The present study was designed to develop an animal model of multiple risk factors, including obesity, hypertension, non-insulin-dependent diabetes mellitus, and hyperlipidemia. Hypothalamic obesity was induced by neonatal monosodium glutamate (MSG) treatment in spontaneously hypertensive rats (SHR). Female newborn SHR were treated intraperitoneally with 2 or 4mg/kg body weight of MSG for 5 days. Obesity developed in SHR treated with 4mg/kg of MSG but not in SHR treated with 2mg/kg of MSG. Obese SHR had impaired glucose tolerance, hyperinsulinemia, and hypertriglyceridemia. However, the severity of hypertension was attenuated in obese SHR as compared with control SHR. The degree of obesity was closely related to the metabolic abnormalities, but inversely correlated with the blood pressure level. Macrovascular changes were investigated in obese SHR at 14 months of age. Intimal thickening was accelerated in the carotid artery of obese SHR as compared with that of nonobese SHR. Aortic contents of DNA and total cholesterol were significantly increased in obese SHR. SHR associated with MSG-induced obesity showed major manifestations of metabolic syndrome X. This animal model may be useful to study the clustering of risk factors for the development of macrovascular diseases. (Hypertens Res 1998; 21: 1-6)

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We have previously reported that C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, is produced in vascular endothelial cells and suggested that CNP might be a local regulator of vascular tone and growth. To evaluate the biological actions of CNP as compared with human atrial natriuretic peptide (hANP), we intravenously administered synthetic CNP (0.43nmol/kg) and α-hANP (0.43 and 0.043nmol/kg) to healthy humans. The experiments were done on different days in thesame five healthy volunteers (31±1 yr old). CNP injection caused a transient but significant decrease in both systolic and diastolic blood pressure (-4.3±1.3, -4.1±1.0mmHg) with a significant increase in heart rate (+7.6±2.6bpm), and exerted significant diuretic and natriuretic activities (+130±80%, +160±100% over the basal level). These effects of CNP (0.43nmol/kg) were comparable to, or less than, those of α-hANP (0.043nmol/kg). CNP injection also significantly suppressed aldosterone secretion (22% reduction as compared with the basal level). Our results demonstrate that intravenously-administered CNP acts as a natriuretic peptide with less potency than ANP. (Hypertens Res 1998; 21: 7-13)

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Responses of endocrine systems to acute and chronic salt loading were examined in normotensive and hypertensive subjects. In the acute salt load study, isotonic saline (20ml/kg for 1h) was intravenously infused in 10 normotensive subjects and 12 patients with essential hypertension. Plasma noradrenaline was suppressed by saline infusion in the normotensive subjects (-19%, p<0.05), but was not suppressed in the hypertensive patients (-5%, NS). Plasma brain natriuretic peptide concentration was significantly increased in the hypertensive patients (+15%, p<0.05), while it was unchanged in the normotensive subjects. In the chronic salt load study, 9 normotensive subjects and 30 patients with essential hypertension underwent two 7-d periods of 30 and 260mmol/d sodium intake. On the basis of the blood pressure change, 17 hypertensive patients were classified as salt-resistant and 13 as salt-sensitive. The salt-sensitive hypertensive patients had suppressed plasma renin activity even during low-salt intake. During high salt intake, the plasma noradrenaline concentration failed to decrease in the salt-sensitive hypertensive patients (-6%, NS), whereas it fell significantly in the normotensive subjects (-27%, p< 0.05) and the salt-resistant hypertensive patients (-33%, p<0.01). The high-salt intake also increased plasma concentrations of brain natriuretic peptide as well as atrial natriuretic peptide in all groups. In the salt-sensitive hypertensive patients, there was a positive correlation between the increase in blood pressure and that in atrial natriuretic peptide (r=0.84, p<0.01). These data indicate that brain natriuretic peptide is involved in chronic changes in body fluid volume. In patients with essential hypertension, acute volume expansion also evokes the response of brain natriuretic peptide. Salt-sensitive hypertension seems to be characterized by blunted response of the sympathetic nervous system. In addition, an increase in atrial natriuretic peptide is likely to play an important role in mechanisms counteracting salt-induced elevation of blood pressure. (Hypertens Res 1998; 21: 15-22)

