Referring to the mosaic theory of Page, the authors present an overview of recent topics related to the participation of endocrine and auto-paracrine factors, such as steroids, ouabain-like substance, insulin, renin-angiotensin and endothelin, in the pathogenesis of primary hypertension. These factors promote the development of hypertension in either a direct or indirect manner; in addition, they promote, to some extent, the proliferation of vascular smooth muscle cells. Future research should attempt to elucidate interactions between these factors in cardiovascular tissues and to define how these factors interact with various vasodepressor substances to regulate blood pressure. (Hypertens Res 1995; 18: 171-179)

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Elevated blood pressure is a common and powerful predisposing factor for stroke, coronary disease, cardiac failure and peripheral artery disease imposing a 2-3 fold increased risk of one or more of these atherosclerotic sequelae. The risk ratio imposed by hypertension is greatest for cardiac failure and stroke, but in Western countries coronary disease is the most common and lethal hazard. In hypertensive men and women respectively, 35% and 45% of myocardial infarctions are silent or unrecognized necessitating routine periodic ECG examination for its detection. Comparison of the impacts of systolic and diastolic blood pressure gives no indication of a greater impact of diastolic pressure and isolated systolic hypertension is distinctly hazardous. Over-reliance on diastolic pressure to assess risk can be misleading, particularly in advanced age. Attributable risk estimates suggest that 78% of hypertension in men and 65% in women is directly attributable to adiposity, making weight control of paramount importance for primary prevention of hypertension. The likelihood of development of cardiovascular disease in the hypertensive patient is greatly enhanced by the presence of metabolically-linked risk factors and already existent cardiovascular conditions. These influence the urgency and choice of therapy. Rational and efficient assessment of the hypertensive candidate for cardiovascular disease requires use of a cardiovascular risk profile evaluating the joint effect of multiple risk factors and effective treatment improves multivariate risk. (Hypertens Res 1995; 18: 181-196)

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Electrical stimulation of afferent renal nerves and activation of intrarenal receptors increases plasma vasopressin concentration, but the role of afferent renal nerves in the control of vasopressin secretion is not clear. Recently, we reported that activation of renal mechanoreceptors stimulates the release of vasopressin. However, Intrapelvic pressure was increased to 50mmHg, and this increase is above the normal physiological range. Therefore, in the present study, we investigated the effect of moderately increased intrapelvic pressure on plasma vasopressin concentration in anesthetized rabbits. First, we measured renal tissue pressure while Intrapelvic pressure was increased stepwise in 10-mmHg increments. Basal renal tissue pressure was 17±2mmHg. Renal tissue pressure increased only when Intrapelvic pressure was higher than the basal tissue pressure of each animal. Usually, increases in intrapelvic pressure less than 20mmHg did not increase renal tissue pressure. This finding suggests that only increases in Intrapelvic pressure more than 20mmHg can activate renal mechanoreceptors. Based on this finding, the effects of moderate increases in intrapelvic pressure (15 and 30mmHg) were studied. With a 15-mmHg increase in intrapelvic pressure, plasma vasopressin concentration did not change significantly. However, when Intrapelvic pressure was increased to 30mmHg, plasma vasopressin concentration increased from 5.6±1.4 to 9.5±2.8pg/ml at 5min (p<0.05) and to 8.8±2.0pg/ml at 10mm (p< 0.05). Plasma renin activity and mean arterial pressure also increased when intrapelvic pressure was increased to 30mmHg. We conclude that moderate increases in intrapelvic pressure stimulate vasopressin secretion. This provides further evidence that the kidneys participate in the physiological control of vasopressin release by way of afferent renal nerves. (Hypertens Res 1995; 18: 197-202)

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To determine whether recombinant human erythropoietin (rHuEPO) exerts a direct vasoconstrictive effect on renal arteries or affects renal function, we measured renal hemodynamics and renal function during a 30-min intrarenal infusion of rHuEPO in anesthetized rabbits without renal failure. Intrarenal infusion of rHuEPO at a rate of 100U/min did not alter mean arterial pressure, renal blood flow, or renal vascular resistance, as compared with controls treated with vehicle. There were no significant rHuEPO-associated changes in glomerular filtration rate, filtration fraction, or arterial hematocrit. However, urine volume, urinary excretion of sodium and potassium, and fractional sodium excretion were significantly reduced by intrarenal infusion of rHuEPO. These observations indicate that rHuEPO has no direct effects on mean arterial pressure or renal hemodynamics, but that it stimulates net tubular sodium reabsorption, and reduces urine volume and urinary excretion of sodium and potassium in anesthetized rabbits without renal failure. (Hypertens Res 1995; 18: 203-207)

