Genomic research that is part of current DNA sequencing projects is having a great impact in many fields of study. With the discovery of sequence information for human and mouse genomes, an explosion of genetical and functional data will be revolutionizing mechanistic studies of hypertension syndrome. Assuming the availability of genome sequences, the challenge includes identifying genes, predicting the proteins they encode, determining when and where genes are expressed and how they interact, and learning how these expression and interaction profiles change in response to environmental ignals. As the hypertension research community enters the post-genome era, the study of gene expression patterns and phenotypes in model animals will be a part of analyzing the role of genes involved in the pathogenesis of hypertension. The molecular dissection of hypertension genetics is a complex multidisciplinary challenge and a medical imperative. The understanding of complex disorders such as hypertension has advanced considerably through the use of genetically engineered mice. Studies of hypertension using transgenic and knockout mice have uncovered multiple potential functions of the regulatory systems controlling blood pressure. In this review, I discuss the molecular basis of the hierarchy and network of genomic expression cascades of hypertension by focusing on the functional significance of the renin-angiotensin system. (Hypertens Res 2000; 23: 545-552)

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Large 24-h blood pressure (BP) variability and an excessive drop in BP during nighttime are associated with a higher risk of cardiovascular events. Data are lacking regarding the prognostic significance of variability in BP measured during office visits. We analyzed the relationship between office BP variability and the risk of brain infarction in elderly patients receiving antihypertensive therapy. Patients who experienced their first-ever stroke at the age of 60 years or over were registered in the study. At least 2 sex- and age-matched control patients were registered for each case patient. Office BP at each clinic visit and known cardiovascular risk factors were recorded. The BP variability was defined as the variation coefficient (VC) of office BP. In this report, we analyze the data of brain infarction patients. The VC of both systolic and diastolic BPs was significantly higher in the brain infarction patients than in the control patients. Higher office BP variability was associated with a higher risk of brain infarction after adjustment for BP level and other confounding factors. Regarding diastolic BP, the association of brain infarction with the maximal value for the difference of office BPs taken at any consecutive two visits (Max-ΔBP) or the difference between the highest and lowest values of office BP (BP-range) recorded during a 1-year period prior to the event was also significant. In conclusion, a retrospective case-control study suggested that office BP variability was an independent predictor of brain infarction. Either the Max-ΔBP or the BP-range may be surrogate indices of diastolic BP variability. (Hypertens Res 2000; 23: 553-560)

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Accumulating evidence strongly suggests that an alteration in nitric oxide metabolism is involved in the pathogenesis of hypertension. We recently found 2 polymorphisms in the endothelial nitric oxide synthase (eNOS) gene, a Glu298Asp missense variant in exon 7 and a T^-786→C variant in the 5′-flanking region, which are not linked to each other. In our previous reports, we showed a positive association between the Glu298Asp variant and essential hypertension, myocardial infarction, and coronary spastic angina. We also revealed that the T^-786→C variant is strongly associated with coronary spastic angina and leads to the reduction of the eNOS gene promoter activity. To further investigate the genetic involvement of the eNOS gene in essential hypertension, we examined the frequency of T^-786→C variant in two independent populations of persons with essential hypertension in Kyoto (n=215) and Kumamoto (n=186) and compared the frequency with that in each age- and gender-matched control (233 controls in Kyoto and 223 controls in Kumamoto). In both groups, the frequency of T^-786→C variant was similar in patients with hypertension and normal controls. In conclusion, the T^-786→C variant was not positively associated with essential hypertension. Given the evidence of positive association of another polymorphism in the eNOS gene, the Glu298Asp polymorphism, with essential hypertension, special attention will be required to interpret the results of a case-control study for genetic risk factors. (Hypertens Res 2000; 23: 561-565)

