Phase IV studies, which are commonly referred to as "postmarketing surveillance (PMS)" or pharma-coepidemiological studies, play an important role in evaluating the long-term safety of medicines. The system for conducting PMS in Japan consists of three components; spontaneous reporting of side effects, "reexamination of newly marketed agents" and "reevaluation of agents used in practice." The reevaluation is to be repeated at given intervals. However, the present system applied for PMS has many problems which must be solved. Particularly in regard to antihypertensive therapy, since most hypertensive patients are required to take antihypertensive agents for the rest of their life, scientifically sound PMS is indispensable. In this article, the present system for PMS in Japan will be overviewed, the preliminary results of prospective phase IV studies which are being conducted to evaluate the long-term efficacy and safety of calcium antagonists will be reported, and some proposals will be mentioned to improve phase IV studies, PMS, on the basis of the preliminary results which are currently available. (Hypertens Res 1992; 15: 121-126)

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Twenty-four-hour ambulatory blood pressure (BP) was monitored in 540 healthy Japanese adults whose casual BP was less than 140mmHg in systole and less than 90mmHg in diastole. A total of 304 men and 236 women, ranging in age from 20 to 79 years, with a mean of 40.9±12.8 years, were studied. BP was measured every 30min using ABPM-630 (Nippon Colin Co.) for 24h in 395 subjects and for 48h in 145 subjects. Periodic regression curves were obtained and the coefficients of determination (R²) was calculated for each periodic component. The periodic regression curves by age and sex were tested statistically for differences in terms of the level (mean value) and the pattern (amplitude and acrophase) of the curves using periodic analysis of covariance (PERCOVA). The periodic regression curve composed of 24- and 12-h periods was fitted satisfactorily to the measured BP values (R²=0.97 for systolic BP and 0.98 for diastolic BP). The level of the periodic regression curve increased significantly with increasing age, being significantly higher in males than in females. The pattern of BP curve did differ among some age groups but not significantly between the sexes.(Hypertens Res 1992; 15: 127-135)

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This study was performed to elucidate the effect of a hypocaloric diet on blood pressure and sodium balance in overweight women with essential hypertension. Hospitalized patients were fed a hypocaloric diet (900 kcal/day) for 3 weeks after being fed a standard diet (SD) for more than 2 weeks. During the study, the sodium and potassium intake was kept constant as was the level of exercise activity. After the mean arterial pressure (MAP) and body weight had stabilized during the last week on the SD, caloric restriction significantly reduced the body weight by 1.5kg in the first week and by 0.8-0.9 kg in subsequent weeks, and reduced the MAP by 5mmHg and by 1-3mmHg, respectively. Although caloric restriction reduced the excretion of urinary norepinephrine and C-peptide, and elevated the serum levels of ketone bodies that would induce natriuresis, the urinary sodium excretion remained unchanged, indicating that sodium balance was unchanged even by caloric restriction. These results suggest that caloric restriction lowers the blood pressure in a short time with no significant change in sodium balance. (Hypertens Res 1992; 15: 137-142)

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To examine a pathogenetic role of α₂-adrenoceptor (α₂-AR) in genetically hypertensive rats, we compared the α₂-AR gene of spontaneously hypertensive rats (SHR) and its normotensive control Wistar-Kyoto (WKY) rats by restriction fragment length polymorphism (RFLP) analysis and did a genetic cosegregation study. After screening with 52 restriction endonucleases (RE), an RFLP was found by digestion of the genomic DNA of SHR and WKY rat with Dde I RE and using a human platelet α₂-AR probe, the gene (ADRA2R) which is localized in chromosome 10. Restriction mapping analysis revealed that the RFLP is located in the 5′ region of the α₂-AR gene. This RFLP was used as a marker in a genetic cosegregation study to examine the correlation of genotype with blood pressure in F₂ rats of SHR and WKY rat cross. The distribution of the genotypes based on the RFLP conformed to a 1:2:1 ratio in male F₂ rats as expected for Mendelian inheritance, but not in female F₂ rats. The number of female F₂ rats with double SHR alleles was decreased about 68% from expected. Blood pressure of the male or female F₂ rats homozygous for the SHR α₂-adrenoceptor alleles was not significantly higher than the F₂ rats heterozygous or homozygous for the WKY alleles with either indirect or direct blood pressure measurement. The additional finding was that males had higher blood pressure than females. This study ruled out the cosegregation of α₂-adrenoceptor RFLP with higher blood pressure in the F₂ rats of SHR and WKY cross. However, Since the abnormality of the renal α₂-adrenoceptor in genetically hypertensive rats is one of altered regulation, and the RFLP we found is located in the 5′ region of the gene where functionally important sequences are located which regulate gene expression, this RFLP may still be of interest in genetically hypertensive rats. (Hypertens Res 1992; 15: 143-148)

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To assess the possible pathophysiological role of endothelin-1 (ET-1) in pregnancy-induced hypertension (PIH), plasma immunoreactive ET-1 levels were consecutively followed at the 3rd trimester, as well as 1 week and 1 month postpartum, in PIH (n=6), pregnancy-induced proteinuria without hypertension (PIP)(n=2), and normal pregnancy (n=7). Before delivery, the ET-1 levels in PIH (4.4±0.5pg/ml) and PIP (4.5±0.6pg/ml) were higher than normal pregnancy (1.5±0.2pg/ml) (p<0.01, p<0.01). The ET-1 level during pregnancy correlated with BP (mean BP; r= 0.69, p<0.01), serum uric acid (r=0.75, p< 0.05), the degree of proteinuria (r=0.62, p<0.05), and ET-1 level in cord venous blood (r=0.58, p< 0.05); in addition, it also tended to correlate with plasma renin activity (r=-0.58, p<0.06). In PIH, BPs were normalized within 1 month after the delivery, whereas the ET-1 level decreased slowly. These results suggest that the maternal ET-1 level was elevated in PIH; however, ET-1 may not be the primary cause of the BP increase. (Hypertens Res 1992; 15: 149-154)

