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.     

A case of aldosterone-producing adrenocortical adenoma associated with a probable post-operative adrenal crisis: histopathological analyses of the adrenal gland.

We describe a case of aldosterone-producing adrenocortical adenoma (APA) associated with a probable post-operative adrenal crisis possibly due to subtle autonomous cortisol secretion. The patient was a 46-year-old female who suffered from severe hypertension and hypokalemia. CT and MRI scans revealed a 2-cm diameter adrenal mass. The patient's plasma aldosterone level was increased, and her plasma renin activity was suppressed, both of which findings were consistent with APA. Cushingoid appearance was not observed. Morning and midnight serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were all within the normal range. Her serum cortisol level was suppressed to 1.9 microg/dl as measured by an overnight 1-mg dexamethasone suppression test, but was incompletely suppressed (2.7 microg/dl) by an overnight 8-mg dexamethasone suppression test. In addition, adrenocortical scintigraphy showed a strong uptake at the tumor region and a complete suppression of the contra-lateral adrenal uptake. After unilateral adrenalectomy, she had an episode of adrenal crisis, and a transient glucocorticoid replacement improved the symptoms. Histopathological studies demonstrated that the tumor was basically compatible with APA. The clear cells in the tumor were admixed with small numbers of compact cells that expressed 17alpha-hydroxylase, suggesting that the tumor was able to produce and secrete cortisol. In addition, the adjacent non-neoplastic adrenal cortex showed cortical atrophy, and dehydroepiandrosterone sulfotransferase immunoreactivity in the zonae fasciculata and reticularis was markedly diminished, suggesting that the hypothalamo-pituitary-adrenal (HPA) axis of the patient was suppressed due to neoplastic production and secretion of cortisol. Together, these findings suggested that autonomous secretion of cortisol from the tumor suppressed the HPA axis of the patient, thereby triggering the probable post-operative adrenal crisis. Post-operative adrenocortical insufficiency should be considered in clinical management of patients with relatively large APA, even when physical signs of autonomous cortisol overproduction are not apparent.     

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.