Recent findings have increased our understanding of the role of the renin-angiotensin system in cardiovascular diseases. This was possible by the progress made in molecular biology and the import of this methodology into cardiovascular research by several groups in the past few years. Studies by these groups accumulated evidence especially for the existence and physiological importance of organ-based renin-angiotensin systems and their involvement in the pathogenesis of hypertension and the accompanying disorders of the heart, the kidney, and the vessels. This Review will focus mainly on the relevance of the local renin-angiotensin systems for cardiovascular diseases and the value of transgenic animals as models to analyse these systems (Hypertens Res 1994; 17: 1-16).

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The purpose of the present study is to clarify the role of intracellular sodium concentration and the autonomic nervous system in the maintenance of blood pressure, and to examine genetic effects on these systems in young normotensives. First, the effects of sodium chloride intake on blood pressure and erythrocyte sodium concentration were examined in young normotensive men. The change in dietary sodium chloride from 50mmol/day to 340mmol/day induced no significant change in blood pressure or erythrocyte sodium concentration regardless of a family history of hypertension. The relationship between intraerythrocytic sodium concentration and blood pressure under pharmacological autonomic blockade was examined in normotensive subjects with and without a family history of hypertension under free sodium intake. After total autonomic blockade with atropine, propranolol and phentolamine, mean blood pressure did not change in normotensive subjects without a family history of hypertension (81.0±8.6 to 82.8±7.9mmHg) but increased in normotensive subjects with a family history of hypertension (84.8±9.9 to 91.6±8.3mmHg, p<0.01). The difference in mean blood pressure between the two groups was significant only after autonomic blockade (p<0.05). Intraerythrocytic sodium concentration was higher in normotensive subjects with a family history of hypertension than in normotensive subjects without a family history of hypertension, but the difference was not significant. In the combined groups, intraerythrocytic sodium concentration was significantly correlated with mean blood pressure after total autonomic blockade (r=0.68, p=0.003) rather than with basal blood pressure. These results suggest that intrinsic blood pressure, excluding the effects of the autonomic nervous systems may be associated with intracellular sodium concentration and that intrinsic blood pressure increased via elevated intracellular sodium level may be compensated for by the autonomic nervous system in normotensive subjects with a hereditary predisposition to hypertension. (Hypertens Res 1994; 17: 17-22)

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We examined the chronic effects of Intracerebroventricular (ICY) endothelin on blood pressure (BP) and water and sodium metabolism in rats. Endothelin-1 (ET-1) at doses of 10, 30, 100ng/h or artificial cerebrospinal fluid (CSF) at a dose of 1μl/h was administered continuously into the lateral ventricle for 7 days (n=6 each). Intravenous (IV) administration of either ET-1 (100ng/h) or saline (control) was additionally done in two other groups of rats. The highest dose of ICV ET-1 produced a mild but significant increase in systolic BP on days 6 and 7 (from 125±3 to 138±5mmHg, m±SE). It transiently increased urine volume on day 1 and day 2, and sodium excretion on day 1 without stimulating water intake. These changes were not produced by the lower doses of ICY ET-1 or ICV artificial CSF. The same dose of IV ET-1 (100ng/h) also failed to produce these effects. On day 7, the pressor effect of the highest dose of ICV ET-1 was confirmed by direct BP measurement in conscious rats. Plasma norepinephrine level was significantly higher in the ICV ET-1 (100ng/h) group than the control group (384±61 vs. 222 ±40pg/ml, p<0.05), while plasma vasopressin was similar in the two groups. Depressor response to intravenous hexamethonium (20mg/kg) was significantly greater in the ICV ET-1 group than the control group. These results suggest that chronic ICV ET-1 elevates BP mainly due to activation of the sympathetic nervous system. Endothelin may also act on the brain to increase water and sodium excretion without stimulating water intake. (Hypertens Res 1994; 17: 23-28)

