Mayumi Minami

Vitamin E Ameliorates the Renal Injury of Dahl Salt-Sensitive Rats

Recently, hyperlipidemia as well as hypertension has been observed in Dahl salt-sensitive (S) rats. In this study, to investigate whether the lipid abnormality is involved in the renal injury of Dahl S rats, we examined the effect of vitamin E on glomerular sclerosis, as vitamin E is an inhibitor of lipid oxidation. Dahl S rats were given a high salt diet (8% NaCl) containing either normal vitamin E (2 mg/100 g) or high vitamin E (50 mg/100 g) for 4 weeks. Dahl salt-resistant (R) rats were given a high salt and normal vitamin E diet. The blood pressure in the Dahl rats increased and was not suppressed by the vitamin E supplement. Serum cholesterol and triglycerides in Dahl S rats were higher than in Dahl R rats at both 0 and 4 weeks. Vitamin E lowered the serum cholesterol level in Dahl S rats at 4 weeks (126 +/- 5 v 150 +/- 12 mg/dL, P < .01). Urinary protein excretion and serum creatinine increased in Dahl S rats, and vitamin E inhibited the increases significantly (urinary protein, 70.7 +/- 0.9 v 178.0 +/- 8.8 mg/day, P < .01; serum creatinine, 0.45 +/- 0.02 v 0.63 +/- 0.05 mg/dL, P < .01). Serum lipid peroxide (LPO) was higher in Dahl S rats than in Dahl R rats, and vitamin E lowered LPO in Dahl S rats (2.10 +/- 0.03 v 2.70 +/- 0.04 nmol/mL, P < .01). In the histologic study, sclerosing score (SS) of glomeruli, which represents the degree of glomerulosclerosis semiquantitatively, was higher in Dahl S rats than in Dahl R rats. Vitamin E lowered SS (114 +/- 3 v 157 +/- 6, P < .01) and ameliorated arterial injuries such as medial thickness with partial necrosis and severe fibrinoid proliferation with inflammatory cell infiltration. In all rats, SS was strongly correlated with urinary protein (r = 0.93, P < .01), serum cholesterol (r = 0.86, P < .01), and serum LPO (r = 0.89, P < .01). These results suggest that the renal injury in Dahl S rats is caused not only by hypertension but also by hyperlipidemia. Therefore, vitamin E might ameliorate the renal damage by inhibiting the oxidation of lipids.

Pressor hyperreactivity to mental and hand-grip stresses in patients with hypercholesterolemia.

OBJECTIVE To investigate the role of hypercholesterolemia in the regulation of blood pressure. SUBJECTS AND METHODS We compared blood pressure responses to arithmetic stress and hand-grip tests in normotensive patients with hypercholesterolemia n = 15) and a mean (+/- SEM) age of 49 +/- 3 years, and normal cholesterolemic controls (n = 22) aged 48 +/- 1 years. Blood pressure and heart rate were measured throughout the tests. We examined the intracellular Ca2+ concentration in platelets with or without low-density-lipoprotein stimulation (2.9 nmol/l, 10 mg/ml). The plasma nitrite plus nitrate and cyclic GMP were determined before and at the end of each test to evaluate nitric oxide production and activity. RESULTS Both tests showed that systolic/diastolic blood pressure was higher in the hypercholesterolemic patients than in the normal controls (stress test: 139 +/- 3/91 +/- 4 versus 127 +/- 2/80 +/- 3 mmHg, P < 0.01/P < 0.05; hand-grip test: 164 +/- 5/106 +/- 5 versus 144 +/- 3/88 +/- 3 mmHg, P < 0.01/P < 0.01). The intracellular Ca2+ concentration in platelets and the increase in response to low-density-lipoprotein stimulation were higher in the hypercholesterolemic patients (without stimulation: 72 +/- 3 versus 64 +/- 3 nmol/l, P < 0.01; with 2.9 nmol/l stimulation: 145 +/- 21 versus 89 +/- 6 nmol/l, P < 0.01). The increase in Ca2+ in response to 2.9 nmol/ml stimulation with low-density lipoprotein was positively related to the increase in mean blood pressure in response to the stress test (r = 0.56, P < 0.002). Nitric oxide production appeared to be increased in the hypercholesterolemic patients (65 +/- 5 versus 51 +/- 4 mmol/l, P < 0.05), and was not affected significantly by the tests. In contrast, cyclic GMP was lower in the patients and was increased significantly in the normal controls by the hand-grip test (P < 0.05). As a result, plasma cyclic GMP was lower in the patients (1.9 +/- 0.2 versus 2.5 +/- 0.1 nmol/l, P < 0.01). The ratio of plasma cyclic GMP to nitric oxide was also lower in the hypercholesterolemic patients at rest (P < 0.05), and at the end of the mental stress (P < 0.02) and hand-grip (P < 0.001) tests. CONCLUSIONS Patients with hypercholesterolemia showed an exaggerated blood pressure response to both mental stress and exercise, even if resting blood pressure was normal. Increases in the intracellular Ca2+ concentration can contribute to these excessive responses. A disproportionately lower level of cyclic GMP to nitric oxide in plasma may also be involved in these abnormal responses.

