Substantial, but still circumstantial evidence, supports strongly a role for a circulating digitalis-like factor in the pathogenesis of salt-sensitive hypertension. Although supported by many lines of evidence, this intriguing concept remains controversial, in large part because the responsible factor has proven to be very elusive. A very large number of candidates from a wide range of chemical classes have been proposed. Indeed, the large number of candidates, none supported by absolutely definitive evidence, has contributed to the controversy. In this essay, we have attempted to define the information that will be required before a candidate becomes widely accepted. Because the current situation resembles so strikingly the situation late in the nineteenth century- when efforts focused on the attempt to identify a specific micro-organism as the agent responsible for specific disease- we employed Koch's postulates as the organizing principle. The challenge faced by Robert Koch over a century ago is identical to the challenge that we face today. (Hypertens Res 1995; 18: 1-6)

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The renin-angiotensin system (RAS) plays a key role in the regulation of the circulation and is critically involved in the pathogenesis of several diseases, including hypertension. Renin is synthesized mainly in the kidney and is secreted into the bloodstream. It catalyzes the rate-limiting cleavage of substrate angiotensinogen, which is derived mainly from the liver, to generate angiotensin I. Renin and angiotensinogen genes have been isolated and their structure has been determined by the methods of molecular biology. Renin and angiotensinogen genes are expressed in many tissues, and the tissue-specific regulation of these genes has been studied. The existence of local RASs in contrast to the classical circulating RAS has been suggested, although their exact functional role remains to be determined. Recent molecular analyses have led to a detailed description of the transcriptional mechanism of the renin and angiotensinogen genes, and have made it possible to study the regulation of the expression of these genes in several physiological and pathological states. In addition, several types of transgenic animals have been developed to study the functional importance of the RAS in vivo.Transgenic mice with human renin and human angiotensinogen genes may be a good model of human hypertension. In such mice, the human genes are expressed in the normal tissue-specific pattern, the circulating RAS is activated, and blood pressure is high. Finally, angiotensinogen-deficient mice have also been developed by homologous recombination in mouse embryonic stem cells. These mice do not produce angiotensinogen in the liver. As a result, they have no plasma immunoreactive angiotensin I and are hypotensive. The profound hypotension in these mice indicates the importance of the RAS in maintaining blood pressure. (Hypertens Res 1995; 18: 7-18)

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We studied vasodilatator innervation in canine cerebral arteries and analyzed mechanisms of neurally induced vasodilatation. Available pharmacological, biochemical and histological evidence supports the hypothesis that nitric oxide (NO) synthesized in nerve terminals acts as a neurotransmitter that activates soluble guanylate cyclase in vascular smooth muscle and increases the production of cyclic GMP, resulting in relaxation. Peripheral arteries, such as the mesenteric, temporal, saphenous, uterine, and retinal, arteries, respond to nerve stimulation with contractions that are reversed to relaxations by α-adrenoceptor blockade. The relaxation is also mediated by NO derived from perivascular nerves. Thus, reciprocal regulation by NO-mediated (nitroxidergic) and adrenergic nerves is speculated. Potentiation by NO synthase inhibitors of the arterial contraction associated with adrenergic nerve stimulation in vitro is ascribed to depressed vasodilator nerve function. Systemic blood pressure in anesthetized dogs is increased by intravenous injections of NO synthase inhibitors. Our evidence strongly suggests that the pressor response is associated with suppressed synthesis and release of NO derived mainly from vasodilator nerves. It is concluded that nitroxidergic vasodilator nerves play important roles in the regulation of vascular tone in vitro and in vivo and in the control of systemic blood pressure. Presented here are new concepts for the mechanism of hypertension and the role played by NO-mediated nerve function. (Hypertens Res 1995; 18: 19-26)

