To investigate the effects of doxazosin on blood pressure and sympathetic nervous activity, we analyzed the circadian variation of blood pressure and the power spectrum of R-R intervals using an ambulatory multibiomedical monitoring system (TM2425) in 10 untreated outpatients with essential hypertension. After a 2-wk placebo period (P-period), we administered 1 to 4mg of doxazosin mesilate to the patients for 2 to 6wk (T-period). We measured systolic and diastolic blood pressure (SBP, DBP), heart rate, R-R intervals, posture, and activity with the use of TM2425. Power spectral analysis of R-R intervals was used to calculate the ratio of low to high frequency components (LF/HF). The values were compared between the P-period and T-period. Although daytime blood pressure significantly decreased during the T-period (SBP, 148.1±5.9 vs. 130.3±4.4mmHg; DBP, 92.3±3.2 vs. 83.6±2.6mmHg, p<0.01), nighttime DBP did not. The LF/HF of R-R intervals in the daytime (5.8±2.0 vs. 4.9±1.2, p<0.01) and the morning rise in blood pressure also decreased significantly (SBP, 17.5±9.4 vs. 12.1±6.5mmHg; DBP, 12.5±6.5 vs. 8.3±5.3mmHg, p<0.05). We conclude that doxazosin may suppress the morning rise in blood pressure in association with a decrease in sympathetic nervous activity. (Hypertens Res 1997; 20: 149-156)

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It is well known that cardiovascular accidents such as myocardial infarction frequently occur in the morning, but their triggering mechanisms are not clear. The present study investigated circadian variations of hemodynamics and baroreflex functions. Twenty-three patients with essential hypertension were studied. Direct blood pressure (BP) and ECG were recorded by telemeter over 24h, and then computeranalyzed. The pulse-contour method was used to measure cardiac output (CO) and total peripheral vascular resistance (TPR). The ratio of low to high frequency components (LF/HF) of the RR-interval on ECG was calculated by power spectral analysis. The baroreflex sensitivity index (BRI) was measured on the basis of the ratio ΔRR/ΔPs (ΔPs=spontaneous decrease in systolic BP, ΔRR=change in RR). Furthermore, 24-h BP changes were transformed algebraically into positive load component (PC) and negative load component (NC) by using a Windkessel model. The circadian variation of hematocrit (Ht) was also measured. The least squares method was used to determine the time at which the maximum and minimum value of each measurement occurred. Whereas the maximum values for BP and CO occurred in the evening (18:30, 17:00), the maximum values for TPR and LF/HF occurred between 06:30 and 08:00, and the minimum value for BRI occurred at 08:00. PC significantly correlated with Ps, heart rate, and CO (r=0.81, 0.92, 0.67), and NC significantly correlated with BRI and LF/HF (r=0.71, 0.64). PC (related to cardiovascular function) reached a maximum and NC (related to baroreflex function) reached a minimum in the late morning (11:00). Ht was highest immediately after the subjects got out of bed. These hemodynamic imbalances may negatively influence coronary blood flow in the morning. (Hypertens Res 1997; 20: 157-166)

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We investigated the utility of home blood pressure measurements for determining the risk of stroke. We also analyzed the relationship between home blood pressure and the incidence of stroke. Home blood pressure and screening blood pressure measurements were obtained from 1, 789 residents (aged 40yr or older) of a rural Japanese community. Blood pressure was measured at home with a semiautomatic device. A mean (±SD) of 23.0±7.5 measurements were made for each subject. Subjects without a history of stroke and who were not receiving medication for hypertension (n=1, 256) were prospectively followed up for 4.4±2.1yr. Subjects were subdivided into quintiles according to their baseline blood pressure. The association between the baseline blood pressure and the incidence of the first-ever stroke was examined with the Cox proportional hazards regression model, adjusted for age and sex. The lowest risk of stroke morbidity occurred in the subjects in the third quintile for home systolic blood pressure (117-123mmHg) and in those in the second quintile for home diastolic blood pressure (66-70mmHg). The subjects in the fifth quintiles for home systolic (_??_133mmHg) and diastolic blood pressure (_??_81 mmHg) had a significantly increased risk of stroke morbidity. The subjects in the first and the second quintiles for home systolic blood pressure and those in the first quintile ffor home diastolic blood pressure tended to have an increased risk as compared with subjects in the lowest risk groups, although this increase was not statistically significant, indicating two possibilities: a trend toward a J-shaped relationship or no decrease in risk of the first-ever stroke in subjects with home blood pressure level less than 123/70mmHg. This relationship was not observed for screening blood pressure. We conclude that home blood pressure measurements can provide additional prognostic information to that obtained from blood pressure measurement in a medical environment. (Hypertens Res 1997; 20: 167-174)

