Research done in our laboratory has uncovered novel pathways and enzymes of the circulating and tissue renin angiotensin system. These findings followed the discovery that angiotensin-(1-7) has cellular functions different from those established for angiotensin II. Although Ang-(1-7) is not an agonist in terms of stimulating thirst or promoting aldosterone release, the heptapeptide causes neuronal excitation and vasopressin release to a degree similar to that found with angiotensin II. Furthermore, angiotensin-(1-7) stimulates the production of prostanoids by a receptor-mediated event that causes no associated rise in intracellular Ca²⁺. These actions of angiotensin-(1-7) illustrate the heterogenous role of angiotensin peptides as modulators of a wide range of regulatory functions in mammals. (Hypertens Res 1992; 15: 61-66)

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This article first deals with the definition and measurement of insulin resistance, and makes a distinction between primary and secondary insulin resistance. The closest proxy of insulin action, i.e., plasma insulin concentration, is then discussed together with its relationship with insulin action. The available epidemiological evidence, both from cross-sectional and longitudinal studies, is rather consistent in indicating an association between insulin levels and hypertension independent of obesity, glucose intolerance, and aging. A weak association between insulin levels and blood pressure has been found, in some series, even in normotensive, healthy individuals. However, there are marked interethnic differences in this association. So far, case-control studies have univocally confirmed the presence of insulin resistance in hypertensive patients as a group; pathophysiological experiments have shown that the skeletal muscle is an important site of such insulin sensitivity. Furthermore, it is clear that the insulin resistance of essential hypertension is selective for glucose metabolism, other actions of insulin being unaffected. The possible pathogenic significance of insulin resistance in essential hypertension is then discussed by focusing on the interactions between insulin and hemoynamics, particularly in skeletal muscle tissue. Finally, the fact that insulin resistance tends to cluster with abnormalities of blood pressure regulation, glucose tolerance and lipid metabolism is discussed in the context of atherosclerotic cardiovascular diseases. The cluster itself, and, possibly, hyperinsulinemia/insulin resistance, are potentially atherogenic; the clinical and therapeutic implications of this synergism are evident. (Hypertens Res 1992; 15: 67-75)

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To assess the clinical implications of protein load in essential hypertension, we measured renal plasma flow (RPF) and glomerular filtration rate (GFR) at 30-min intervals after initiating 10% amino acid infusion (6.7mg/kg/min for 30min) in 10 untreated patients with essential hypertension and 8 subjects with normotension. Amino acids provoked significant and equivalent renovasodilation without alteration of systemic hemodynamics in both hypertensive and normotensive groups (% change of RPF induced by amino acids: +12.8±3.0% in hypertensive vs. +15.3±4.4% in normotensive group). GFR also significantly increased in both groups, but the magnitude of this rise was lower in the hypertensive than in the normotensive group (+8.7±3.2% vs. +34.1±4.0%, p<0.01). Consequently, filtration fraction did not change following the amino acid infusion in hypertensive patients (0.28±0.01 to 0.27± 0.02, ns), whereas it significantly increased in normotensive subjects (0.23±0.02 to 0.27±0.02, p< 0.01). Amino acids also increased plasma glucagon to a comparable level (120.6±14.5pg/ml in hypertensive vs. 101.1±14.8pg/ml in normotensive group) in both groups, and this level was correlated with the degree of hyperfiltration induced by amino acids in the normotensive group (r=0.79, p< 0.05). In conclusion, renal functional reserve estimated by the increase in GFR following the amino acid infusion was lower in the hypertensive than in the normotensive group. This abnormality found in essential hypertension might be related to enhanced responsiveness of efferent arterioles to the vasodilatory stimuli induced by amino acids. (Hypertens Res 1992; 15: 77-84)

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Dietary NaCl-induced changes in blood pressure and agonist and antagonist binding properties to renal α₂-adrenoceptors were studied in inbred (Rapp) strains of Dahl salt-sensitive (S) and salt-resistant (R) rats. S and R rats were placed on either salt-deficient (0.13% NaCl in chow) or high salt (1% NaCl solution to drink plus 0.13% NaCl chow) diets for 1 to 8 weeks. Saturation binding studies with [³H]-rauwolscine and [³H]-p-aminoclonidine and competition studies with [³H]-rauwolscine and epinephrine were then performed in renal plasma membranes from each group. Systolic blood pressure rose significantly in S rats on the salt-deficient diet for 2 or more weeks, and was further increased by high salt intake, indicating that there are salt-sensitive and salt-insensitive components to the hypertension in inbred S rats. The blood pressure of R rats was unaffected by dietary NaCl content. Two or more weeks of high salt feeding significantly elevated renal α₂-adrenoceptor density ([³H]-rauwolscine binding) in S but not R rats. Interestingly, NaCl restriction in weanling S rats completely prevented this increase in α₂-adrenoceptor density over the course of the study. The number of high affinity agonist binding sites (assessed with [³H]-p-aminoclonidine and epinephrine displacement of [³H]-rauwolscine) was increased in S rats after high salt feeding. Removal of the high salt diet failed to reverse the NaCl-induced elevations in total and high affinity α₂-adrenoceptor density in S rats. We conclude that: 1) the initiation of renal α₂-adrenoceptor overexpression in Dahl S rats is entirely dependent on dietary NaCl content; 2) the overexpression of renal α₂-adrenoceptors was independent of the salt-insensitive component of hypertension in S rats, precluding a causal linkage between these parameters; 3) the rise in renal α₂-adrenoceptors was closely paralleled by salt-sensitive increments in blood pressure, suggesting a functional relationship between these two variables; 4) In contrast to reported changes in renal α₂-adrenoceptor properties following renal denervation, dietary NaCl augments the number of high affinity renal α₂-adrenoceptor agonist binding sites in S rats but does not increase the proportion of these sites relative to total receptor number. (Hypertens Res 1992; 15: 85-92)

