This study was conducted to quantify coronary blood flow (CBF) noninvasively according to the fractionation principle and to elucidate the relation between CBF and left ventricular hypertrophy. CBF/cardiac output (CO), estimated on the basis of the ratio of myocardial uptake/total injected dose of thallium-201(% cardiac uptake), was determined in 14 control subjects and 40 patients with essential hypertension. CBF and CBF per 100g of myocardium (unit CBF) were calculated according to the following formulas: CBF=% cardiac uptake×CO, and unit CBF=(CBF/LVM)×100, where CO and left ventricular mass (LVM) are echocardiographically determined. There was good reproducibility of % cardiac uptake (r=0.983, p<0.0001). Percent cardiac uptake was greater in hypertensive patients (4.65±1.44%) than in control subjects (3.64±0.64%), and there was a positive correlation between % cardiac uptake and LVM. CBF (ml/min) was greater in hypertensive patients (240.7±80.5) than in control subjects (194.9±36.9), but unit CBF (ml/min/100g) was less in hypertensive patients (102.2± 26.7) than in control subjects (150.3±30.5). Multiple regression analyses showed that LVM was the most potent independent predictor of resting CBF in hypertension. Our results indicate that CBF, determined by thallium-201 myocardial scintigraphy, increases parallel to the increase in LVM, but unit CBF decreases even in the resting condition in patients with essential hypertension. (Hypertens Res 1998; 21: 227-234)

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A parallel controlled clinical trial was carried out to investigate the effect on blood pressure (BP) of replacing normal salt with mineral salt in seasonings. After a 2-wk run-in period, 21 subjects (10 men and 11 women; age, 66.0±7.6yr) were given mineral salt in seasonings instead of normal salt [mineral salt (MS) group], while 20 subjects (10 men and 10 women; age, 65.9±7.4yr) continued to receive normal salt in seasonings [regular salt (RS) group] for the next 5wk in the experimental (E) period. In the MS group, systolic (S) and diastolic (D) BP decreased significantly from 134.7±17.2/77.2±9.7 at baseline (week O) to 127.3±12.0/73.5±8.9mmHg at the end of the E period (week 5), and the reductions in both SBP and DBP were larger in hypertensive subjects than in normotensive subjects in the MS group. The serum sodium and chloride concentrations decreased significantly, while the serum potassium and HDL-cholesterol concentrations increased significantly at week 5. The 24-h urinary sodium excretion decreased, and the 24-h potassium and magnesium excretions increased significantly from week O to week 5 in the MS group. In contrast, SBP, DBP, serum chemistry, and urinary electrolyte excretion did not change significantly in the RS group. These findings suggest that the excessive salt content and insufficient potassium and magnesium content of the present Japanese diet could be easily and safely corrected by replacing seasonings prepared with regular salt with those prepared with mineral salt. (Hypertens Res 1998; 21: 235-243)

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In resting condition, obese subjects are described as having impaired diastolic filling. To examine the effect of mild to moderate obesity on left ventricular diastolic performance during stress in hypertension, we determined the filling responses to dynamic submaximal exercise in 19 obese hypertensive patients (body mass index, 26 to 30kg/m²) with a normal left ventricular structure, 19 age- and sex-matched, non-obese hypertensive patients, and 19 age- and sex-matched, non-obese normotensive controls (mean age, 55±3yr). Doppler echocardiographic studies were performed at baseline and 1min after exercise on a supine ergometer bicycle. At rest, systolic function and filling indices, peak velocities of early (E) and late (A) filling, and their ratio (E/A), were similar in the two hypertensive groups, while normotensive controls had higher peak velocities of E and E/A. At a maximum workload of 75W, blood pressure and heart rate increased similarly in the two hypertensive groups. Peak velocities of E and A increased significantly after exercise. The percentage change in the peak velocity of E was greater in obese hypertensive patients than in non-obese hypertensive patients and normotensive controls (23±4 vs. 12±3 and 14±3%, p<0.05). Percentage changes in A and E/A were similar in the three groups. Our study suggests that mild to moderate obesity does not further worsen left ventricular diastolic filling at rest and mitigates diastolic filling abnormalities after exercise in hypertensive patients. (Hypertens Res 1998; 21: 245-250)