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We evaluated risk factors involved in regional differences in atherosclerotic lesions in patients with hypertension, diabetes mellitus, or both. Using ultrasonography, we examined the brachial, common carotid, and common femoral arteries in 65 hospitalized Japanese patients (15 controls, 18 patients with hypertension, 16 with diabetes mellitus, and 16 with both hypertension and diabetes mellitus). They ranged in age from 39 to 81yr, mean 60.3yr. The thickness of the intima-media complex of the far wall was measured, and the severity of atherosclerotic plaques was graded according to maximal lumen stenosis. The intima-media thickness in the carotid and femoral arteries was significantly greater in the hypertensive patients and the hypertensive patients with diabetes than in the controls. Severity of plaque was greater in the hypertensive patients with diabetes than in the controls. Plaque grades were higher in the carotid and femoral arteries than in the brachial artery. Multiple regression analysis revealed that age and mean blood pressure were strongly associated with the intima-media thickness in all three arteries. In the femoral artery, cigarette smoking and hyperglycemia also significantly correlated with the intima-media thickness. Plaque grades increased with age in the carotid and brachial arteries, while in the femoral artery the grade increased with cigarette smoking and serum cholesterol concentration. These findings suggest that the extent of atherosclerosis and its underlying risk factors differ among arterial sites. In addition, risk factors may partly differ according to the stage of athesosclerosis. To prevent or reverse atherosclerosis, the above differences should be taken into account. (Hypertens Res 1997; 20: 175-181)

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The cardiovascular effects of chronic inhibition of nitric oxide synthesis and dietary salt were studied in 9-wk-old spontaneously hypertensive rats (SHR). Nω-nitro-L-arginine methyl ester (L-NAME, 0.025% in food, about 20mg/kg/d) was given to rats receiving diets containing low, moderate, and high salt levels (NaCl 0.2%, 1.1%, and 6.0% of the dry weight of the chow) for 3 wk. L-NAME increased systolic blood pressure by 50 to 60mmHg in all treated groups, as compared with an average rise of 10 to 20mmHg in the control SHR. The high-salt diet did not further increase blood pressure. L-NAME also induced cardiac and renal hypertrophy, and these changes were aggravated by the high-salt diet. In addition, 19 of the 30 rats treated with L-NAME suffered strokes and all of them had several myocardial infarctions and renal damage, while the rats not treated with L-NAME had no evidence of stroke or myocardial or renal injury. Responses of mesenteric arterial rings in vitro were studied at the end of the experiment. The vascular contractile responses to noradrenaline were increased, and the relaxation responses to acetylcholine were inhibited in the L-NAME treated groups. In addition, the high-salt diet alone tended to inhibit the response to acetylcholine. Plasma renin activity was markedly increased by L-NAME treatment and decreased by the high-salt diet. The 24-h urine protein excretion was increased both by the L- NAME treatment and by the high-salt diet. The combination of L-NAME and the high-salt diet markedly raised the serum creatinine concentration. Our findings show that the coronary and renal functions are particularly vulnerable in SHR during impaired nitric oxide synthesis, and that the end-organ damage is worsened by an increased intake of dietary salt. We suggest that dysfunction of the endothelium is the primary cause of the effects observed in this study. (Hypertens Res 1997; 20: 183-192)