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To evaluate the effect of antihypertensive therapy on platelet activation in essential hypertension, the plasma levels of β-thromboglobulin (β-TG) were examined in 45 patients with essential hypertension and 20 age-matched normotensive control subjects. Hypertensive patients were assigned to monotherapy with one of five different antihypertensive drugs for 6 months, and the change of plasma levels of β-TG was reexamined after the completion of the monotherapy. The plasma β-TG increased in hypertensive patients ompared with levels in normotensive control subjects. Monotherapy with each drug resulted in sufficient blood pressure control in all hypertensive patients. The plasma β-TG decreased significantly after monotherapy with an α-blocker or an angiotensin-converting enzyme inhibitor (ACEI). The plasma β-TG increased with the use of a diuretic but did not change with the use of a β-blocker or calcium antagonist. The platelet activation observed in patients with essential hypertension is reversed by monotherapy with an α-blocker or an ACEI. It is possible that these drugs reduce the development of hypertensive vascular complications due to suppression of platelet activation in patients with essential hypertension. (Hypertens Res 2000; 23: 567-572)

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We investigated the effects of walking 10, 000 steps/day or more on blood pressure and cardiac autonomic nerve activity in mild essential hypertensive patients. All subjects were males aged 47.0±1.0 (mean±SEM) years old. The original cohort consisted of 730 people in a manufacturing industry who measured the number of steps they walked each day using a pedometer. Eighty-three of these subjects walked 10, 000 steps/day or more for 12 weeks. Thirty-two of these were hypertensives with systolic blood pressure (SBP) greater than 140mmHg and/or diastolic blood pressure (DBP) greater than 90mmHg. Thirty of these hypertensive subjects (HT) were examined twice, once during the pre- and once during the post-study period, for body mass index (BMI), maximal oxygen intake (V_O2max), blood pressure, heart rate (HR), and autonomic nerve activity by power spectral analysis of SBP and HR variability. In the HT group, walking 13, 510±837 steps/day for 12 weeks lowered blood pressure (from 149.3±2.7/98.5±1.4 to 139.1±2.9/90.1± 1.9mmHg; p<0.01, respectively). In both the 34 normotensive controls and 17 hypertensive sedentary controls, blood pressure did not change. Walking also significantly lowered low-frequency fluctuations in SBP as an index of sympathetic nerve activity, from 1.324±0.192 to 0.738±0.154 mmHg²/Hz (p<0.05). VO₂max rose significantly from 26.1±2.4 to 29.5±2.5ml/kg/min (p<0.05). There were no changes in parasympathetic nerve activity, baroreceptor reflex sensitivity, or BMI. Our results indicate that walking 10, 000 steps/days or more, irrespective of exercise intensity or duration, is effective in lowering blood pressure, increasing exercise capacity, and reducing sympathetic nerve activity in hypertensive patients. (Hypertens Res 2000; 23: 573-580)

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Hypotension is a major cardiovascular complication of hemodialysis, and enhanced production of nitric oxide (NO) may be involved in hemodialysis hypotension. Human hepatocyte growth factor (hHGF), which induces endothelial proliferation, causes NO-mediated hypotension in animals. Because heparin, which is routinely used during hemodialysis, increases circulating hHGF concentration in humans, circulating hHGF may be involved in hemodialysis hypotension via increased NO production. To investigate the involvement of hHGF in NO production and hypotension in hemodialysis patients, we measured concentrations of serum hHGF and plasma NO₃^-, an index of endogenous NO production, in 114 patients undergoing maintenance hemodialysis. The mean serum hHGF concentration before dialysis was greater (p< 0.01) in subjects with lower blood pressure (BP) (mean BP before dialysis ≤75mmHg, n=16, 0.251±0.050 ng/ml) than in those with middle BP (mean BP before dialysis 76 to 109mmHg, n=75, 0.143±0.016ng/ml) or higher BP (mean BP before dialysis ≤110mmHg, n=23, 0.088±0.017ng/ml). The mean serum hHGF concentration after dialysis was higher in subjects with lower BP (1.854±0.242ng/ml) than in those with middle BP (1.280±0.120ng/ml) or higher BP (0.688±0.130ng/ml). Serum hHGF concentration was positively correlated with plasma NO₃^- concentration (r=0.608, p=0.0001, n=114). Circulating hHGF may participate in the mechanism of chronic hemodialysis hypotension by affecting endogenous NO production. (Hypertens Res 2000; 23: 581-586)

