Kimika Eto

Increased expression of gp91phox homologues of NAD(P)H oxidase in the aortic media during chronic hypertension: involvement of the renin-angiotensin system.

Although vascular cells express multiple members of the Nox family of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, including gp91phox, Nox1, and Nox4, the reasons for the different expressions and specific roles of these members in vascular injury in chronic hypertension have remained unclear. Thus, we quantified the mRNA expressions of these NAD(P)H oxidase components by real-time polymerase chain reaction and evaluated superoxide production and morphological changes in the aortas of 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar Kyoto rats (WKY). The aortic media of SHRSP had an approximately 2.5-fold greater level of Nox4 mRNA and an approximately 10-fold greater level of Nox1 mRNA than WKY. The mRNA expressions of gp91phox and p22phox in SHRSP and WKY were comparable. SHRSP were treated from 24 weeks of age for 8 weeks with either high or low doses of candesartan (4 mg/kg/day or 0.2 mg/kg/day), or a combination of hydralazine (30 mg/kg/day) and hydrochlorothiazide (4.5 mg/kg/day). The high-dose candesartan or the hydralazine plus hydrochlorothiazide decreased the blood pressure of SHRSP to that of WKY, whereas the low-dose candesartan exerted no significant antihypertensive action. Media thickening and fibrosis, as well as the increased production of superoxide in SHRSP, were nearly normalized with high-dose candesartan and partially corrected with low-dose candesartan or hydralazine plus hydrochlorothiazide. These changes by antihypertensive treatment paralleled the decrease in mRNA expression of Nox4 and Nox1. These results suggest that blood pressure and angiotensin II type 1 receptor activation are involved in the up-regulation of Nox1 and Nox4 expression, which could contribute to vascular injury during chronic hypertension.

Comparative actions of insulin sensitizers on ion channels in vascular smooth muscle.

Thiazolidinedione and isoxazolidinedione insulin sensitizers activate peroxisome proliferator-activated receptor gamma (PPAR gamma). Some thiazolidinediones modify ion channels in smooth muscles; however, the mechanism by which their actions occur has not been clarified. We, thus, examined the effects of three thiazolidinediones (troglitazone, pioglitazone, and rosiglitazone) and isoxazolidinedione (JTT-501), as well as an intrinsic ligand for PPAR gamma, 15-deoxy-Delta(12,14) prostaglandin J(2) (prostaglandin J(2)), on voltage-operated Ca(2+) currents (I(Ca)), voltage-dependent K(+) currents (I(Kv)), and Ca(2+)-activated K(+) currents (I(Kca)), to clarify whether a thiazolidinedione structure or PPAR gamma activation is related to their actions on ion channels. The whole-cell patch clamp method was used to record currents in smooth muscle cells from guinea-pig mesenteric arteries. Thiazolidinediones inhibited I(Ca) in a dose-dependent manner (troglitazone>pioglitazone=rosiglitazone). Troglitazone (> or =1 microM) and rosiglitazone (100 microM), but not pioglitazone, inhibited I(Kv). Rosiglitazone (> or =10 microM) enhanced, troglitazone (> or =1 microM) inhibited, and pioglitazone did not affect I(Kca). A high concentration of JTT-501 (100 microM) inhibited I(Ca), I(Kv), and I(Kca) to a similar extent. Prostaglandin J(2) enhanced I(Kca), but affected neither I(Ca) nor I(Kv). In summary, the three thiazolidinediones and isoxazolidinedione act differently on Ca(2+) and K(+) channels in vascular smooth muscle. The action of thiazolidinediones on I(Ca) could be attributed to specific regions of the molecules and not to activation of PPAR gamma. Involvement of PPAR gamma activation in the stimulation of I(Kca) is possible but should be tested further.