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Serum N-acetyl-β-D-glucosaminidase activity (NAG) is a possible predictor of vascular injury in hypertension. We assessed whether the activity of this enzyme reflects vascular damage in a genetic rat model of non-insulin-dependent diabetes mellitus (NIDDM) in humans. Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a regular chow were treated with the angiotensin converting enzyme (ACE) inhibitor imidapril for 16wk. Systolic blood pressure increased in a time-dependent manner in the untreated OLETF rats as compared with that in the control Long-Evans Tokushima (LET) rats. The blood pressure elevation was associated with increases in cardiac and aortic weight. Imidapril treatment significantly attenuated the blood pressure elevation and reduced the increases in cardiac and aortic weight. The untreated OLETF rats had higher plasma glucose and insulin concentrations than did the LET rats and presented with glucosuria at the age of 22wk. Imidapril treatment strikingly decreased plasma glucose levels and the glucosuria. Plasma insulin concentrations decreased, approaching those of the non-diabetic control LET rats. ACE inhibitor treatment attenuated the nodular lesions in the glomeruli of OLETF rats and improved the kidney function. Serum NAG activity increased significantly by 35% in the untreated rats; this increase was attenuated significantly by imidapril treatment. The reduction in serum NAG activity correlated with improvement in cardiovascular injury. In contrast, there were no changes in urinary NAG excretion in the three OLETF rat groups. In addition, NAG excretion did not correlate with indices of cardiovascular injury. These data suggest that serum NAG activity is useful in predicting injury in the cardiovascular system in rats with diabetes mellitus. (Hypertens Res 1997; 20: 193-199)

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To investigate changes in systemic and regional hemodynamics during the development of human hypertension, we simultaneously measured cardiac index (CI) by the indocyanine green (ICG) dye dilution method, hepatosplanchnic blood flow (HBF) by the ICG clearance method using a two-compartment model, and renal blood flow (RBF) by the p-aminohippurate clearance method in patients with borderline and essential hypertension. In patients with borderline hypertension (BH, n=27), HBF (435±15 ml/min/m²) and HBF/CI (16±1%) were significantly (p<0.05) lower than in age-matched normotensive controls (528±21 and 19±1, respectively, n=21), while CI, RBF and RBF/CI were similar. In patients with essential hypertension (EH, n=32), HBF, RBF, and RBF/CI were all significantly (p<0.01) lower than in the control subjects. Hepatosplanchnic vascular resistance (HVR) in patients with BH was preferentially increased, while total peripheral resistance (TPR) and renal vascular resistance (RVR) remained in the normal range. In patients with EH, TPR, HVR, and RVR were all increased. These results indicate that hemodynamic changes in patients with BH do not occur uniformly among the various regional circulations and suggest that hemodynamic changes in the hepatosplanchnic region precede those in other organ circulations during the development of human hypertension. (Hypertens Res 1997; 20: 201-207)

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The purpose of this study was to investigate the effects of arginine vasopressin (AVP) on nitric oxide (NO) synthesis in vascular smooth muscle cells (VSMCs). We measured the production of nitrite, a stable metabolite of NO, and the expression of inducible NO synthase (iNOS) mRNA in cultured rat VSMCs. Incubation of VSMCs for 24h with interleukin-1β (IL-1β) caused a significant increase in NO production. Both AVP and the V_1a receptor agonist [Phe², Ile³, Orn⁸]vasopressin inhibited NO synthesis in IL-1β-stimulated cells, but not in unstimulated cells, in a dose-dependent manner. The V_1a receptor antagonist [d(CH₂)₅¹, O-Me-Tyr², Arg⁸]vasopressin completely inhibited the effect of AVP. Incubation with IL-1β for 24h induced the expression of iNOS mRNA in VSMCs, while AVP suppressed its expression. After functional depletion of protein kinase C activity by treating cells with phorbol 12-myristate 13-acetate for 24h, AVP did not inhibit IL-1β-induced NO production. The effect of AVP was also inhibited in the presence of the protein kinase C inhibitor calphostin C in a dose-dependent manner. These results indicate that AVP inhibits IL-1β-induced iNOS expression in VSMCs through the V_1a receptor, which is mediated at least partially via activation of protein kinase C. (Hypertens Res 1997; 20: 209-216)