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To determine the factors that affect seasonal variation in blood pressure (BP) in a fairly large number of patients with essential hypertension who stayed almost entirely indoors in a stable environmental temperature and who took a calcium channel blocker during the study. This prospective study of hypertensive patients was conducted during the summer and winter. BP was measured by ambulatory blood pressure monitoring; the indoor temperature was measured at the time of the BP measurement using an electrothermometer with the subject awake and indoors. Subjects comprised 38 men and 57 women. The subjects spent virtually the entire day indoors during both the summer (men, 22.1±1.6h; women, 23.0±0.9h) and winter (men, 23.0±0.9h; women, 22.9±0.9h). During the waking hours, the systolic/diastolic BPs were significantly higher during the winter than the summer. The differences were 8±9/4±5mmHg in men and 5±11/2±6mmHg in women; these values were not significantly different between men and women. No significant seasonal differences in BP during the sleeping hours were noted. There was a significant difference of approximately 6°C in the environmental temperature during waking hours, but there was no significant difference in urinary excretion of sodium or in exercise activity between the seasons. Only body height was significantly correlated with the winter increase in waking BP in both men and women, even after adjustment for potential confounding variables. Body height was a determinant of the increase in waking BP during the winter in hypertensive patients who lived almost entirely indoors. (Hypertens Res 2000; 23: 587-592)

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Many investigators have reported that angiotensin-converting enzyme (ACE) inhibitors have antiproteinuric effects and retard the progression of renal impairment in diabetic patients. On the other hand, those effects of ACE inhibitors have not been well established in patients with essential hypertension. This study was conducted to prospectively evaluate whether an ACE inhibitor, temocapril, could modify the urinary microalbumin excretion rate (UAE) in hypertensive outpatients who had no signs of renal impairment. To compare the long-term effect of temocapril with that of a diuretic on UAE, hypertensive patients treated with a diuretic (trichlormethiazide) were enrolled in a prospective study if they had normal serum creatinine levels and no overt proteinuria during a 3-month screening period. A urinary microalbumin-to-urinary-creatinine ratio (mg albumin/mmol Cr) was used as an estimate of UAE. Patients visited the hospital monthly to determine blood pressure (BP) and UAE. After baseline observation during the treatment with the diuretic, the subjects were randomly divided into two groups. In group A, the diuretic was switched to temocapril, 2 to 4mg once daily for 12months. In group B, the subjects continued to receive the diuretic for an additional 12months. Seventy-six outpatients (41 men and 35 women; mean age, 59.0±1.4 years) with essential hypertension entered the study. The effects of temocapril on BP appeared to be clinically similar to those of the trichlormethiazide, but the use of temocapril significantly decreased UAE. In group A (n=37), UAE decreased significantly (p<0.01) from the baseline value of 4.19±0.37mg albumin/mmol Cr to 2.47±0.29 and 2.68±0.28mg albumin/mmol Cr at the 6th and 12th month of temocapril therapy, respectively. In contrast, in group B (n=39) UAE was unchanged (baseline, 4.16±0.63mg albumin/mmol Cr; 6 months, 4.92±0.72; 12 months, 4.71±0.74). These results indicate that long-term therapy with temocapril may be superior in reducing UAE than is diuretic therapy in patients with essential hypertension who had no signs of renal impairment. (Hypertens Res 2000; 23: 593-600)

