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.     

LONG‐TERM FOLLOW UP OF PATIENTS WITH SMALL GASTROINTESTINAL STROMAL TUMORS IN THE STOMACH USING ENDOSCOPIC ULTRASONOGRAPHY‐GUIDED FINE‐NEEDLE ASPIRATION BIOPSY

Background: Gastrointestinal stromal tumors (GIST) are one of the most common mesenchymal tumors of the gastrointestinal tract. GIST are defined by positive immunohistochemical staining for KIT or CD34 and thus are generally diagnosed after surgery. Because small GIST are rarely diagnosed before surgery, the clinical course of these small tumors is not clear. The aim of the present study was to follow changes in size and configuration of small GIST that were pathologically confirmed using endoscopic ultrasonography‐guided fine‐needle aspiration biopsy (EUS‐FNAB). Methods: Between July 1997 and December 2003, 16 tumors in 16 patients (10 men and 6 women) with an immunohistochemical diagnosis of GIST were regularly followed in our hospital. The median patient age when EUS‐FNAB was performed was 62 years (range 26–82 years) and the median follow‐up period was 4.9 years (range 0.5–9.6 years). Results: Fourteen tumors showed no remarkable changes in size and shape during follow up compared with the initial diagnosis. Two tumors enlarged: one tumor approximately doubled its diameter in 8 years and the other tumor increased from 1.8 cm at diagnosis to up to 10 cm after only 2 years. Doubling time of the latter tumor was calculated as 3.1 months. Conclusions: We conclude that EUS‐FNAB might be a good modality for final diagnosis of GIST without surgery, and that GIST without rapid growth on follow up can be endoscopically followed.     

Congenital quadricuspid aortic valve with tetralogy of Fallot and pulmonary atresia

We report the case of a 4-year-old girl who had quadricuspid aortic valve regurgitation with tetralogy of Fallot and pulmonary atresia. This combination is very uncommon. Aortic valve replacement was performed successfully due to aortic regurgitation which had progressed one year after the total repair. The dilated aortic annulus plus quadricuspid aortic valve may result in progressive aortic regurgitation for a short period.     

Sequence-dependent Termination of Mammalian DNA Polymerase Reaction by a New Platinum Compound, (–)-(R)-2-Aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)-2-platinum(II) Monohydrate

We examined the mechanisms of the inhibition of DNA synthesis by a new platinum compound, (-)-( R )-2-aminomethylpyrrolidine(1,1-cyclobutane-dicarboxylato)-2-platinum(II) monohydrate (DWA-2114R), a derivative of the antitumor drug cis- diamminedichloroplatinum(II) (CDDP), using prokaryotic and eukaryotic DNA polymerases. Preincubating activated DNA with CDDP or DWA-2114R reduced its template activity for prokaryotic and eukaryotic DNA polymerases in a dose-dependent manner. DWA2114R required six times greater drug concentration and two times longer incubation time to show the same decrease of the template activity compared to CDDP. Treatment of primed pUC118 ssDNA templates with the two drugs followed by second-strand synthesis by prokaryotic and eukaryotic DNA polymerases revealed that DWA2114R bound to DNA in a similar manner to CDDP and these adducts blocked DNA elongation by DNA polymerases of eukaryotes as well as of prokaryotes. With these two drugs, the elongations by E. coli DNA polymerase I (Klenow fragment), T7 DNA polymerase and calf thymus DNA polymerase α were strongly arrested at guanine-guanine sequences (GG). Stop bands were also observed at adenine-guanine sequences (AG) guanine-adenine-guanine sequences (GAG) and mono-guanine sequence (G). Calf testis DNA polymerase β was also arrested efficiently at AG, GAG and G, but much more weakly at GG. This pattern was common to DWA2114R and CDDP.     

Effects of N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (DM-9384) on learning and memory in rats

Effects of N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide (DM-9384) on learning and memory were studied using four different experimental rat models. In electroconvulsive shock- or scopolamine-induced amnesia in the step-through passive avoidance task, DM-9384 improved both types of amnesia when administered before the training trial. Aniracetam also showed similar but somewhat weaker effects. Furthermore, in the scopolamine amnesia model, an improvement was confirmed with arecoline. The dose-response curves for these compounds were bell-shaped. In the shuttle box active avoidance task, DM-9384 administered daily 1 hr before each training session facilitated the acquisition process of the avoidance response. In addition, the experiment of light-dark discrimination task with positive reinforcement showed that this compound administered daily after each session slightly accelerated the acquisition process of the correct response. These results suggest an ability of DM-9384 to enhance cognitive functions.