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This experiment was designed to investigate the possible involvement of angiotensin II (Ang II) and platelet-derived growth factor (PDGF) in the mechanism underlying stretch-induced proliferation of vascular smooth muscle cells (SMCs). SMCs from the rabbit aortic media were grown on polystyrene rubber-bottomed dishes coated with type I collagen. Cells were stretched cyclically by a vacuum-operated downward flexion of the culture dish bottom. A 1.4- to 1.6-fold increase in proliferation of SMCs was induced by cyclic stretching, as determined by [³H]-thymidine incorporation, in a stretch force-dependent manner in the range of 5% to 15% elongation, 30 cycles/min for 24h. Expression of PDGF-B chain mRNA was up-regulated in a time-dependent manner in the range of 2 to 24h, 10% elongation, and 30 cycles/min. Saralasin, a selective antagonist of Ang II, and captopril, an angiotensin I converting enzyme inhibitor, significantly suppressed the stretch-induced proliferation of SMCs. Blockade of angiotensinogen mRNA translation by antisense oligonucleotide inhibited proliferation under the mechanical strain. Stretch-induced proliferation was inhibited by 78% in the presense of anti-PDGF-AB neutralizing antibody. Increased expression of PDGF-B chain mRNA under the mechanical strain was inhibited by treatment with saralasin. Our results indicate that the stretch-induced proliferation of cultured SMCs is mediated at least in part via increased production of Ang II by the local renin-angiotensin system and a subsequent up-regulation of PDGF-B chain mRNA in an autocrine-paracrine manner. (Hypertens Res 1997; 20: 217-223)

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To determine the effects of insulin on intracellular calcium and platelet aggregatory responses in hypertensive subjects with insulin resistance, we measured insulin sensitivity in terms of glucose disposal rate (GDR) by the hyperinsulinemic euglycemic clamp technique (GC) in 14 non-diabetic untreated hypertensive subjects, and determined basal ([Ca²⁺]_i) and thrombin-stimulated (T-[Ca²⁺]_i) platelet-free calcium concentrations and thrombin-stimulated platelet aggregatory response (AG) before (PRE[Ca²⁺]_i, T-PRE[Ca²⁺]_i, and PRE AG, respectively) and during (POST[Ca²⁺]_i, T-POST[Ca²⁺]_i, and POST AG, respectively) GC. As a control for GC, vehicle (normal saline) was infused on another day. No significant difference was observed between PRE[Ca²⁺]_i and POST[Ca²⁺]_i, T-PRE[Ca²⁺]_i and T-POST[Ca²⁺]_i, or PRE AG and POST AG. GDR inversely correlated with Δ[Ca²⁺]_i (POST[Ca²⁺]_i- PRE[Ca²⁺]_i, r=-0.75, p<0.02), ΔT-[Ca²⁺]_i (T-POST[Ca²⁺]_i-T-PRE[Ca²⁺]_i, r=-0.63, p<0.02) and ΔAG (POST AG-PRE AG, r=-0.67, p<0.01). No significant changes were observed in these variables during vehicle infusion. [Ca²⁺]_i, T-[Ca²⁺]_i, and AG decreased during GC as compared with baseline in hypertensive subjects with normal insulin sensitivity, but were unchanged in those with insulin resistance, suggesting that the vasodilatory and anti-platelet aggregatory effects of insulin are impaired in patients with insulin-resistant hypertension. (Hypertens Res 1997; 20: 225-231)

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