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Patients with type 2 diabetes mellitus and hypertension are thought to be at high risk for cardiovascular diseases. Recent guidelines for treatment of hypertension such as the JNC VI and WHO/ISH guidelines, recommend that antihypertensive agents be strated at as low as at 130/85mmHg and that blood pressure be lowered to less than 130/85mmHg. Our study was designed to clarify how well and to what extent blood pressure (BP) was controlled in Japanese hypertensive patients with or without type 2 diabetes mellitus. We interviewed two hundred physicians, randomly sellected from among the members of the Japanese Society of Hypertension (JSH) (n=98) and the Japanese Diabetes Society (JDS) (n=102) and obtained information regarding five most recent cases of hypertension with (n=954 in total) and their 2 most recent cases of hypertension without diabetes (n=371 in total). The achieved BP was below 140/90mmHg in 40.5% of non-diabetic and 38.3% of diabetic hypertensives. The percentage of patients whose BP was less than 130/85mmHg was 10.8% in nondiabetics and 11.4% in diabetics. The average number of hypotensive agents used was 1.46 in nondiabetics and 1.52 in diabetics. Physicians prescribed more ACE inhibitors and α-blockers in diabetics than in nondiabetics, although Ca-antagonists were administered in more than 70% of patients irrespective of whether or not they had diabetes. In contrast, fewer β-blockers and diuretics were administered to diabetics. These results suggest that although Japanese physicians are considering the effects of hypotensive agents on metabolism and renal function when they treat diabetic hypertensives, the achieved blood pressure in both hypertensives with and those without diabetes is insufficient, with only one of ten patients having a blood pressure less than 130/85mmHg even among diabetics. Improved blood pressure control will therefore be needed to treat high risk groups such as patients with diabetes mellitus. (Hypertens Res 2000; 23: 601-605)

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The present study was designed to evaluate the effects of an ACE inhibitor, lisinopril, and a calcium antagonist, nitrendipine, on urinary albumin excretion (UAE) and renal function in mild to moderate essential hypertensive patients with microalbuminuria. After the 4-week drug-free period, 17 patients were randomly divided into two groups. The first group (group 1: n=8) received lisinopril 10-20mg daily for 8 weeks followed by nitrendipine 5-10mg daily for another 8 weeks. The second group (group 2: n=9) received nitrendipine 5-10mg daily for 8 weeks followed by lisinopril 10-20mg daily for another 8 weeks. The mean blood pressure (MBP) significantly decreased in a similar manner in both groups. UAE significantly decreased after 8 weeks of treatment with lisinopril in group 1 and after 8 weeks of subsequent treatment with lisinopril in group 2. On the other hand, UAE was not altered by treatment with nitrendipine. The changes in UAE were significantly correlated with changes in MBP after 8 weeks of treatment with nitrendipine, but not after 8 weeks of treatment with lisinopril. No significant changes in creatinine clearance, urinary excretion of sodium or urinary N-acetyl-β-D-glucosaminide were observed by any treatment in either group. These results suggest that lisinopril, not nitrendipine, reduces UAE in essential hypertensive patients with microalbuminuria independently of its effective antihypertensive properties. (Hypertens Res 2000; 23: 607-612)

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Serial changes of left ventricular (LV) geometry and function during the development of hypertension were studied in 50 Dahl salt-resistant (DR) and 88 Dahl salt-sensitive (DS) rats fed an 8% NaCl diet beginning at the age of 6 weeks. Echocardiography at 6, 8, 11, 13, 14, 15, and 18 weeks and in vivo invasive hemodynamic determination at 6, 8, 11, 14, and 18 weeks were performed. After 11 weeks, 33 DS rats were observed for survival analysis. The survival analyses showed that the incidence of death was 57.6% due to heart failure, 27.3% due to stroke, and 15.2% due to sudden death. However, death in the early stages of hypertension was due almost entirely to sudden death or stroke. A high value of relative wall thickness (RWT) and a small end-diastolic dimension were predictive of sudden death and stroke, but LV mass (LVM) was not. Concerning the change in LV geometric patterns, LVM continued to increase to 18 weeks. The RWT increased or remained at a plateau up to 13 weeks, and then progressively decreased after 13 weeks. In contrast, LV function was hyperdynamic between 8 and 11 weeks when compared to DR rats. However, after 13 weeks, all hemodynamic variables of DS rats deteriorated progressively, and all DS rats died of heart failure. Thus, our study indicates that the cardiovascular events associated with the progression of hypertension vary widely according to the stage of hypertension and that RWT is more sensitive in predicting LV conditions than LVM in hypertension. (Hypertens Res 2000; 23: 613-623)

