A number of controversies concerning clinical aspects of hypertension are addressed. These include the need for out-of-the-office blood pressure readings in order not to incorrectly label the many people who have "white-coat" elevations of pressure as being hypertensive. A second issue is determining the need for antihypertensive drug therapy after institution of an appropriate program of lifestyle modifications. Emphasis is placed upon the need to go beyond the level of blood pressure and to incorporate both the degree of target organ damage and the presence of concomitant cardiovascular risk factors in deciding upon the need for drug therapy. Once therapy is begun, the choice of initial therapy should be based upon certain demographic features and, mainly, the concomitant conditions that may be either adversely or positively influenced by the agent chosen. Since a J-curve of coronary disease likely exists, caution is advised not to lower the pressure below the lower limit of coronary perfusion. Lastly, the potential for prevention of hypertension is supported. (Hypertens Res 1994; 17: 205-213)

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Over the past two decades there has been a precipitous fall in the age-adjusted rate of deaths due to cerebrovascular disease in Japan, while the rate of deaths due to heart disease has fallen only slightly. Mortality from heart disease since 1984 has been greater than that from cerebrovascular disease. However, an epidemiologic survey in Okinawa indicates that the incidence of stroke is 4.4times higher than that of acute myocardial infarction: the average age-adjusted annual incidences of stroke and acute myocardial infarction per 100, 000 people aged 40years and older were 315 and 72, respectively. The National Nutrition Survey and National Survey on Circulatory Disorders revealed that during the last 10 years the averages of systolic and diastolic blood pressures of Japanese decreased, especially in those aged 50 and older, and the prevalence of hypertension as well as of left ventricular hypertrophy diagnosed by electrocardiography decreased significantly in both men and women. This may be attributable to widespread education concerning hypertension and antihypertensive treatment. However, the average serum total cholesterol concentration increased by 12mg/dl in men and 16mg/dl in women and the prevalence of hypercholesterolemia increased in both men and women during the last 10years. Furthermore, 61% of men still smoke. Research results show that the mortality and morbidity rates for cardiovascular diseases are changing in Japan. This seems to be related to the fact that Japanese people are adopting a more westernized pattern of food intake. There is a concern that the incidence of acute myocardial infarction might greatly increase in the near future. (Hypertens Res 1994; 17: 215-219)

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We studied electrocardiographic (ECG) and echocardiographic findings in relation to the evolution of left ventricular hypertrophy (LVH) over 5 years in 77 unmedicated men with borderline and mild hypertension. Although blood pressure did not significantly change during this period, the left ventricular mass index (LVMI) increased significantly (from 107±21 to 125±28g/m²). When LVH was defined as an LVMI>125g/m², ECG findings indicating a diagnosis of LVH based on SV₁+RV₅>35mm, SV₃+RaVL>28mm, sum of 12-lead QRS voltage >175mm, and Romhilt & Estes point score >4, showed predictive values of 21.1%, 50.0%, 18.9%, and 33.3%, respectively. ECG voltage changes determined by these criteria did not correlate with changes in LVMI during the observation period. These findings indicate that conventional ECG voltage criteria are inappropriate for the diagnosis of LVH or for the assessment of its progression in borderline and mild hypertension. (Hypertens Res 1994; 17: 221-225)

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The interaction between flow-induced prostacyclin production and nitric oxide (NO) synthesis in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) was studied. Flow was made by 3cm-amplitude horizontal shaking at various frequencies at 37 °C under 5% CO₂ and 95% air. Basal prostacyclin and NO production rates did not differ between strains. Prostacycnm production during flow was significantly greater with increasing shear stress from shaking frequencies of 120/min to 180/min, and was greater in SHR than in WKY. In contrast, flow-induced NO production was greater in WKY than in SHR. The addition of N nitro-L-arginine further increased the flow-induced increase in the production of prostacyclin in WKY in a dose-dependent manner, but had no effects in SHR. Indomethacin did not affect flow-induced NO production in either strain. We conclude that increases in prostacyclin production in SHR-derived VSMC during shear stress may be due to decreases in the suppression by NO and may compensate for hypertension. (Hypertens Res 1994; 17: 227-232)