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This study evaluated the long-term effects of percutaneous transluminal renal angioplasty (PTRA) on blood pressure and renal function in patients with renovascular hypertension. Seventy-eight patients with hypertension and unilateral or bilateral stenoses of the renal arteries (16 with fibromuscular dysplasia and 62 with atherosclerosis) were studied. All patients with fibromuscular dysplasia (group A) had normal renal function, while 27 of the 62 patients with atherosclerosis (group B) presented with various degrees of renal failure. PTRA was technically successful in 87.5% patients of group A. The overall technical success rate (complete plus partial) was 72.3% (55/76 renal arteries) in group B. Mean follow-up (range) in months was 42 (12-108) for group A and 39 (13-106) for group B. After successful PTRA, the overall benefit rate (cure plus improved) for hypertension was 100% in group A; 10 of 14 patients were cured and 4 of 14 were improved. In group B, the overall benefit rate was 70.8%; 9 of 48 were cured and 25 of 48 were improved. PTRA was technically successful in 18 of 27 patients with renal failure. Renal function improved in 4 of 18 patients, remained stable in 9 of 18, and deteriorated in 5 of 18 patients. The above results suggest that PTRA is an effective method for the long-term management of patients with renovascular hypertension, although the results were less favorable in the presence of bilateral renal artery stenoses: in addition to improved control of blood pressure, PTRA might improve renal function or delay its progressive deterioration. (Hypertens Res 1995; 18: 27-31)

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We previously proposed the "kinin-tensin system, " a unique vasoregulatory system that can produce both angiotensin II and kinins. To verify whether tissue kallikrein is a part of this system in humans, we examined the ability of human urinary kallikrein (HUK) to generate angiotensin (ANG) II directly from homologous renin substrates such as purified human angiotensinogen (AOGEN) and authentic human tridecapeptide renin substrate (13RS). HUK released ANG II not only from ANG I but also directly from both AOGEN and 13RS at an optimum pH of 7.0. The amount of generated ANG II from 7.5 nmol of each of the three substrates at pH 7.0 was as follows: ANG I, 292.7±67.2; 13RS, 1951.7± 239.6; AOGEN, 2.2±0.3 (pmol/3h, n=3 mean±SE). HUK cleaved Phe-His and His-Leu bonds in 13 RS, and Tyr-Ile and Phe-His bonds in ANG I. These results suggest that HUK is a part of the "kinin-tensin system", i.e., HUK can not only release kinins, but can also generate ANG II mainly through ANG I conversion and from AOGEN, the latter being a minor source of ANG II. Furthermore, HUK may play a role in regulating vascular tone under certain conditions in vivo. (Hypertens Res 1995; 18: 33-37)

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The present study was designed to determine whether magnesium (Mg) deficiency is present in patients with essential hypertension. We measured the retention of an intravenously administered Mg load (0.2 mmol/kg MgSO₄ over 4h), and serum and erythrocyte Mg concentrations in 17 inpatients with essential hypertension and in 15 normotensive controls. There was no significant difference between the two groups in erythrocyte Mg concentration (normotensives vs., hypertensives: 2.0±0.5 vs. 2.1±0.4 mmol/l cells), serum Mg concentration (normotensives vs. hypertensives: 2.1±0.2 vs. 2.1±0.2mg/dl), or in urinary Mg excretion (normotensives vs. hypertensives: 65.8±25.5 vs. 73.7±26.7mg/day). However, Mg retention was significantly higher in hypertensives than in normotensives (normotensives vs. hypertensives: 31.8±12.1 vs. 41.9±13.3%). These results suggest that a systemic Mg deficiency, which is undetectable by serum or erythrocyte Mg determination, may exist in patients with essential hypertension. (Hypertens Res 1995; 18: 39-42)