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This experiment was designed to determine how the angiotensin-converting enzyme inhibitor, lisinopril, acts on left ventricular wall stress and cardiac polyamine concentrations in Tsukuba hypertensive mice (THMs) carrying both human renin and angiotensinogen genes. Twelve-week-old THMs were treated with either lisinopril or hydralazine, or were left untreated, for 8 weeks. C57BL/6 mice of similar age were used as normal controls. Each group consisted of 14 mice. The systolic blood pressure of each mouse was measured once a week. Mice were euthanized at 20 weeks of age, and the left ventricular weight, left ventricular diameter, left ventricular wall stress, and left ventricular polyamine concentrations were measured. The systolic blood pressure of the untreated group was approximately 35mmHg higher than that of the C57BL/6 mice. The left ventricular weight, left ventricular diameter, left ventricular wall stress, and left ventricular polyamine concentrations in the untreated group were significantly higher compared to those in the C57BL/6 mice. The lisinopril group had significantly decreased systolic blood pressure and other measurement items, except the left ventricular wall stress, in comparison with the untreated group. The hydralazine group also had significantly decreased systolic blood pressure and left ventricular wall stress when compared with the untreated group, but no significant differences in other measurement items when compared with the untreated group. These findings indicate that lisinopril reduces left ventricular hypertrophy and polyamine concentration without reducing left ventricular wall stress, and that simply decreasing blood pressure does not suppress left ventricular hypertrophy. (Hypertens Res 2000; 23: 625-631)

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The aim of the present study was to examine the effects of L-glutamate and glycine microinjected into the rostral ventrolateral medulla (RVLM) in conscious unrestrained rats. Microinjection of 2 nmol of L-glutamate increased the mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in the conscious rats. The RSNA responses were significantly larger in the conscious rats than in anesthetized rats, while the magnitude of the pressor responses was similar in conscious and urethane-anesthetized rats. L-Glutamate injection significantly decreased heart rate in the conscious rats, whereas it increased the heart rate slightly but not significantly in the anesthetized rats. Microinjection of 100 nmol of glycine into the RVLM of conscious rat decreased MAP and RSNA. In 2 of the 6 rats examined, the depressor and sym-pathoinhibitory responses were preceded by a few seconds of a pressor and sympathoexcitatory phase. The decreases of RSNA in response to glycine injection were significantly larger in the conscious rats than in the anesthetized rats, whereas the magnitude of the depressor responses was similar in the two groups of rats. Heart rate decreased in response to glycine injection into the RVLM in the conscious and the anesthetized rats. In conclusion, in conscious unrestrained rats, as well as in urethane-anesthetized rats, L-glutamate acts as a sympathoexcitatory agent and glycine acts as a sympathoinhibitory agent in the RVLM. The sympathetic responses to these amino acids are larger in conscious rats than in anesthetized rats. (Hypertens Res 2000; 23: 633-641)

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Both integrins and endothelins (ETs) are known to play important roles in vascular remodeling via proliferation, apoptosis, and migration of vascular smooth muscle cells (VSMCs), whose dysfunctions have been implicated in the pathogenesis of end-organ damage associated with hypertension and arteriosclerosis. However, whether there is any interaction between endothelin-1 (ET-1) and integrins remains unknown. Therefore, the aim of the present study was to elucidate whether ET-1 regulates the expression of integrin α_v in rat VSMCs. ET-1 dose- and time-dependently suppressed the integrin α_v messenger RNA (mRNA) transcripts, as quantified by a real-time quantitative polymerase chain reaction (PCR) method, and decreased the transcriptional activity of integrin α_v gene, as demonstrated by integrin α_v-luciferase assay. The inhibitory effect of ET-1 on integrin α_v gene expression was abrogated by an ET_A receptor antagonist (BQ123) but not by an ET_B receptor antagonist (BQ788). ET-1 also suppressed the cell surface expression of integrin α_vβ₅ and the adhesion to vitronectin, but not to fbronectin. These results demonstrate that the adhesion of vitronectin to rat VSMCs is inhibited by ET-1 via the ET_A receptors by suppressing integrin α_v gene transcription, suggesting that ET-1 is involved in regulation of vascular integrin α_v gene expression. (Hypertens Res 2000; 23: 643-649)