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Regional vascular responses to NKY-722 (NKY), a novel dihydropyridine derivative calcium channel blocker, and the effects on the responses to endothelin (ET) were investigated using tracer microspheres with a reference sample method in anesthetized rats. Intravenous injections of NKY, 0.2 and 2mg/kg, decreased blood pressure and total peripheral resistance dose-dependently. Cardiac index significantly increased only with the high dose regardless of bradycardia. Regional blood flow significantly changed with NKY: It increased in the brain, brown adipose tissue (BAT), intestine, colon and skin, but decreased in the liver, spleen, kidneys, adrenals and skeletal muscle. NKY decreased the regional vascular resistance in the brain, heart, lungs, BAT, intestine, colon and skin, but increased it in the liver, spleen and skeletal muscle. ET significantly increased blood pressure, but this was abolished by pretreatment with the low and high doses of NKY. Cardiac index became significantly lower with ET, and was not affected by NKY. Total peripheral resistance after ET remained lower with NKY pretreatments. ET decreased the blood flow mainly in the liver, spleen, kidneys, adrenals, BAT, intestine, colon, and skeletal muscle. Pretreatments with NKY prevented the decrease of flow caused by ET in the kidneys, adrenals, BAT, intestine, colon and skeletal muscle. These findings indicate that NKY lowers blood pressure mainly by decreasing the peripheral vascular resistance, and that NKY blunts many, but not all, endothelin effects on vasculature. (Hypertens Res 1994; 17: 29-34)

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To assess renal benefits of calcium channel blockers (CCBs) and angiotensin converting enzyme inhibitors (ACEIs) in diabetic rats with renal impairment, we administered CCBs, nifedipine (NIF) and benidipine (BEN), or ACEIs, captopril (CAP) and trandolapril (TRA), for 12 weeks, and studied changes in systolic blood pressure (SBP) and urinary protein excretion (UP) in uninephrectomized spontaneously hypertensive rats and Wistar-Kyoto rats with diabetes mellitus induces by streptozotocin administration (WKY-STZ and SHR-STZ). In WKY-STZ, both the CCBs and the ACEIs decreased SBP and UP similarly. UP of SHR-STZ was more than that of WKY-STZ. Both the CCBs and the ACEIs attenuated the development of hypertension in SHR-STZ similarly. However, UP in the ACEIs group was significantly less than that of the control (no treatment), whereas UP in the CCBs group was not significantly less than that of the control. These results indicate that hypertension may accelerate diabetic nephropathy. They also indicate that reduction of systemic blood pressure does not always lessen the renal injury in this model of rats. ACEIs were more potent in reducing proteinuria than CCBs in this diabetic model in rats partly because ACEIs may preferentially reduce the intraglomerular capillary pressure. (Hypertens Res 1994; 17: 35-41)

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The coincidence of increased red blood cell mass with obesity and hypertension has been confirmed in a number of studies. Since erythropoietin (EPO) induces hypertonic effect, we aimed to study the possible involvement of endogenous EPO in the pathogenesis of obesity-related hypertension (ORH). Seventy-two non-obese (body mass index-BMI<25kg/m²) and 47 obese (BMI>30kg/m²) patients with essential hypertension, and 32 non-obese normotensive control subjects were studied on 120mmol Na/24h diets for 3 days and 30mmol Na/24h diets for the following 3 days. Serum EPO levels, plasma renin activity (PRA), aldosterone (PAC) and urinary sodium and potassium excretion were estimated under both conditions. Hematocrit, hemoglobin and serum iron, ferritin and TIBC were measured in basal conditions. Patients with ORH showed significantly higher hematocrit values, hemoglobin levels and erythrocyte counts (p<0.05) than non-obese essential hypertensives and controls, although no differences in serum EPO levels (13.6±1.1 and 12.8±1.0mU/ml, 15.3±1.2 and 13.3±1.1, 12.2±2.0 and 10.95±1.7, respectively) and log EPO×%Hct product were found between groups. In both hypertensive groups, BMI but not blood pressure positively correlated with hematocrit. A negative correlation between changes in EPO and PRA induced by sodium restriction was found in lean hypertensive subjects only (r =-0.42, p<0.01). This finding suggests that in contrast to non-obese patients with essential hypertension, in subjects with ORH activity of the renin-angiotensin-aldosterone system does not seem to be related to EPO secretion. Since in both lean and obese essential hypertensive subjects EPO and log EPO ×%Hct product are within normal range, the contribution of endogenous EPO to the pathogenesis of hypertension in these patients is unlikely. (Hypertens Res 1994; 17: 43-48)

