemoattractant but also as an adhesion molecule, and is expressed on endothelial cells activated by proinflammatory cytokines. The fractalkine receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes including NK cells and cytotoxic effector T cells (T(CE)), mature monocytes/macrophages, and mucosal dendritic cells, all of which play important roles in elimination of pathogens and cancer cells. Recently, accumulating evidence in both clinical studies and animal disease models has shown that fractalkine is also involved in the pathogenesis of various chronic inflammatory diseases, such as rheumatoid arthritis and atherosclerosis. This article reviews the unique functions of fractalkine and its pathophysiological roles in various clinical conditions.     

Intense immunoreactivity for Mn-superoxide dismutase (Mn-SOD) in cholinergic and non-cholinergic neurons in the rat basal forebrain

The immunohistochemical localization of manganese (Mn)-superoxide dismutase (Mn-SOD) was studied in the rat basal forebrain using polyclonal antibodies to Mn-SOD. Neurons of the basal forebrain exhibit a high density of Mn-SOD immunoreactivity. Double immunostaining with a monoclonal antibody to choline acetyltransferase demonstrated that both cholinergic and non-cholinergic neurons in the basal forebrain are intensely immunoreactive for Mn-SOD.     

Enhancement by sulpiride of the inhibitory effects of cysteamine on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats

The effects of sulpiride on cysteamine inhibition of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and on the BUdR labelling index of gastric mucosa were investigated in inbred Wistar rats. After 25 weeks of oral treatment with MNNG, rats received one of the following alternate-day injections: cysteamine (2 doses), cysteamine (2 doses) plus sulpiride or sulpiride. At week 52, prolonged administration of cysteamine significantly reduced the incidence of adenocarcinomas of the glandular stomach. Cysteamine at low dose had no effect on the incidence of gastric cancers, but a combination of low-dose cysteamine and sulpiride caused a significantly greater reduction in the incidence of gastric cancers. Administration of sulpiride alone had no influence on gastric carcinogenesis. The labelling index of the antral mucosa was significantly lower in rats treated with high but not low doses of cysteamine. However, a combination of low-dose cysteamine and sulpiride significantly decreased the labelling index of the antral mucosa. Our findings indicate that cysteamine suppressed gastric carcinogenesis and that sulpiride enhanced this inhibition. Because sulpiride is a dopamine antagonist, these findings also indicate that dopamine may play an important role in cysteamine inhibition of gastric carcinogenesis.     

Products in the fluorometric reaction of purines with 4,5-dimethyl-o-phenylenediamine after oxidation using N-bromosuccinimide

Twelve purines oxidized with 4,5-dimethyl-o-phenylenediamine (DMPD) was found to react with N-bromosuccinimide (NBS) to give fluorescent derivatives. In this paper, the identification of oxidation and fluorescent products have been described. In compliance with the substituent on purine skelton, three alloxans were obtained from twelve purines after oxidation by using NBS. The three alloxans reacted with DMPD to form two quinoxalines and an alloxazine, all of which being fluorescent.     

A case report of the limited form Wegener's granulomatosis]

The classical from of Wegener's granulomatosis (WG) is a necrotizing granulomatous angiitis that involves the upper and lower airways, and kidneys. A limited form of WG is characterized by pulmonary lesions identical to those of classical form WG without renal involvement. The authors report a case of limited form WG. A 58-year-old Japanese woman was admitted because of an abnormal pulmonary shadow. Pathological examination revealed granulomatous angiitis consistent with WG. No other organ involvement was found. The pulmonary shadow improved with cyclophosphamide therapy. The patient is now well and without evidence of exacerbation of the disease 18 month after the discharge.     

Development of an animal model for neuroleptic malignant syndrome: heat-exposed rabbits with haloperidol and atropine administration exhibit increased muscle activity, hyperthermia, and high serum creatine phosphokinase level

The neuroleptic malignant syndrome (NMS) is a life-threatening complication of neuroleptic treatment. To elucidate the pathogenesis of NMS, an animal model has been developed. Experimental rabbits treated with haloperidol (1 mg/kg) by intramuscular injection, were studied for the diagnostic symptoms of increased muscle rigidity, elevated body temperature, and high serum creatine phosphokinase (CPK) level. Administration of haloperidol (1 mg/kg) and atropine (0.4 mg/kg), and exposure to high ambient temperature (35°C) induced a significant increase in electromyographic activity with muscle rigidity similar to that observed in patients with NMS. Such rabbits also showed elevated body temperature and serum CPK value. In addition to the similarity of the signs and symptoms, all parameters measured (muscle rigidity, body temperature, and serum CPK level) were normalized by dantrolene treatment. The effectiveness of dantrolene in the experimental animal partially confirms the validity of this animal model for NMS. This experimental animal model for NMS may be useful to elucidate the pathogenesis of NMS.