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To study the relationship between blood volume and the plasma level of endothelin-1 (ET-1), we examined the effects of blood volume depletion and expansion on the plasma ET-1 level in the rat. Anesthetized Wistar rats were subjected to hemorrhage (7ml/kg), blood transfusion (7ml/kg), or sham treatment. The same blood volume depletion and expansion were performed in other groups of rats, after bilateral cervical vagotomy or administration of intravenous atropine, to examine the role of the cardiopulmonary baroreflex. Hemorrhage produced mild decreases in the central venous pressure and arterial blood pressure, and an increase in the heart rate. Blood transfusion caused the opposite responses. The plasma ET-1 level was significantly higher in the volume-depleted rats (4.7±0.4pg/ml, mean±SE, p<0.05 vs. control), and was lower in the volume-expanded rats (2.6±0.2pg/ml, p<0.05) than in the control group (3.5±0.3pg/ml). In the vagotomized rats, the blood volume depletion decreased and the volume expansion increased the central venous pressure and the arterial pressure, but they did not change the heart rate or the plasma ET-1 level. Vagal efferent inhibition with atropine did not affect the volume-induced changes in the plasma ET-1 level. These results indicate that the plasma level of ET-1 increases with blood volume depletion, and decreases with volume expansion. The cardiopulmonary baroreflex may play an important role in the regulation of plasma ET-1 levels when the blood volume is altered. (Hypertens Res 1995; 18: 43-46)

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Twelve adults (age 32-61 years) with essential hypertension were recruited from the outpatient clinics of National Defense Medical College hospital to serve as subjects in the present study. They were treated with nilvadipine, a Ca-antagonist, 4mg b.i.d. for 4 weeks. LDL samples were isolated by ultracentrifugation at the beginning (week 0) and at the end (week 4) of the treatment regimen. The formation of conjugated dienes was measured by incubating 100μg of LDL protein with 2μmol CuSO₄ in 2ml phosphate buffered saline (PBS). There were no significant differences between lipids levels, composition and anti-oxidant levels of LDL at weeks 0 and 4. The lag time of LDL oxidation was 71.1±11.3min at week 0 and 81.3±13.2min at week 4 (p<0.05). In vitro studies of LDL oxidation, evaluated by thiobarbituric acid reactive substances (TBARS) and by agarose electrophoretic mobility, indicated that nilvadipine inhibited the oxidative modification of LDL while amlodipine, used as control, did not. Nilvadipine, a lipophilic Ca-antagonist, significantly prolonged the lag time of conjugated diene formation of LDL by 12.6% but amlodipine, a hydrophilic Ca-antagonist, had no major effect on LDL oxidation. These results suggest that Ca-antagonists are effective for the prevention of atherosclerosis but the effect is dependent upon the lipophilicity of the drugs. (Hypertens Res 1995; 18: 47-53)

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Nitric oxide plays an important role in the regulation of arterial pressure by its actions to dilate vascular smooth muscle, alter sympathetic neural activity, and modulate the vasoconstrictor action of norepinephrine, angiotensin II and vasopressin. Nitric oxide may also influence blood pressure regulation by altering the secretion of renin and vasopressin. To test this possibility, we investigated the effects of inhibiting nitric oxide synthesis on the cardiovascular, renin and vasopressin responses to hypotensive hemorrhage, a situation in which the renin-angiotensin system and vasopressin contribute significantly to the control of blood pressure. Arterial blood was withdrawn from conscious, chronically-prepared rabbits at 1.0ml/kg/min for 15min under control conditions, and during i.v, infusion of the nitric oxide synthase inhibitor L-NAME. Hemorrhage decreased mean arterial pressure from 69±2 to 45±4mm Hg (p<0.01) and increased heart rate from 211±10 to 270±15bpm (p<0.05). Plasma renin activity increased from 7.7±1 to 36.1±9.6ng/ml/2h at 15min (p<0.01), while plasma vasopressin concentration increased from 1.7±0.6 to 183.2±98.5pg/ml (p<0.05). Infusion of L-NAME increased blood pressure and plasma vasopressin concentration, and decreased heart rate and plasma renin activity. L-NAME markedly attenuated the hypotensive response to hemorrhage (72±3 to 62±4mmHg), but did not alter the increases in heart rate, plasma renin activity or plasma vasopressin concentration. In separate experiments, L-NAME did not alter the setpoint or gain of the baroreceptor reflex control of heart rate. These results demonstrate that inhibition of nitric oxide synthesis significantly improves blood pressure regulation during hemorrhage, but indicate that this improvement is not associated with alterations in the heart rate, renin or vasopressin responses to hemorrhage. (Hypertens Res 1995; 18: 55-61)