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The objective of this study was to determine the relative importance of angiotensin II (Ang II) and aldosterone in cardiovascular hypertrophy. Rats were given an infusion of Ang II (200ng/kg/min) subcutaneously for 8 weeks with a mini-osmotic pump, with or without oral spironolactone (200mg/kg) or MK-954 (30mg/kg) daily. Ang II infusion resulted in marked hypertension of around 207mmHg, which was associated with cardiac hypertrophy, with a heart-to-body-weight ratio of 0.35±0.005% and thoracic aorta medial thickness of 0.166±0.005mm (vs. 0.285±0.002% and 0.113±0.003mm, respectively, in control rats). Concomitant administration of spironolactone or MK-954 reduced the blood pressure in rats given Ang II to the same degree (164 and 171mmHg, respectively). Aldosterone receptor blockade by spironolactone prevented Ang II-induced cardiac hypertrophy heart-to-body-weight ratio= 0.307±0.009%, but the Ang II-receptor antagonist MK-954 did not (heart-to-body-weight ratio=0.331 ±0.007%), although aortic vascular wall thickening in rats given Ang II was attenuated by both drugs. Renal hypertrophy induced by Ang II was not completely normalized by either drug. These results suggest that blockade of mineralocorticoid receptors is more effective than antagonism of Ang II receptors in preventing cardiac hypertrophy, and is as effective as antagonism of Ang II receptors in reducing vascular medial hypertrophy. They also indicate that, in addition to Ang II, aldosterone may play a pivotal role in regulating the growth of cardiac myocytes and vascular smooth muscle cells during Ang II-dependent hypertension. (Hypertens Res 1994; 17 233-237)

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The hemodynamic and humoral effects of i.v. fructose infusion and a control infusion were studied in 12 borderline hypertensive patients according to a single-blind, cross-over, randomized protocol. Fructose infusion decreased urinary sodium excretion and significantly increased plasma insulin, plasma Na⁺/K⁺ ATPase inhibitory activity, and forearm arterial and venous tone (+13%), the last of which was not observed during the control infusion (-2.5%). Levels of ANF and PRA in plasma were not altered by either infusion. We conclude that the sodium retention caused by acute i.v. fructose loading could be related to the increase in plasma insulin levels, which may directly affect individual susceptibility to sodium by enhancing sodium reabsorption at renal tubules. This sodium retention could contribute to the release of a plasma Na⁺-pump inhibitor apparently unrelated to extracellular volume expansion and potentially responsible for the early peripheral vascular involvement found in hypertension-prone men. (Hypertens Res 1994; 17: 239-242)

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The purpose of the current study was to define the critical phase in the development of genetic hypertension during which time application of an angiotensin converting enzyme inhibitor, captopril, would produce long-term antihypertensive effects. In addition, we evaluated two potential mechanisms underlying the long-term antihypertensive effect of early treatment with captopril: alterations in baroreflex sensitivity and cardiovascular remodeling. Separate groups of SHR were placed on captopril in utero, or at 1, 7 or 30 days post birth. The length of therapy was 1-2 months. We also removed captopril from SHR treated in utero at 1, 7 and 30days post birth. Mean arterial pressures and heart weights were monitored in all rats between 3-4 months of age. Tests of baroreflex function (control of heart rate) were performed in 4- and 9- month old rats using intravenous infusion of phenylephrine and nitroprusside to raise and lower blood pressure, respectively. Mean arterial pressures of SHR placed on captopril at 1 (145±9), 7(141±4) and 30 days (129±4) for 1month were significantly lower than control SHR (176± 7, mmHg), but higher than SHR treated in utero with captopril and maintained on therapy for two months (114±4mmHg). Similarly, SHR treated with captopril in utero with treatment discontinued at 1, 7 or 30 days post birth showed significantly lower mean arterial pressures than untreated SHR. None of these groups showed blood pressures as low as SHR treated in utero until 2 months of age. These rats continued to show normotensive mean arterial pressures even at 9months of age. In 4- and 9-month-old captopril treated SHR the sensitivities of baroreflex control of heart rate (slope of the relationship between changes in mean arterial pressure and change in pulse interval) were significantly greater than in untreated SHR. Additionally, the heart weight to body weight ratios of these rats were significantly lower than control rats. These results indicate that early treatment with captopril enhances baroreflex control of heart rate in SHR. This enhancement of baroreflex function may be permanent since it persisted even after captopril had been stopped for 7 months; moreover, the effect of captopril on baroreflex sensitivity may be due to mechanisms other than lowering arterial blood pressure. Our data suggest that captopril treatment applied in short-term intervals from in utero to 2 months of age is effective in lowering the magnitude of hypertension in SHR. Augmentation of baroreflex function and prevention of remodeling of the cardiovascular system may contribute to the permanent prevention of the evelopment of hypertension in SHR treated with captopril. (Hypertens Res 1994; 17: 243-251)

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Coughing is an adverse reaction to angiotensin-converting enzyme (ACE) inhibitors, but some ACE inhibitors cause more coughing than others. To test the hypothesis that this difference is related to a difference in their effects on bradykinin (BK), the potencies for inhibition of the hydrolysis of BK and angiotensin (Ang) I of four ACE inhibitors, captopril, enalaprilat, ramiprilat, and imidaprilat, were tested with purified canine lung ACE. The accumulation of BK relative to the inhibition of Ang II formation was significantly less with imidaprilat than with the three other ACE inhibitors. This may explain why imidapril was associated with less coughing than ramipril in clinical trials. ACE inhibitors may be classified by their relative potencies for the inhibition of the hydrolysis of BK and Ang I. (Hypertens Res 1994; 17: 253-258)

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