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We investigated the ability of the ET_A receptor antagonist T-0115 and the angiotensin-converting enzyme (ACE) inhibitor imidapril hydrochloride to prevent hypertensive complications induced in rats by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), N^G-nitro-L-arginine methyl ester (L-NAME) 500mg/l, or L-NAME plus imidapril 10mg/l in the drinking water. In rats treated with L-NAME 500mg/l plus T-0115, T-0115 was given in the food at a dose of 0.2mg/g food or 0.6mg/g food. We then collected 24-h urine samples at 2, 4, and 6wk, obtained blood samples at 6wk, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90&plusmn;0.65 vs. 0.05&plusmn;0.02mg/d/100g in control), and the area of the left ventricular wall (83.3&plusmn;3.0 vs. 69.8&plusmn;1.8mm² in control). The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of T-0115 0.6mg/g food with L-NAME ameliorated the tail-cuff pressure and the albuminuria (0.56&plusmn;0.23mg/d/100g), although to a lesser extent than the changes seen with imidapril 10mg/l. T-0115 0.6mg/g food prevented left ventricular hypertrophy as effectively as imidapril 10mg/l(70.8&plusmn;1.8 with T-0115 vs. 68.3&plusmn;2.7mm² with imidapril). Chronic inhibition of NO synthesis produced left ventricular hypertrophy and nephrosclerosis. Our results demonstrate that inhibition of the renin-angiotensin system morely effectively prevents nephrosclerosis than does the blockade of ET_A receptors in a model of hypertension induced by chronic NO blockade. However, inhibition of the ET-1 pathway appeared to be as effective as ACE inhibitors in preventing left ventricular hypertrophy in this model. (Hypertens Res 1998; 21:251-257)

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To assess whether we could predict left ventricular (LV) geometric patterns on echocardiography from voltages in standard electrocardiograms (ECG) in patients with essential hypertension, standard 12-lead ECG and echocardiograms were recorded in 106 consecutive, untreated patients (50±11yr old) with essential hypertension. Subjects were assigned to the following four groups based on relative wall thickness (RWT) and LV mass index (LVMI) as determined by echocardiography: a normal geometry group (n=44), a concentric remodeling group (increased RWT and normal LVMI, n=10), an eccentric hypertrophy group (increased LVMI and normal RWT, n=23), and a concentric hypertrophy group (increased RWT and LVMI, n=29). The following ECG variables were determined: Sokolow-Lyon voltage (SV₁+RV₅: SL), Cornell voltage (R_aV_L+SV₃: CN), sum of 12-lead QRS voltage (12-lead sum), and RV₆/RV₅ ratio (RV₆/V₅). LVMI correlated with SL, CN, and 12-lead sum, but not with RV₆/V₅ in the study group as a whole. The concentric hypertrophy group showed increased voltages for all ECG variables except RV₆/V₅. The concentric remodeling group showed increased voltages for SL and 12-lead sum, but a decreased RV₆/V₅ ratio. In contrast, the eccentric hypertrophy group had increased voltage only for the 12-lead sum. The combination of SL, RV₆/V₅, and CN showed modest sensitivity and specificity in the diagnosis of concentric remodeling, concentric hypertrophy, and normal geometry, but not in the diagnosis of eccentric hypertrophy. Conventional ECG criteria can predict LVMI, but not LV geometry in the patients with essential hypertension. The combination of SL, CN, and RV₆/V₅ is useful in differentiating the four LV geometric patterns seen in essential hypertension. (Hypertens Res 1998; 21: 259-266)

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To clarify the role of nitric oxide (NO) in the pathogenesis of renovascular hypertension, we examined the effects of long-term oral administration of either the precursor substrate L-arginine or the NO synthesis inhibitor N^ω-nitro-L-arginine (L-NA) on systemic and renal hemodynamics in dogs with chronic two-kidney, one-clip (2K-1C) renovascular hypertension. Furthermore, the importance of NO in maintaining kidney function in chronic renal ischemia was evaluated. Chronic inhibition of NO production aggravated the rise in blood pressure (L-NA 117.7±6.8 vs. control 107.2±3.3mmHg, p<0.05 on day 1) and stimulated marked bradycardia (L-NA 84.9±3.2 vs. control 94.6±2.6 beats/min, p<0.05 on day 1). These changes were associated with significant reductions in renal plasma flow (RPF, L-NA 0.03± 0.02 vs. control 0.85±0.20ml/min/kg, p<0.01) and glomerular filtration rate (GFR, L-NA 0.02±0.01 vs. 0.22±0.05ml/min/kg, p<0.01) in the ischemic kidney. In contrast, in the contralateral non-clipped kidney, chronic inhibition of NO production induced a significant reduction in RPF with no significant change in GFR. Oral administration of L-arginine had no effect on the magnitude of hypertension. L-arginine significantly improved RPF (2.76±0.49ml/min/kg) and GFR (0.61±0.08ml/min/kg) in the ischemic kidney, whereas the elevation of RPF and GFR in the non-clipped kidney was not significant. Unilateral renal artery occlusion in these hypertensive dogs resulted in diffuse atrophic tubulointerstitial changes in the ischemic kidney. These changes were markedly aggravated by NO synthesis inhibition. On the other hand, L-arginine treatment significantly protected against the morphological changes of renal ischemia. These data show that NO plays a key role in the maintenance of renal function during the evolution of hypertension induced by chronic renal ischemia. In addition, these data demonstrate that renovascular hypertension is associated with a compensatory increase in the vasodilator function of the vascular endothelium. (Hypertens Res 1998; 21: 267-277)