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To investigate the seasonal variations in ambulatory blood pressure patterns, 24-h blood pressure was measured every 15 minutes noninvasively in ten young normotensive women. Urine was collected every 4 hours. The examinations were repeated in spring, summer, autumn, and winter in a standardized living environment. The 24-h average systolic and diastolic blood pressures did not differ significantly among the seasons. Similarly, there were no significant differences in the average values of either daytime or nighttime blood pressure. In contrast, the average pulse rate during nighttime was significantly higher in winter than in summer (64±2beats/min vs. 59±2beats/min, p<0.05). The variabilities of either blood pressure or pulse rate did not change significantly among the seasons. The mesors and acrophases of both systolic and diastolic blood pressures, determined by a single cosinor method, were not significantly different among the seasons. On the other hand, the acrophase of pulse rate appeared significantly later in winter (16:19) compared with those in spring (14:54), summer (14:42), and autumn (14:21). Urine volume and urinary excretion of norepinephrine were significantly greater in winter than in summer. These results indicate that the 24-h pattern of blood pressure is reproducible and shows no seasonal difference in young normotensive women. (Hypertens Res 1995; 18: 209-214)

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Although insulin resistance often occurs in association with hypertension, considerable variation is observed in the degree of insulin resistance among hypertensive patients. Since there is evidence of a genetic basis in the development of insulin resistance in hypertension, we analyzed the contribution of genetic factors to insulin resistance in hypertensive patients. Sixty-six Japanese hypertensive patients were studied. These patients were divided into two groups (hyperinsullinemia group and normoinsulinemia group) according to plasma insulin response during a 75-g oral glucose tolerance test (75g-OGTT). Insulin receptor gene (INSR) was studied for association with insulin resistance in hypertensive patients. A microsatellite polymorphism in intron-2 of the insulin receptor gene was analyzed by the polymerase chain reaction method. Five alleles were detected in the INSR microsatellite. The frequency of C/C genotype in the hyperinsulinemia group was significantly higheer than that in the normoinsulinemia group (73% vs. 43%, p=0.02). There was no difference in genotype frequency of INSR between hypertensive patients and control subjects. When the hypertensive patients were divided into two groups, the frequency of ClC genotype in the hyperinsulinemia group was significantly higher than that in the control group (73% vs. 45%, p=0.014). There was no significant difference between the normoinsulinemia group and control group. These data suggest that the insuulin receptor gene may contribute to insulin resistance in hypertensive patients with hyperinsulinemia. (Hypertens Res 1995; 18: 215-218)

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Atrial natriuretic peptide (ANP) has been implicated in the development of hypertension in Dahl R and S rats. To test the responses of DR and DS kidneys in the absence of the influence of neural and humoral mechanisms, we investigated the pharmacokinetics and pharmacodynamics of ANP in isolated perfused DR and DS kidneys, obtained from rats given a high or low sodium diet, after a bolus injection of ANP (1μg) or after a bolus injection plus infusion of ANP to maintain the perfusate concentration at 1000pg/ml. The elimination rate constant was not different between the groups (DR, 0.044min^-1 vs. DS, 0.050min^-1). Clearance of ANP was 4 times greater than the glomerular filtration rate, indicating that a receptor-mediated peritubular clearance is probably the primary route of elimination. DS kidneys excreted 50% less sodium than DR kidneys. However, ANP caused a 5-fold increase in fractional sodium excretion in both DR and DS. ANP also increased sodium excretion, creatinine clearance, and urine flow. No alteration in ANP kinetics occurred to account for the reportedly increased circulating concentrations of ANP seen in DS rats. We conclude that isolated DR and DS kidneys respond differently to ANP after bolus ANP administration to concentrations of 10, 000pg/ml. This difference in response is due to the sodium excretory defect inherent in the DS kidney and not to an alteration in the DS kidney's ANP responsiveness. (Hypertens Res 1995; 18: 219-225)

