Vasorelaxing effect of mesaconitine, an alkaloid from aconitum japonicum, on isolated rat small gastric artery: possible involvement of EDHF

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Comparisons of Therapeutic Effects of Allopurinol and Febuxostat in Chronic Hemodialysis Patients

More than few patients on maintenance hemodialysis present with hyperuricemia, and the control of serum uric acid level is an important issue in the long-term management. In addition to allopurinol, febuxostat can be used as a xanthine oxidase inhibitor in hemodialysis patients. In this study, the clinical effects of febuxostat were compared with allopurinol in chronic hemodialysis patients. Eligible hemodialysis patients taking allopurinol were randomly assigned to take 100 mg allopurinol（n＝26）or 20 mg febuxostat（n＝23）for 12 weeks. Serum uric acid was markedly lowered in the febuxostat group（0-week 6.7 mg/dL, 12-week 4.3 mg/dL, p＜0.001）as compared with the allopurinol group（0-week 6.0 mg/dL, 12-week 5.8 mg/dL）and systolic blood pressure was lowered by 5 mmHg（p＝0.036）at 4-week in the febuxostat group while blood pressure was not significantly changed in the allopurinol group throughout the study period. In addition, the dose of erythropoiesis stimulating agent was reduced（0-week 22.2 μg/wk, 12-week, 17.1 μg/wk, p＝0.012）and serum phosphate level was lowered（0-week 5.9 mg/dL, 12-week 5.1 mg/dL, p＝0.027）in the febuxostat group but not in the allopurinol group. It is concluded that febuxostat is more effective in lowering serum uric acid than allopurinol in hemodialysis patients. In addition, it is suggested that febuxostat has an advantage in the management of renal anemia and hyperphosphatemia as well as hyperuricemia

Comparisons of Increasing Calcium Channel Blocker dose and Adding Thiazide Diuretic in Hypertensive Patients Given Medium-dose Angiotensin II Receptor Blocker and Amlodipine

We compared the efficacies of 2 prescriptions, one of a medium-dose angiotensin II receptor blocker （ARB） with high-dose of calcium channel blocker （CCB） and another of medium-dose of ARB with medium-dose of CCB and a thiazide diuretic in 22 hypertensive patients who did not achieve the target blood pressure level with the combination of medium-dose of ARB and medium-dose of CCB. A randomized crossover study was performed giving a fixed combination of 100 mg irbesartan with 10 mg amlodipine or a fixed-dose combination of 100 mg irbesartan with 5 mg amlodipine added by 1 mg trichlormethiazide for 12-16 weeks each. The blood pressure measured in hospital was comparable between the high-dose CCB period （130/77 mmHg） and the thiazide period （130/79 mmHg）. The morning and the evening blood pressures measured at home were also comparable in the high-dose of CCB and the thiazide periods, while the evening heart rate was higher in the thiazide period than in the high-dose CCB period. As for the laboratory data, hemoglobin A1c （＋0.2％, p＝0.013）, serum nonHDL cholesterol （＋12 mg/dL, p＝0.047） and serum uric acid （＋0.8 mg/dL, p＝0.001） were significantly higher in the thiazide period than in the high-dose CCB period. On the other hand, urinary albumin excretion （－28.8％，p＝0.026） and estimated glomerular filtration rate （－5.8％，p＝0.012） were significantly lower in the thiazide period than in the high-dose CCB period. In the combination drug therapy of hypertension, the increase of CCB dose is preferable in preserving renal function and in avoiding adverse effects on metabolisms of glucose, lipid and uric acid

Cellular density‐dependent increases in HIF‐1α compete with c‐Myc to down‐regulate human EP4 receptor promoter activity through Sp‐1‐binding region