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Adrenomedullin (AM) is a peptide with potent vasodilatory and hypotensive properties. Plasma AM levels in rats with experimentally induced hypertension, such as Dahl salt-sensitive rats and two-kidney, one-clip hypertensive rats, are higher than those in normotensive rats. We previously noted, however, that plasma AM levels in spontaneously hypertensive rats (SHR) are similar to those in Wistar-Kyoto rats. To define the role of AM in rats with severe hypertension, we investigated changes in circulating and tissue AM levels in stroke-prone spontaneously hypertensive rats (SHRSP/Izm). The immunoreactive rat AM levels in plasma, urine, and tissue measured with a sensitive radioimmunoassay, and the AM mRNA levels in various tissues in 15-wk-old SHRSP/Izm were compared with those in age-matched Wistar-Kyoto rats (WKY/Izm). The plasma and urinary AM levels in SHRSP/Izm were significantly lower than those in WKY/Izm [plasma AM, 2.14±0.06 (SE) vs. 3.24±0.16fmol/ml, p<0.001; urinary AM, 16.36+3.21 vs. 36.12±6.09fmol/ml, p<0.01]. A negative correlation was found between the plasma AM level and the systolic blood pressure in both SHRSP/Izm and WKY/Izm. Reverse-phase high-performance liquid chromatography showed that the molecular components of plasma immunoreactive AM in SHRSP/Izm were similar to those in WKY/Izm. Furthermore, tissue AM levels in various organs in SHRSP/Izm were not lower than those in WKY/Izm. In conclusion, low levels of circulating AM may contribute to the maintenance of high blood pressure in 15-wk-old SHRSP/Izm. These low plasma AM levels may be caused by accelerated metabolism of circulating AM in SHRSP/Izm. (Hypertens Res 1998; 21: 23-28)

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Recently, a molecular variant of α-adducin (with tryptophan instead of glycine at amino acid number 460) has been reported to be more common among Italian and French hypertensive individuals than among controls. Moreover, hypertensive individuals with Trp460 exhibit a greater sensitivity to changes in sodium balance and a greater fall in blood pressure in response to diuretic treatment. In the present study, we investigated the association between Gly46OTrp polymorphism of the α-adducin gene and hypertension in Japanese subjects. The study population comprised 283 subjects enrolled at our outpatient clinic. The subjects were divided into normotensive (NT), borderline (B), and hypertensive (HT) groups. The α-adducin genotype was determined by allele-specific oligonucleotide hybridization. The genotype frequency of Gly46OTrp polymorphism differed significantly among the NT, B, and HT groups (p=0.0113). The GG genotype of the adducin gene was more common in the NT group than in the HT group. Moreover, the Trp460 allele was significantly associated with lower plasma renin activity (p= 0.0075). However, this polymorphism was unrelated to left ventricular mass and height as assessed by echocardiography. The present study suggests that Gly46OTrp polymorphism of the α-adducin gene may be involved in hypertension, particularly the low-renin type, in Japanese individuals. (Hypertens Res 1998; 21: 29-32)

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Studies using the whole-cell voltage-clamp technique have demonstrated that L-type Ca²⁺ channel activity is increased in vascular smooth. muscle cells from spontaneously hypertensive rats (SHR). We recorded L-type Ca²⁺ channel currents in cultured mesenteric artery smooth muscle cells from SHR and Wistar Kyoto (WKY) rats by using the cell-attached patch-clamp technique. Depolarizing voltage steps from a holding potential of -40mV elicited voltage-dependent inward Ba²⁺ currents. There was no difference in the L-type Ca²⁺ channel I-V curve or in the open probability between SHR and WKY. The inward currents were inhibited by the Ca²⁺ antagonists nifedipine and verapamil, but were enhanced by the Ca²⁺ agonist Bay K 8644 in a concentration-dependent manner. The Bay K 8644-induced increase and the nifedipine-induced inhibition of the inward currents were enhanced in SHR, whereas there was no difference in the verapamil-induced inhibition of the currents between the two strains of rats. These results suggest that the enhanced L-type Ca²⁺ channel activity observed in vascular smooth muscle cells from SHR is not due to altered function of a single L-type Ca²⁺ channel. It appears that the sensitivity of dihydropyridine receptors in the channels is enhan ced in SHR. (Hypertens Res 1998; 21: 33-37)

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Tsukuba hypertensive mice (THMs) are transgenic mice carrying human renin and angiotensinogen genes. The aim of this study was to evaluate the role of the renin-angiotensin system (RAS) in cardiac hypertrophy and renal disorders in THMs. After a 2-wk control period, 10-wk-old THMs were treated with lisinopril (ACEI group) or hydralazine (hydralazine group) or left untreated (control group) for 8 wk. C57BL/6 mice of similar age (wild group) were used as normal controls. Systolic blood pressure and urinary albumin excretion were measured once a week. All mice were sacrificed at 20 wk of age, and heart to body weight ratio, cardiac myocyte diameter, renal glomerular sclerosis index, and glomerular size were measured. Fibronectin expression was also evaluated. At 20 wk of age, systolic blood pressure and urinary albumin excretion in the control group were significantly higher than those in the wild group and significantly lower than those in the ACEI and hydralazine groups. Heart to body weight ratio and cardiac myocyte diameter were significantly higher in the hydralazine and control groups than in the other groups. Renal glomerular sclerosis index and glomerular size were also significantly higher in the control group than in the other groups, and there were significant differences between the ACEI and hydralazine groups in these variables. Fibronectin expression was marked in the control and hydralazine groups. These findings suggest that the RAS plays an important role in cardiac hypertrophy in THMs, but that both the RAS and elevation of blood pressure contribute to the pathogenesis of renal glomerular sclerosis. (Hypertens Res 1998; 21: 39-46)