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We investigated the clinical implications of blood pressure changes after 20min of rest and during exercise in particular for predicting the progression of left ventricular hypertrophy (LVH) in unmedicated male subjects with borderline and mild hypertension. We studied 155 subjects who were enrolled in a hypertension management program that included routine annual physical check-ups and cardiovascular follow-up studies, including echocardiography and treadmill exercise stress testing, every 3 years. Sixty-nine subjects were followed for 5 years without pharmacological intervention. Left ventricular mass index (LVMI) was correlated with systolic pressure at peak exercise (max Ps) and 20-min resting systolic pressure in 155 subjects. Stepwise multiple linear regression analysis showed that the initial LVMI and max Ps had significantly higher percent explained variances in relation to the LVMI increase over the 5-year observation period compared with other variables. Hyper-responders, subjects with an initial max Ps above 200mmHg, showed a greater increase in LVMI than subjects with an initial max Ps below 200mmHg, although there was a small but significant increase in LVMI, without any increase in the blood pressure variables, even in those showing a normal response. In conclusion, max Ps appears to be a simple and reliable predictor of LVH progression. (Hypertens Res 1992; 15: 155-161)

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The systolic and diastolic blood pressures (BP) measured by the conventional auscultatory method tend to be lower and higher respectively than the corresponding values obtained with invasive direct measurement. This study aims to develop a new, noninvasive device employing a liquid-filled cuff to mea sure BP accurately. The new BP recorder employs hydraulic pressure instead of air pressure in a double cuff (outer cuff and inner cuff with an implanted pressure transducer) surrounding the upper arm. The basic principle of this method is based on evidence that the pulsatile pattern of the pressure tracings obtained changes when the inner-cuff pressure reaches diastolic BP and changes again when it exceeds systolic BP. BP values measured directly from the brachial artery were compared with those obtained simultaneously by the conventional auscultatory method or by our new method in 7 normotensives and 14 hypertensive patients. The differnce in systolic BP between the auscultatory and direct methods was -6.8±4.0 (SD) mmHg and the diastolic BP difference was 1.1±6.5mmHg. In contrast, the systolic BP difference between the new method and the direct method was -0.6±2.0mmHg and that for diastolic BP was 0.6±1.9mmHg. These values were significantly smaller than the differences obtained with the auscultatory method (p<0.05). Improved conduction of brachial artery pulsation through the liquid-filled cuff to the transducer apparently improved the analysis of arterial pulsation. This new device employing a liquid-filled cuff could be useful for assessing hypertension. (Hypertens Res 1992; 15: 163-169)

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The effect of recombinant interleukin-2 (IL-2) on endothelin-1 (ET-1) secretion was studied in bovine pulmonary arterial endothelial (BPAE) cells. IL-2 at concentrations of 1 to 10U/ml significantly suppressed the basal secretion of ET-1 from BPAE cells. The maximal suppression, which was obtained with 1 U/ml of IL-2, was 74% of the control value during 24h incubation. Moreover, incubation for 1h with IL-2 at a concentration of 1U/ml significantly lowered the prepro ET-1 mRNA level, measured by Northern blot analysis. Additions of 10^-5M of N^G-nitro-L-arginine, an inhibitor of nitric oxide (NO) synthesis, and of 10^-5M of methylene blue, an inhibitor of soluble guanylate cyclase, abolished the IL-2-induced suppression of ET-1 secretion. On the other hand, while addition of 10U/ml of thrombin (TB) for 24h significantly enhanced the secretion of ET-1 to about 128% of the control value, this enhancement was also inhibited by 100U/ml of IL-2. IL-2 at more than 1U/ml significantly increased the concentration of 6-keto-prostaglandin F_1^α in the medium. However, addition of indomethacin (10^-5M) did not affect the IL-2-induced suppression of the basal ET-1 secretion, suggesting that prostaglandin I₂ does not participate in the IL-2-induced suppression. These findings indicate that IL-2 suppressed the synthesis of ET-1 at the mRNA transcription level, and that NO/cyclic GMP system enhanced by IL-2 in the endothelial cells may be responsible for IL-2-induced suppression of ET-1 synthesis. (Hypertens Res 1992; 15: 171-175)

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A case of renovascular hypertension is presented with special emphasis on segmental hypoperfusion resulting from single vessel stenosis in the presence of bilateral duplex renal arteries. A forty-year-old male patient presenting with progressive elevation of blood pressure and proteinuria was admitted to our hospital for further evaluation. The elevation of plasma renin activity (PRA) was confirmed only after two-hour standing or under angiotensin converting enzyme inhibition with captopril. PRA obtained from the left renal vein was significantly higher than that from the right renal vein, and the angiogram disclosed bilateral duplex renal arteries and stenosis of 90% or more at the proximal portion in the left upper renal artery. Successful percutaneous transluminal renal angioplasty (PTRA) to the affected single renal artery resulted in normalization of the blood pressure and renin-angiotensin-aldosterone axis. This is the first clinical demonstration of renovascular hypertension resulting from segmental hypoperfusion of a unilateral kidney with lateralizing renal venous renin determination, that was successfully treated by revascularization. (Hypertens Res 1992; 15: 177-180)

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