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We previously demonstrated that intra-arterial infusion of insulin attenuates vasoreactivity to phenylephrine and angiotensin II in the forearm of normotensive humans, which suggests that the pressor effects of insulin via sympathetic activation may be offset in peripheral arteries. In the present study, we investigated the effects of insulin on vasoreactivity in hypertensive humans. Seven male patients with essential hypertension (age, 26±2yr; blood pressure, 159±4/103±4mmHg; mean±SEM) were studied. We measured forearm blood flow by a strain gauge plethysmograph while infusing phenylephrine (1, 4, 12nmol/min) and angiotensin II (5, 10, 20pmol/min) locally into the brachial artery before and during simultaneous intra-arterial infusion of human insulin (0.15mU/kg/min). Forearm vascular resistance was calculated from directly measured arterial pressure and forearm blood flow. Intra-arterial infusion of insulin raised the local plasma insulin level without changing the blood glucose level, basal forearm blood flow, or forearm vascular resistance. Phenylephrine and angiotensin II increased forearm vascular resistance dose-dependently before and during insulin infusion. In contrast to the previous results in normotensive subjects, locally infused insulin did not attenuate vasoconstrictive responses to phenylephrine and angiotensin II in patients with essential hypertension. These results suggest that the balance between the pressor and depressor effects of insulin might be altered in favor of a pressor effect in patients with hypertension. (Hypertens Res 1995; 18: 227-233)

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Patients with mild to moderate essential hypertension were treated mainly with an ACE inhibitor (delapril, n=980) or a Ca antagonist (n=956) for 12 months, and the incidence of cerebrovascular and cardiovascular events as well as drug-related side effects were compared between the two groups. There were no significant differences between the clinical backgrounds of the two groups. In both groups, the blood pressure was decreased significantly from 1 month of treatment onwards, with the degree of reduction being greater in the Ca antagonist group throughout the study period (p<0.001). Cerebrovascular or cardiovascular events occurred in 11 out of 980 patients in the delapril group and 18 out of 956 patients in the Ca antagonist group (p=NS). Cerebrovascular disease developed in 5 delapril-treated patients and 11 Ca antagonist-treated patients, and heart disease developed in 5 and 7 patients, respectively (both p=NS). Discontinuation of treatment due to side effects was significantly more common in the delapril group than in the Ca antagonist group (p<0.001). There was no significant difference in the incidence of cerebrovascular and cardiovascular events between the two groups, and the results suggested that blood pressure reduction per se did not necessarily lead to a parallel decrease in cerebrovascular and cardiovascular complications. (Hypertens Res 1995; 18: 235-244)

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Interest in cardiovascular protection by calcium channel antagonists has grown over the past decade. We investigated the prevention of cardiac remodeling and renal injury by the long-acting calcium channel antagonist benidipine using 12 week-old Dahl salt-sensitive (Dahl S) rats fed a high-salt (4% NaCl) diet. Six-week benidipine treatment (10mg/kg chow) decreased systolic blood pressure by 22% in Dahl S rats. This blood pressure reduction was associated with decreases in cardiac mass and weight of the aortic wall. Collagen content in the left ventricle tended to decline with benidipine treatment. In addition, glomerular filtration rate increased by 33% and arterial and glomerular lesions improved morphologically with this treatment. Regression of cardiac mass and collagen content in the left ventricle was due mainly to blood pressure reduction; however, collagen content in the low-pressure right ventricle was not only related to systemic blood pressure but to the severity of renal lesions. These data suggest that the calcium channel antagonist benidipine attenuates cardiac and renal injury in hypertensive Dahl S rats, and that part of the cardiac hypertrophy is due to a non-hemodynamic mechanism that might be responsible for, or be a consequence of, the lesions in the kidney. (Hypertens Res 1995; 18: 245-253)

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We present a unique case of renovascular hypertension due to combined renal artery disease in a 22-year-old woman. Renal angiography revealed renal artery stenosis with poststenotic dilatation and an aneurysm due to fibromuscular dysplasia in the left kidney, and a congenital arteriovenous fistula in the right kidney. The results of a captopril test and plasma renin sampling demonstrated that the renin-angiotensin-aldosterone system was stimulated in both kidneys, accounting for the hypertension in this patient. Almost all cases of renovascular hypertension are due to only one underlying renal artery disease. This is the first case of renovascular hypertension associated not only with renal artery stenosis and an aneurysm due to fibromuscular dysplasia, but also with a congenital arteriovenous fistula. (Hypertens Res 1995; 18: 255-257)

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