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In order to test the hypothesis that intracellular Na⁺ accumulation and cellular Mg²⁺ deficiency may be involved in the abnormalities in Ca²⁺ handling and reactivity in spontaneously hypertensive rats (SHR) platelets, the metabolism of Na⁺, Ca²⁺ and Mg²⁺ was determined in fluorescent dye loaded platelets from 15 SHR and 15 Wistar-Kyoto rats (WKY) at 12 weeks of age. Mg²⁺ leak was estimated as the Mg²⁺ influx induced by an increase in extracellular [Mg²⁺] (from 1 to 5mmol/l) and Mg²⁺/Na⁺ exchange activity was estimated as the Mg²⁺ influx induced by a decrease in extracellular [Na⁺] (from 140 to 50mmol/l). Cellular metabolism of the fluorescent dye was similar in the two groups. Mean platelet [Ca²⁺]i was significantly increased under basal and thrombin (0.1U/ml)-stimulated conditions in SHR compared to WKY, both in the presence and absence of extracellular Ca²⁺. Mean Ca²⁺ discharge capacity was similar between the two groups. There was no difference in mean [Na⁺]i between the two groups. Basal [Mg²⁺]i was also increased in SHR platelets. Mg²⁺ leak was higher in SHR than in WKY, while Mg²⁺/Na⁺ exchange activity was similar in the two groups. There was no difference in serum Mg²⁺ concentration between SHR and WKY. These data suggest that abnormal Ca²⁺ handling is accompanied by elevation in [Mg²⁺]i via increased permeability of platelet cell membranes to Mg²⁺ in SHR without any alteration in [Na⁺]i, and do not support the Mg²⁺ deficiency hypothesis in genetically hypertensive rats. (Hypertens Res 2000; 23: 651-657)

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Recent evidence suggests the possible involvement of inducible nitric oxide synthase (iNOS) in the development and maintenance of hypertension in certain animal models. Inflammatory cytokines activate nuclear factor (NF)-xB, which plays a major role in transactivation of the inducible nitric oxide synthase (iNOS) gene. However, it remains unknown whether cytokine-mediated iNOS expression in vascular smooth muscle cells (VSMCs) requires signaling pathway(s) other than NF-xB activation. The purpose of this study was to determine whether the p42/p44 MAP kinase pathway is involved in cytokine-induced NF-xB activation and/or iNOS expression in cultured rat VSMCs. Nitrite/nitrate (NO_x) production stimulated by interleukin (IL)-1β or tumor necrosis factor (TNF)-α in VSMCs was markedly suppressed by inhibiting MAP kinase by pretreatment with a p42/p44 MAP kinase kinase (MAPKK)-1 inhibitor (PD98059) or by transfecting the dominant-interfering form of the nonphosphorylated MAPKK-1 expressing construct (MAPKK S222A). Inhibition of p42/p44 MAP kinase also antagonized the upregulation of iNOS mRNA and protein, as demonstrated by the quantitative RT-PCR method and Western blot analysis, respectively. Furthermore, rat iNOS promoter activity using an iNOS-luciferase construct stimulated by cytokines was inhibited by MAPKK-1 inhibition. However, xB-dependent transcription analysis revealed that cytokine-stimulated NF-xB activity was unaffected by MAP kinase inhibition. Western blot analysis using anti-IxB-α and anti-phospho-IxB-α antibodies showed that PD98059 had no effect on transient phosphorylation or degradation of IxB-α by cytokines. An electrophoretic mobility shift assay using synthetic oligonucleotide corresponding to the downstream NF-xB site of rat iNOS promoter as a probe showed that MAP kinase inhibition did not block cytokine-stimulated activation of NF-xB. These data suggest that the MAP kinase pathway is in part involved in cytokine-induced iNOS expression independent from NF-xB activation in rat VSMCs. (Hypertens Res 2000; 23: 659-667)