Long-Term Compliance with Salt Restriction in Japanese Hypertensive Patients

The purpose of the present study was to investigate the long-term compliance with salt restriction in Japanese hypertensive patients. Subjects included 389 patients, 230 women and 159 men, mean age 58±11 years, who underwent successful 24-h home urine collection more than three times over an interval of a year. Urinary salt, potassium, and creatinine were measured. Additionally, family history, habitual alcohol intake, smoking habit, physical activities, and job status were assessed by use of a questionnaire. During the follow-up period (average 3.5 years), participants underwent urine collection 4.6 times in average. Urinary salt excretion at the last visit was significantly lower than that at the first visit (8.7±3.4 vs. 9.6±4.1 g/day; p<0.01). Urinary potassium excretion also decreased significantly during this period (from 2.0±0.7 to 1.9±0.7 g/day; p<0.05). Among the mean 4.6 urine collections, 45.2% (men 34.6%, women 52.6%) of the patients successfully achieved <6 g (100 mmol of sodium)/day of salt excretion on at least one occasion. The rate of achievement of averaged urinary salt excretion <6 g/day dropped to 10.3% (men 4.4%, women 14.3%). Only 2.3% (men 0.6%, women 3.5%) of the patients achieved <6 g/day on all occasions. There were no significant differences in age, habitual alcohol intake, smoking habit, physical activities, or job status between patients who complied with the salt-restricted diet and those who did not. Results suggest that long-term compliance with salt restriction is poor in Japanese hypertensive patients. Since no specifically defining characteristics were found in the compliant patients, repeated measurements of urinary salt excretion seem to be important to encourage salt restriction.

Antiproteinuric effect of an N-type calcium channel blocker, cilnidipine

The objective of the present study was to determine antiproteinuric effect of an N-type calcium channel blocker—cilnidipine. Subjects were 43 essential or renal hypertensive subjects who had been taking calcium channel blockers other than cilnidipine for at least 6 months. All patients had proteinuria greater than 0.2 g/day in spite of fair blood pressure control (< 150/90 mmHg). Calcium channel blockers in 25 patients (62 ± 3 years) were switched to cilnidipine (cilnidipine group), whereas other 18 patients (58 ± 3 years) continued to take originally prescribed calcium channel blockers (control group). The 24-hr urine collections were done at baseline and after 6 months of the follow-up period. Baseline characteristics including age, blood pressure levels, body mass index and creatinine clearance were similar between cilnidipine and control groups. Urinary protein excretion also was comparable between cilnidipine (0.61 ± 0.10 g/day) and control (0.86 ± 0.17 g/day) groups. Urinary protein significantly decreased after 6 months in cilnidipine group (− 0.21 ± 0.11 g/day, − 36%, p < 0.01), whereas it did not change in control group (+ 0.01 ± 0.15 g/day, 0.4%, ns). There were no significant changes in blood pressure, serum creatinine, creatinine clearance, estimated protein intake, and urinary salt excretion during the follow-up period in either group. The reduction of urinary protein by cilnidipine was evident in essential hypertensives (− 54 ± 9%, n = 18, p < 0.01) but not in renal hypertensives (+ 10 ± 35%, n = 7, ns). Results suggest that cilnidipine has an antiproteinuric effect especially in patients with essential hypertension.

Usefulness of the |[alpha]|1-Blocker Doxazosin as a Third-Line Antihypertensive Drug

It has been reported that a substantial majority of hypertensives receive insufficient blood pressure (BP) control. As combination therapy for the treatment of hypertension, Ca channel blockers (CCBs), angiotensin II (AII) receptor blockers (ARBs), and/or AII-converting enzyme (ACE) inhibitors are mainly prescribed, while the efficacy of α1-blockers in such combination therapy remains unknown. The aim of this study was to investigate the efficacy of a low dose of an α1-blocker added to combination therapy with CCBs and either ARBs or ACE inhibitors for the treatment of hypertension. Subjects were 41 hypertensive patients (23 women and 18 men, mean age 66±12 years) who had been followed at the National Kyushu Medical Center. All patients showed poor BP control despite haven taken a combination of CCBs and ARBs or ACE inhibitors for more than 3 months. Doxazosin at a dose of 1 to 2 mg was added to each treatment regimen. The changes in various clinical parameters, including BP and blood chemistry, following the addition of doxazosin were then evaluated. The mean follow-up period was 170 days. BP decreased from 152±14/81±12 mmHg to 135±14/70±11 mmHg after the addition of doxazosin at a mean dose of 1.5 mg/day (p<0.001). When good systolic blood pressure (SBP) control was defined as <140 mmHg, the prevalence of patients with good SBP control increased from 24% to 61% (p<0.01). Similarly, the prevalence of patients with good diastolic blood pressure (DBP) control (<90 mmHg) increased from 78% to 98% (p<0.01). Patients whose SBP decreased more than 10 mmHg (n=25) showed significantly higher baseline SBP, serum total cholesterol and low-density lipoprotein (LDL) cholesterol levels compared to those who showed less SBP reduction (<10 mmHg) (n=16, p<0.01). Comparable BP reductions were obtained between obese (body mass index [BMI] ≥25, ΔBP at 3 months: −15±15/−12±9 mmHg, n=18) and non-obese (BMI<25, ΔBP: −14±19/−7±8 mmHg, n=23) patients. The results suggest that addition of a low dose of the α1-blocker doxazosin effectively reduces BP in patients taking CCBs and ARBs or ACE inhibitors. Thus, doxazosin seems to be useful as a third-line antihypertensive drug.