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The association between restriction fragment length polymorphism (RFLP) in the 3′-untranslated region of the dopamine β-hydroxlase (DBH) gene and essential hypertension, and the relationship between this RFLP and plasma DBH activity were investigated. A 322bp segment of the 3′-untranslated region of the human DBH gene was amplified by polymerase chain reaction (PCR). The restriction enzyme SphI cleaved the 322bp PCR product into 201 and 121bp fragments for that allele which contained the SphI cutting site. This allele was designated S. The allele that lacked the SphI restriction site was designated L. Plasma DBH activity was determined by a spectrophotometric method. For this polymorphic restriction site, the frequency of the minor allele of the polymorphism was similar in the hypertensive and normotensive groups (0.39 vs. 0.35, respectively). In the normotensive group, there was a significant (p< 0.01) relationship between plasma DBH activities and genotypes: 65±24, 55±20 and 45± 14IU/I for homozygotes (LL), heterozygotes (LS) and homozygotes (SS), respectively. In the hypertensive group, no significant relationship was observed. These results demonstrate that a SphI RFLP in the 3′-untranslated region of the DBH gene is not associated with essential hypertension in the group studied. However, in only normotensive subjects, this RFLP may be responsible in part for the variance of plasma DBH activity. (Hypertens Res 1994; 17: 49-53)

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An association study of the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene with myocardial infarction (MI) was performed in middle-aged Japanese men. The DD genotype was significantly more frequent in 101 MI subjects (0.42) than in 102 matched control subjects (0.16) compared with the two other genotypes (IDandII) (p<0.00005). A significant association was observed not only in the low-risk group but also in the high-risk group who were defined according to plasma total cholesterol ≥ 220mg/dl and body mass index ≥ 26kg/m². These results indicate that ACE/DD genotype is a potent and important risk factor for MI in Japanese. (Hypertens Res 1994; 17: 55-57)

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The present high levels of sodium chloride (regular salt, RS) intake interfere with the therapeutic effects of angiotensin converting enzyme inhibitors. In previous studies a novel potassium-, magnesium- and 1- lysine-enriched and sodium-reduced salt alternative (SA) has been virtually devoid of the hypertensive, left ventricular hypertrophy producing, and life-span shortening effects, characteristic of RS. We therefore compared the influence of SA on the cardiovascular effects of enalapril with that of RS in male stroke-prone spontaneously hypertensive rats (SHRSP). During the 28-day experiment, RS alone produced a marked rise in blood pressure, induced remarkable left ventricular hypertrophy, and caused the death of five out of 18 SHRSP. Oral enalapril treatment did not significantly affect either of the detrimental cardiovascular effects of RS but there were no deaths in the enalapril-treated group. The SA supplemented diet neither caused mortality nor induced any significant rise in blood pressure as compared to control SHRSP, and caused significantly less cardiac hypertrophy than RS. During SA, enalapril had a marked antihypertensive effect and it also completely blocked the salt-induced left ventricular hypertrophy. During SA+enalapril or SA alone, there was no tendency to hyperkalemia in any of the SHRSP. There was not any difference in the plasma renin activity (PRA) between control, RS and SA groups. Enalapril increased PRA to the same extent, approximately three-fold, in the RS and in the SA supplemented SHRSP. Hence, PRA does not explain the marked improvement of the effects of enalapril by SA in comparison to RS. Our findings suggest that replacement of regular salt by the novel salt alternative may remarkably improve the cardiovascular effects of enalapril treatment. (Hypertens Res 1994; 17: 59-69)

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To investigate the gender difference in the pathophysiology of essential hypertension, we investigated baroreflex sensitivity (BRS), aortic pulse wave velocity (PWV), blood pressure responses to mental arithmetic tests (MAT) and isometric handgrip exercise (IHG) in normotensive subjects (NT) and essential hypertensive patients (EHT) of both genders. EHT were classified as stage I (EHT-I) or stage II (EHT- II) according to the WHO stage classification. BRS in males tended to decline with increasing age and showed a significant (p<0.01) inverse correlation with PWV. Male EHT-II showed a significantly lower BRS than NT and EHT-I, and BRS in EHT-I was similar to that in NT. On the other hand, BRS in females decreased with age, reached a nadir around the first half of the fifth decade of life and tended to increase afterwards. Female EHT-I showed a substantially reduced value for BRS compared with NT, and BRS in EHT-II was similar to that in EHT-I. BRS in female EHT showed a significant (p<0.01) inverse correlation with serum gonadotropin level. Blood pressure response to MAT and clinic blood pressure were closely related to BRS in female subjects. We showed that male BRS declined gradually with aging and the progress of hypertension, while BRS in female EHT was substantially reduced even in the early stage of hypertension. The activation of the sex center regulating gonadotropin secretion may be one of the causative factors of the baroreflex impairment in females. These findings suggest that ovarian dysfunction is an another important factor influencing the baroreflex function in addition to aging and blood pressure, and that the baroreflex impairment in females characterizes the gender difference in the pathophysiology of essential hypertension. (Hypertens Res 1994; 17: 71-78)

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