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Vascular endothelium has been shown to play an important role in the regulation of vascular tone and, hence, impairment of the endothelium may induce hypertension. Although magnesium (Mg) deficiency could induce hypertension, the role of Mg on the endothelium is unclear. We examined the effects of Mg removal on endothelium-dependent and -independent responses using ring preparations of femoral arteries obtained from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Norepinephrine (10^-9-10^-4M) evoked concentration-dependent contractions in arteries with endothelium. The maximal response was greater in SHR than in WKY. Removal of external Mg augmented the contraction in WKY but not in SHR. As a result, the contraction obtained in arteries with endothelium was identical in the two groups. Removal of the endothelium enhanced the contraction in both strains, with a greater response occurring in WKY than in SHR in Krebs, but not in Mg-free, solution. As a result, in arteries without endothelium, the contractions were identical in WKY and SHR both in Krebs and Mg-free solutions. Acetylcholine (10^-9-10^-4M) evoked concentration-dependent relaxation in arteries with, but not in those without, endothelium obtained from WKY and SHR. The relaxation did not differ between the two strains, nor was it altered by Mg removal. Thus, Mg removal impairs inhibitory function of the endothelium against contraction induced by norepinephrine, without affecting endothelium-dependent relaxation in response to acetylcholine, in the rat femoral artery. The effect of Mg removal is not apparent in SHR. The fact that after removal of external Mg the contraction in response to norepinephrine in arteries with endothelium is identical in WKY and SHR suggests that a normotensive artery with Mg deficiency may mimic a hypertensive artery through endothelial impairment. (Hypertens Res 2000; 23: 669-675)

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The migration as well as proliferation of coronary artery medial smooth muscle cells (SMC) into the intima is proposed to be an important process of intimal thickening in coronary atherosclerosis. In the current study, we examined the effects of the angiotensin type 1 receptor antagonist valsartan on angiotensin II (Ang II)-induced migration of cultured human coronary artery SMC using Boyden's chamber methods. Ang II significantly stimulated human coronary artery SMC migration in a concentration-dependent manner between 10^-6 and 10^-8mol/l when cells of passage 4 to 6 were used. However, the migration response to Ang II was moderately decreased in cells of passage 10 to 12, and was markedly decreased in cells of passage 15 to 17, compared to that of passage 4 to 6. Ang II-induced migration was blocked by the Ang II type 1 (AT₁) receptor antagonist valsartan in a concentration-dependent manner. By contrast, the Ang II type 2 (AT₂) receptor antagonist PD 123319 did not affect Ang II-induced migration. Ang II modestly increased the cell number of human coronary artery SMC after a 24-h incubation. This increase in cell numbers was also clearly blocked by valsartan, but not by PD 123319. These results indicate that Ang II stimulates migration as well as proliferation via AT₁ receptors in human coronary artery SMC when cells of passage 4 to 6 are used. Valsartan may prevent the progression of coronary atherosclerosis through an inhibition of Ang II-induced migration and proliferation in these cells, although in vivo evidence is lacking. (Hypertens Res 2000; 23: 677-681)

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Increased apoptosis of glomerular cells, with progression of glomerulosclerosis, overactivity of the reninangiotensin system and elevation of glomerular pressure, follows chronic nitric oxide synthase (NOS) inhibition in spontaneously hypertensive rats (SHR). To gain insight into the regulation of glomerular cell apoptosis in severe nephrosclerosis, we investigated apoptosis, the expression of proliferative cell nuclear antigen (PCNA) in glomeruli, and glomerular morphometric changes in 20-week-old SHR, SHR treated with NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 80mg/l in drinking water), and SHR treated with L-NAME and the calcium antagonist, efonidipine (20mg/kg per day), for 3 weeks. Apoptosis in non-sclerotic glomeruli was quantified by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling. The increase in systolic blood pressure and the severe proteinuria with severe nephrosclerosis induced by chronic NOS inhibition were completely prevented by efonidipine. Furthermore, the glomerular area and capillary tuft area were markedly increased in rats treated with efonidipine compared with both control rats (+30 and +42%, respectively, p<0.01) and rats treated with L-NAME (+35 and +56%, respectively, p< 0.01)-treated rats. This calcium antagonist also significantly inhibited the both increases of the glomerular cell apoptosis index (-72%) and the PCNA index (+44%), therefore the alteration between apoptosis and proliferation slightly increased the number of glomerular cells (subcapsular, +22%, p<0.01; juxtamedullary, +2%, not significant). Thus, the calcium antagonist efonidipine seems to play an important role in the regulation of apoptosis and proliferation of glomerular cells and may be effective in preventing nephrosclerosis exacerbated by NOS inhibition. (Hypertens Res 2000; 23: 683-691)