A Case of Gitelman's Syndrome with Decreased Angiotensin II–Forming Activity

Gitelmans syndrome (GS) is a variant of Bartters syndrome (BS) characterized by hypokalemic alkalosis, hypomagnesemia, hypocalciuria and secondary aldosteronism without hypertension. A 31-year old Japanese man who had suffered from mild hypokalemia for 10 years was admitted to our hospital. He had metabolic alkalosis, hypokalemia and hypocalciuria. Since he had two missense mutations (R261C and L623P) in the thiazide-sensitive Na-Cl cotransporter (TSC) gene (SLC12A3), he was diagnosed as having GS. He showed hyperreninism and a high angiotensin I (Ang I) level, whereas his angiotensin II (Ang II) and aldosterone levels were not elevated. His angiotensin converting enzyme (ACE) activities were normal, and administration of captopril inhibited the production of Ang II and aldosterone. We evaluated the Ang II–forming activity (AIIFA) of other enzymes in his lymphocytes. Interestingly, chymase-dependent AIIFA was not detected in the lymphocytes. Together, these results suggest that the lack of chymase activity resulted in the manifestation of GS without hyperaldosteronism.

Home blood pressure measurement may lead to less strict control of office blood pressure.

Home blood pressure (HBP) measurement is useful for detecting morning hypertension, white coat as well as masked hypertension. However, target BP levels based on HBP remain unknown. The purpose of the present study was to evaluate the relationship between HBP measurement and office BP control status in hypertensive patients. Subjects were a total of 720 hypertensive outpatients (mean age: 64 ± 11 years; females: 57%). Two-time averaged office BP in 2005 were categorized as excellent (<130/85 mmHg), good (≥130/85 and <140/90 mmHg), or poor (>140/90 mmHg) control. In all patients, 37% were classified as excellent, 37% as good, and 26% as poor control. A total of 393 (55%) patients regularly measured HBP (HBP group). More women belonged to the HBP group (62 vs. 52%, p < 0.05). The HBP group also showed lower body mass index (23.8 ± 3.3 vs. 24.7 ± 3.4 kg/m2, p < 0.01), lower triglyceride (136 ± 78 vs. 158 ± 89 mg/dl, p < 0.01), and lower blood glucose (104 ± 20 vs. 118 ± 42 mg/dl, p < 0.01). HBP group showed a significantly higher prevalence of poor BP control (33 vs. 23%, p <0.01) and higher office SBP (134.5 ± 14.5 vs. 131.3 ± 11.7 mmHg, p < 0.01) than those who did not measure HBP (non-HBP). In a multivariate analysis for office SBP, age (partial r = 0.21, p < 0.05) and HBP measurement (partial r = 0.12, p < 0.05) were detected as significant independent variables. These results suggest that HBP measurement may lead to less strict office BP control unless the target HBP levels are clearly indicated. Until the recommendations or target HBP levels are available, we should make an effort to obtain goal office BP.

Regarding "Adult Reversible Cardiomyopathy with Pituitary Adrenal Insufficiency Caused by Empty Sella" (Angiology 51:319-323, 2000)

In their recent case report describing a patient with reversible cardiomyopathy associated with pituitary adrenal insufficiency, Eto et al (April 2000) found that the administration of hydrocortisone to a patient with empty sella syndrome resolved the symptoms of heart failure. They concluded that the cardiomyopathy was related to adrenal insufficiency. Although they describe the results of the cosyntropin stimulation test, they fail to mention the results of other testing of the pituitary system. Specifically, I would be interested in the results of the thyroid and growth hor-