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Previous studies have shown the selectivity of epidermal growth factor (EGF), in promoting the growth of cultured vascular smooth muscle cells derived from spontaneously hypertensive rats (SHR) compared to cells derived from the normotensive counterpart strain, the Wistar-Kyoto (WKY) rats. We have now examined EGF binding to tissue membranes from intact animals. Using the membrane preparations isolated by differential centrifugation from kidney and aortic tissues of age-matched adult SHR and WKY rats, the specific maximal EGF binding was found to be higher in the SHR than the WKY rats. The EGF binding affinity, however, was similar in the two strains. Analysis of solubilized EGF receptor from the SHR and WKY rat kidney by SDS-polyacrylamide gel electrophoresis revealed no differences in molecular weight. Hydralazine treatment of both strains to chronically lower the blood pressure over a period of 8 weeks, did not significantly change the EGF binding in the kidney or aorta. The increased binding observed in SHR tissues, therefore, is not primarily attributable to increasing blood pressue. The immunoreactive urinary EGF in the hypertensive adult SHR, determined by radioimmunoassay, was about one half of that measured in age mached normotensive WKY rats. These studies lend support to the thesis that the observed increase in EGF binding sites in the kidney and aorta may be related to the putative genetic fault in SHR. (Hypertens Res 1992; 15: 93-98)

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We studied the effect of a rat renin inhibitory peptide (RRIP) on kidney renin synthesis in spontaneously hypertensive rats (SHR). The RRIP was intraperitoneally administered (n=6) via an osmotic minipump to 11-week-old SHR for 7 days, at a rate of 10μg/kg/min. RRIP significantly reduced PRA and suppressed the elevation of systolic blood pressure in treated SHR compared to control. The content of kidney renin messenger RNA (mRNA) in treated SHR was comparable to that of control. Electron microscopic study revealed many renin granules and renin protogranules containing crystalline matrices in juxtaglomerular cells in RRIP-treated SHR. These results suggest that RRIP does not stimulate or suppress renin synthesis in the kidney. (Hypertens Res 1992; 15: 99-104)

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Intracellular free magnesium and calcium concentrations of platelets from 21 mild essential hypertensive patients and 8 normotensive individuals were measured using mag-fura2, a recently developed fluorescent indicator, and fura2, respectively. Compared with normotensives, intracellular free magnesium concentration was significantly decreased (0.32±0.10 vs. 0.50±0.15mmol/l, mean±SD, p<0.001) and intracellular free calcium concentration was significantly increased (40.2±9.0 vs. 21.7±11.8 nmol/l, p<0.001) in the hypertensives. In all subjects, mean blood pressure correlated negatively with intracellular free magnesium (r=-0.57, p<0.001) and positively with intracellular free calcium (r=0.48, p<0.02). Furthermore, intracellular free magnesium correlated negatively with intracellular free calcium. In contrast, serum and intraerythrocyte magnesium concentrations did not differ between the two groups. These results suggest that the decreased intracellular free magnesium of platelets concomitant with the increased intracellular free calcium may participate in the pathophysiology of essential hypertension. (Hypertens Res 1992; 15: 105-110)

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The purpose of the present study is to determine accurate incidence rates of stroke and acute myocardial infarction among the residents in Okinawa, where the census population was 1, 222, 398 in 1990 and mortality due to cerebrovascular and heart diseases is lowest in Japan. A co-operative study group including almost all hospitals and clinics in Okinawa was established for the survey. Between April 1, 1988 and March 31, 1991, 4, 756 cases of stroke and 1, 059cases of acute myocardial infarction were identified. The average age-adjusted annual incidence per 100, 000 population was 137 for stroke and 31 for acute myocardial infarction. In the population aged 40 years and older, the respective values were 315 and 72, indicating the stroke incidence to be 4.4 times higher than that of acute myocardial infarction. The incidence ratio for men to women was 1.7:1 for stroke and 2.9:1 for acute myocardial infarction. Among stroke cases, 51.3% were diagnosed as cerebral infarction, 35.7% as cerebral hemorrhage, 7.7% as subarachnoid hemorrhage and 5.3% as others. Computed tomography of the head was performed in 98.4% of all stroke cases. The case ascertainment, evaluated by comparing the registered cases and death certificates in a certain city, was almost complete. The incidence of acute myocardial infarction is still much lower than that of stroke in Japan. (Hypertens Res 1992; 15:111-119)

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