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The effect of an angiotensin-converting enzyme inhibitor, lisinopril, on gonadal hormones was assessed in 20 patients with essential hypertension. A daily dose of 5 to 20mg of lisinopril was administered for 6 mo. In male patients, the free testosterone (f-T) concentration decreased significantly (before, 13.8±2.4pg/ml; after, 9.9±1.5pg/ml: mean±SEM, p<0.05), whereas the plasma total testosterone (T), estradiol (E₂), and sex hormone binding globulin (SHBG) concentrations were not significantly affected. Lisinopril had no effect on plasma T, f-T, or E₂ concentrations in female patients, but significantly increased the plasma SHBG concentration (before, 48.0±6.1nmol/l; after, 62.7±6.7nmol/l: p<0.01). The results of this preliminary study suggest that lisinopril affects plasma f-T and SHBG concentrations. The clinical implications of lisinopril-induced changes in plasma f-T and SHBG concentrations remain to be clarified. (Hypertens Res 1998; 21: 279-282)

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Insulin is known to stimulate Na⁺/K⁺ ATPase and to relax vascular smooth muscle. We hypothesized that vascular tone in the obese Zucker (fa/fa) rat, a hyperinsulinemic model in which hypertension can develop, may be influenced by insulin's ability to stimulate Na⁺/K⁺ ATPase at the vascular level. We studied isometric preparations of tail and femoral arteries from 10-wk-old, male obese Zucker rats, which were hyperinsulinemic but still normotensive vs. lean controls. Sensitivity to potassium-induced relaxations, an index of vascular Na⁺/K⁺ ATPase activity was significantly greater in the obese Zucker rat than control. Sensitivity to transmural-nerve-stimulation-induced contractions was decreased in the femoral and tail arteries from obese rats as compared with lean controls. Insulin (50 to 200mU/ml) mimicked potassium-induced relaxations in the femoral artery, an effect that was significantly greater in the obese group. These data suggest that in the young hyperinsulinemic Zucker rat, insulin has a stimulatory effect on the vascular Na⁺/K⁺ pump, which may be associated with a decreased presynaptic adrenergic influence on vascular tone. Development of resistance to these vascular relaxant effects of insulin with advancing age might contribute to the onset of hypertension in this model. (Hypertens Res 1998; 21: 283-288)

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The most difficult step in dissecting the molecular basis of a quantitative trait is proceeding from chromosomal locations associated with this trait (i.e., quantitative trait locus, QTL) to determining what gene(s) in the QTL region is causative. Using standard positional cloning methodology to identify candidate genes for a particular QTL has three drawbacks: 1) it is labor intensive; 2) defining variants in genes causing quantitative variation from sequence information alone is difficult or impossible; and 3) many (or most) genes in a particular chromosomal interval will not be relevant for a specific disease/trait because they are not expressed in critical candidate organs. Instead of positional cloning, we propose using a panel of congenic strains, where each carries an allele for a different QTL on a similar genetic background, in conjunction with identification of differentially-expressed genes in target organs of inbred strains of contrasting phenotype. This will identify genes having altered expression in organs critical to regulating blood pressure and the development of hypertension. Radiation hybrid mapping of such genes will result in a transcription map of differentially-expressed genes in a target organ of a rat model of genetic hypertension. This approach could rapidly identify genes mapping to genomic regions near QTL, which will be strong candidates to explain, in part, the observed strain differences in blood pressure. This novel approach, which uses a panel of congenic strains to facilitate the mapping and subsequent identification of differentially-expressed and QTL-associated genes, should be applicable to any genetic model for identifying candidate genes located near QTL, given the availability of a panel of congenic strains. (Hypertens Res 1998; 21: 289-296)

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