The up‐regulated expression of E‐type prostanoid (EP) 4 receptors has been implicated in carcinogenesis; however, the expression of EP4 receptors has also been reported to be weaker in tumor tissues than in normal tissues. Indeed, EP4 receptors have been suggested to play a role in the maintenance of colorectal homeostasis. This study aimed to examine the underlying mechanisms/reasons for why inconsistent findings have been reported regarding EP4 receptor expression levels in homeostasis and carcinogenesis by focusing on cellular densities. Thus, the human colon cancer HCA‐7 cells, which retain some functional features of normal epithelia, and luciferase reporter genes containing wild‐type or mutated EP4 receptor promoters were used for elucidating the cellular density‐dependent mechanisms about the regulation of EP4 receptor expression. In silico analysis was also utilized for confirming the relevance of the findings with respect to colon cancer development. We here demonstrated that the expression of EP4 receptors was up‐regulated by c‐Myc by binding to Sp‐1 under low cellular density conditions, but was down‐regulated under high cellular density conditions via the increase in the expression levels of HIF‐1α protein, which may pull out c‐Myc and Sp‐1 from DNA‐binding. The tightly regulated EP4 receptor expression mechanism may be a critical system for maintaining homeostasis in normal colorectal epithelial cells. Therefore, once the system is altered, possibly due to the transient overexpression of EP4 receptors, it may result in aberrant cellular proliferation and transformation to cancerous phenotypes. However, at the point, EP4 receptors themselves and their mediated homeostasis would be no longer required

Comparison between High-dose Telmisartan and Fixed dose Combination of Telmisartan and Hydrochlorothiazide in Patients with Hypertension

We compared treatment with a high-dose angiotensin II receptor blocker(ARB)and combination of ARB with a thiazide diuretic in 17 patients with hypertension. A randomized crossover study was performed giving 80 mg telmisartan or fixed-dose combination of 40 mg telmisartan and 12.5 mg hydrochlorothiazide for 16 weeks each. Although the clinic blood pressure was comparable between the high-dose ARB period(134/81 mmHg)and the combination period(134/82 mmHg), the morning home blood pressure was lower in the combination period than in the high-dose ARB period(138/82 vs. 151/88 mmHg, p=0.026/0.013). No significant difference was observed in urinary albumin excretion, but estimated glomerular filtration rate was lower in the combination than in the high-dose ARB period(58.9 vs. 62.1 mL/min/1.73 m^2, p=0.039). Serum uric acid was higher in the combination than in the high-dose ARB period(6.7 vs. 5.9 mg/dL p=0.022). The indices of glucose metabolism, serum lipids, oxidative stress, inflammation and adipocytokine did not significantly differ between the two periods. There was no significant difference in the measurement of endothelium-dependent vasodilation between the two periods. It is suggested that the addition of thiazide diuretic to medium-dose ARB is more effective in lengthening the hypotensive effect than high-dose ARB, however, care should be taken for the elevation of serum uric acid and the decrease in renal function

Protective Effects of Olmesartan and Azelnidipine against Cardiovascular Organ Injuries in Spontaneously Hypertensive Rats

In the treatment of hypertension, care should be taken for preventing of hypertensive organ injuries as well as lowering blood pressure to the adequate level in order to reduce the risk of cardiovascular diseases. The purpose of this study is to examine the effects of angiotensin II receptor blockers (ARB), calcium channel blockers (CCB) and their combination on the development of cardiovascular organ injuries in spontaneously hypertensive rats (SHR). Four groups of male 8-week-old SHR (n=9 each) were given vehicle(control), 10 mg/kg azelnidipine (AZL), 10 mg/kg olmesartan (OLM, n=9), or the combination of AZL and OLM(5 mg/kg each)for 12 weeks, and their effects on cardiovascular organ injuries were evaluated. Tail-cuff blood at 12 weeks was similarly lowered by AML, OLM and the combination therapy(148, 143 and 143 mmHg, respectively)as compared with the control SHR (198 mmHg). Pulse rate was significantly less in the AZL group but not in the OLM group or the combination therapy group than in the untreated control group (-27, -12, +6 bpm, respectively). The cardiac ventricular weight (AZL -12%, OLM -15%, combination -18% vs. control) and aortic thickness (AZL -17%, OLM -16%, combination -19% vs. control) were reduced by similar extents in the three groups given antihypertensive treatments. Regarding the myocardial fibrosis, left ventricular hydroxyproline content was reduced in the OLM and the combination groups but the change was not significant in the AZL group (AZL -14%,OLM -30%, combination -27% vs. control). In the echocardiographic evaluation of cardiac function, the index of left ventricular diastolic function is significantly improved in the OLM and the combination groups but not in the AZL group, while the index of systolic function was not different between the four groups. It is suggested that the antihypertensive therapy including ARB is superior to the monotherapy by CCB in preventing the myocardial fibrosis and preserving the left ventricular diastolic function