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The depressor response to electrical stimulation of the spinal cord and the level of calcitonin gene-related peptide (CGRP) mRNA in the dorsal root ganglion (DRG) in the spontaneously hypertensive rat (SHR) was compared with the normotensive Wistar Kyoto rat (WKY) and Wistar rat (WR). The animals were pithed by inserting a stainless-steel rod into the spinal cord. Pithed rats were treated with hexamethonium (2mg/kg/min i.v.) to block autonomic outflow, and mean arterial blood pressure (MBP) was maintained at approximately 100mmHg with continuous infusion of methoxamine (10 to 15μg/kg/min i.v.). Electrical stimulation (2 and 4Hz for 30s) of the lower thoracic spinal cord (T9-12) via the pithing rod caused a frequency-dependent depressor response without a change in heart rate. The depressor response to spinal cord stimulation was significantly smaller in SHR than in WKY and WR. Long-term treatment of 8 week-old SHR with captopril (0.1% in drinking water) for 7 weeks restored the reduced depressor response to spinal cord stimulation. The level of CGRP mRNA in DRG of SHR was significantly lower than that in WKY. These results suggest that the function of CGRP-containing nerves from the spinal cord decreases in SHR and captopril treatment prevents its reduction. (Hypertens Res 2000; 23: 693-699)

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To determine whether chronic salt-loading would alter voltage-dependent Ca²⁺ channels in resistance arteries of Dahl salt-sensitive rats, whole-cell voltage-clamp experiments were performed on single cells that were isolated from small mesenteric arteries. Dahl salt-sensitive rats were fed either an 8% NaCl diet (high-NaCl group) or a 0.3% NaCl diet (low-NaCl group) from the age of 6 or 7 weeks. After 4 to 5 weeks, systolic blood pressure was significantly higher in the high-NaCl group than in the low-NaCl group. In the high-NaCl group, the threshold potential for Ca²⁺ channel current was more negative and the current amplitude that was normalized by cell capacitance was higher at negative command potentials (-40mV to -20mV), as compared with the low-NaCl group. When the current was separated into fast transient current and slow sustained (L-type) current, the alteration in the high-NaCl group was attributable to the change in L-type current. The steady-state inactivation curve was not different between the high-NaCl and low-NaCl groups. In conclusion, L-type Ca²⁺ channels in resistance arteries of Dahl salt-sensitive rats became more available for opening near the resting potential after dietary salt-loading. (Hypertens Res 2000; 23: 701-707)

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A 53-year-old male was found to have hypertension caused by the significant secretion of renin from an atrophic left kidney. He had undergone extracorporeal shock-wave lithotripsy (ESWL) for left renal lithiasis 11 years previously. A renal dynamic study with ^99mTc-diethylenetriaminepentaacetic acid (DTPA) indicated that the rate of renal excretion and uptake was decreased in the left kidney and normal in the right kidney. Renal angiography demonstrated a normal right renal artery and a small but nonstenotic left renal artery. The ratio of PRA in the left renal vein to that in the right renal vein was 1.7. Blood pressure could be lowered to the range of 140-150/80-90mmHg with imidapril, an ACE inhibitor. ESWL may cause hypertension via the well-known Page kidney effect. In this case, the kidney, atrophic probably due to ESWL, released a significant amount of renin. (Hyperfens Res 2000; 23: 709-712)

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