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To detect genetic predisposing factors for hypertension, we screened the genome of the spontaneously hypertensive rat (SHR). We determined the genotypes of all F₂ rats at polymorphic sites between the two strains, using the DNA of F₂ rats derived from mating of SHR and Wistar-Kyoto rats (WKY). Cosegregation analysis was conducted to assess whether the genotypes of polymorphic markers associate with any phenotypic parameters such as directly measured blood pressure, heart rate or body weight. All measurements in F₂ rats were performed at 15 weeks of age. Two polymorphic markers on chromosome 18 cosegregated with body weight. Gap junction protein (heart connexin 43) gene showed the most significant association with body weight as a recessive trait, but no association was noted with other parameters. We conclude that the gap junction protein locus is a new candidate for the determinant gene of body weight in SHR. (Hypertens Res 1995; 18: 63-67)

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The effects of TCV-116, a new non-peptide angiotensin II receptor antagonist, on systemic and renal hemodynamics were studied in conscious normotensive and renal hypertensive (2-kidney, 1-clip Goldblatt type) dogs. When orally administered at 0.03 to 1.0mg/kg, TCV-116 inhibited the pressor response to angiotensin II in conscious normotensive dogs in a dose-dependent fashion. The IC₅₀ and IC₁₀₀ values were 0.06mg/kg and 0.86mg/kg, respectively. TCV-116 at doses of 0.3mg/kg and 1.0mg/kg dose-dependently and persistently decreased systolic and diastolic blood pressure in both dogs with acute renal (hyperreninemic) and those with chronic renal (normoreninemic) hypertension. Even a high dose of TCV-116 (10mg/kg, p.o.) increased effective renal plasma flow without affecting blood pressure or glomerular filtration rate in normotensive dogs. Furthermore, even at this high dose, TCV-116 did not reduce effective renal plasma flow or glomerular filtration rate in dogs with renal hypertension despite marked reduction in systemic blood pressure. The angiotensin converting enzyme inhibitor enalapril (10 mg/kg, p.o.) had renal hemodynamic effects similar to those of TCV-116. These findings indicate that TCV-116 has potent hypotensive effects not only in dogs with acute renal hypertension but also in those with chronic renal hypertension, but does not appear to adversely affect renal hemodynamics. (Hypertens Res 1995; 18: 69-75)

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To investigate the influence of the patient-hospital relationship on the quality of life (QOL) and on medication compliance in elderly patients with hypertension, we developed a comprehensive scale for assessing the patient-hospital relationship. In the first phase, an original questionnaire consisting of 40 items was designed under five fields for global assessment of the concept. We administered this questionnaire to 715 patients with cardiovascular diseases. Variations in the scores were evaluated by factor analysis. Three factors that comprised the majority of variance were derived by principal components analysis and varimax transformation. These orthogonal factors were considered to reflect "convenience of outpatient clinic", "satisfaction with clinical staff", and "communication with physician". We adopted three items under each of the three domains. Using this instrument, we assessed the patient-hospital relationship in 402 elderly outpatients with hypertension at 8 clinical centers. QOL and medication compliance were simultaneously assessed. A linear regression analysis revealed a significant positive correlation between patient-hospital relationship and QOL scores (r=0.403, p<0.0001), which means that patient-hospital relationship explained up to 16% of the total variability in scores on the Overall Quality of Life scale. The medication compliance was also better in patients with higher scores on the Patient-Hospital Relationship scale. These results indicate that the patient-hospital relationship is one of the substantial factors determining QOL and medication compliance in elderly patients with hypertension. (Hypertens Res 1995; 18: 77-83)

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