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Ouabain has been isolated as an endogenous pathogenetic factor in salt-induced hypertension and has been shown to be rich in the adrenals. In this study, organ accumulation of orally administered [³H]- ouabain was examined in rats. Exogenous [³H]ouabain was accumulated in high levels in the adrenals, especially in the zona intermedia, and was not metabolized in the rat. Accumulated [³H]ouabain mimicked the movement of "endogenous" digitalis-like factor, since 1) the plasma [³H]ouabain level decreased in bilaterally adrenalectomized rats, 2) the plasma [³H]ouabain level increased accompanied by a decrease in [³H]ouabain content in the adrenals in reduced renal mass hypertensive rats, and 3) [³H]- ouabain levels in plasma and in the adrenals increased in spontaneously hypertensive rats, as compared with those in respective control animals. Moreover, the rat diet contained a relatively high amount of ouabain-like immunoreactivity (OLI), and the ratio of the [³H]ouabain content to OLI in each organ was comparable to that of the daily intake of dietary [³H]ouabain to OLI. Furthermore, high ³H-radioactivities were also observed in the adrenals of rats that ingested [³H]digoxin and [3H]digitoxin. These data suggest that exogenous ouabain, related cardiotonic glycosides of plant origin, or both accumulate in the adrenals and, at least in part, act as "endogenous" digitalis-like factor(s). (Hypertens Res 1998; 21: 47-56).

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To clarify the association of insulin resistance and hyperinsulinemia with lipid metabolism in patients with essential hypertension (EHT), we used the euglycemic hyperinsulinemic glucose clamp technique (GC) and the 75-g oral glucose tolerance test (OGTT) to compare the characteristics of glucose and lipid metabolism in insulin-resistant patients with essential hypertension (EHT-R) with those in insulin-nonresistant patients with essential hypertension (EHT-N) and normotensive subjects (NT). Twenty-eight NT and 42 EHT whose body mass index (BMI) was less than 28kg/m² were studied to eliminate the effects of obesity on insulin sensitivity and lipid metabolism. Insulin sensitivity was evaluated by GC and expressed as metabolic clearance rate of glucose (M value, mg/m²/min). Mean -1SD of the M value in NT (145.0mg/m²/min) was chosen as the cutoff point for insulin resistance. On the basis of this value, 33.3% of the EHT were EHT-R. There was no significant difference in age or BMI among the three groups. Blood samples were collected before GC to measure levels of total cholesterol (TC), triglyceride (TG), free fatty acid (FFA), and HDL cholesterol (HDL-C). EHT-R had significantly higher levels of fasting blood sugar, fasting immunoreactive insulin, insulin at 120min (IRI-120), and summation of insulin or blood sugar (BS) during the OGTT, as compared with NT and EHT-N. EHT-R also had significantly higher FFA and TG than the other two groups, while there was no difference in FFA or TG between EHT-N and NT. TC and HDL-C were similar in the three groups. There was either a significant negative correlation, or a trend toward negative correlation, between M value and FFA (r=-0.50, p<0.05) or TG (r=-0.24, p<0.1). There were significant positive correlations between IRI-120 and FFA (r=0.35, p<0.05) or TG (r=0.29, p<0.05). There was a positive correlation (r=-0.36, p<0.01) between ∑BS and FFA, while no other significant relation was found between ∑BS and serum lipids. In summary, (i) 33.3% of EHT were found to be insulin resistant, when insulin resistance was defined as M value <145.0mg/m²/min, i.e., mean -1SD of the M value of NT; (ii) these EHT-R had higher levels of BS, insulin, FFA, and TG than did NT and EHT-N; (iii) EHT-N showed no difference in the levels of BS, insulin, or lipid, as compared with NT; and (iv) the levels of FFA and of TG correlated negatively with insulin sensitivity and positively with the insulin level during the OGTT. These results suggest that disturbances of glucose and lipid metabolism in EHT may be related to both insulin resistance and compensatory hyperinsulinemia, and that EHT-R may have more risk factors for arteriosclerotic complications than EHT-N. (Hypertens Res 1998; 21: 57-62)

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