Effects of allopurinol, a xanthine oxidase inhibitor, on renal injury in hypercholesterolemia‐induced hypertensive rats

To investigate if increased lipid peroxidation is involved in hypercholesterolemia‐induced hypertension and renal injury, we examined the effects of allopurinol, a xanthine oxidase inhibitor, on these conditions. Groups of male Sprague–Dawley rats were fed for 8 weeks with a high‐cholesterol diet (4% cholesterol), a high‐cholesterol plus allopurinol (10 mg/kgBW/day) diet or a normal diet. Systolic blood pressure (SBP), serum lipids, uric acid (UA) and malondialdehyde (MDA) as a measure of lipid peroxides, and urinary excretion of protein (UP) were measured after 0, 4 and 8 weeks. Urinary excretion of nitrite plus nitrate (UNOx) and iron (UFe), and MDA in the kidney were measured after 8 weeks. The renal injury was evaluated by the glomerular sclerosis score (SS). The high‐cholesterol diet increased SBP, serum total cholesterol and UA, MDA in the serum and kidney, UP, UNOx, UFe and SS. Allopurinol ameliorated cholesterol‐induced elevation in serum UA, MDA in the serum and kidney, UP, UNOx, UFe and SS, but did not affect SBP. Hence, our results suggest that lipid peroxidation may be involved in hypercholesterolemia‐induced renal injury, and that suppression of lipid peroxidation can reduce such injury.

Effects of acute hypercholesterolemia on blood pressure and pressor response to norepinephrine in rats

To examine if high cholesterol in blood acutely affects the blood pressure, we partly exchanged the blood of normal rats for that of hypercholesterolemic rats. Male Sprague–Dawley rats were fed for 8 weeks with a high‐cholesterol diet (4% cholesterol; HC) or a normal diet (NC). The rats were catheterized, and blood of animals in NC was partly exchanged with that of HC (N‐H) or other animals in NC (N‐N). Systolic blood pressure (SBP) and the pressor response to norepinephrine (NE) in N‐H were compared with those of N‐N. Serum lipids and malondialdehyde (MDA), and urinary excretion of protein (UP) and NE (UNE) were determined. After 8 weeks, SBP, serum total cholesterol (TC), MDA, UP and UNE were higher in the HC. Blood exchange caused an increase in TC, MDA and SBP in only the N‐H. Increases in SBP caused by NE injection were rather less in the N‐H than in the N‐N. The blood pressure increase induced by a high‐cholesterol diet seemed to be caused by certain factors in the blood of hypercholesterolemic rats. Excessive lipid oxidation induced by hypercholesterolemia may be involved in the blood pressure elevation.

Effects of alacepril and amlodipine on the renal injury induced by a high-cholesterol diet in rats.

BACKGROUND A high-cholesterol (HC) diet increases blood pressure and induces renal injury in rats. We compared the effects of alacepril, an ACE inhibitor, and amlodipine, a Ca antagonist, on the renal injury induced by an HC diet in rats. DESIGN AND METHODS Male Sprague-Dawley rats were given either an HC diet only (n = 5), an HC diet and amlodipine (n = 10) or an HC diet and alacepril (n = 10). The control rats (n = 5) were given a normal diet Systolic blood pressure (SBP) was measured by a tail-cuff method. Serum lipids, malondialdehyde (MDA) as a parameter for lipid peroxidation and urinary protein excretion were determined at 0, 4 and 8 weeks. The renal injury was evaluated histologically by the glomeruli sclerosing score. RESULTS The HC diet increased SBP. Amlodipine lowered SBP more significantly than alacepril. Serum total cholesterol was increased by the HC diet and was not affected by either anti-hypertensive agent. HDL-cholesterol was similarly decreased in the three HC diet groups. Alacepril, but not amlodipine, completely attenuated the MDA elevation induced by the HC diet. Urinary protein excretion was decreased by the two anti-hypertensive agents at a similar rate. The renal histological injury assessed by the sclerosing score was ameliorated more significantly by alacepril than by amlodipine. CONCLUSIONS Both amlodipine and alacepril decreased blood pressure and urinary protein, and ameliorated the renal injury induced by the HC diet in rats. The renal effect of alacepril seems to be mediated by the decrease in oxidative stress as well as by reduction of blood pressure, since alacepril lowered the sclerosing score more than amlodipine and completely attenuated MDA, although the blood pressure reduction by alacepril was less than that by amlodipine.

Relation of 24-h ambulatory blood pressure with plasma potassium in essential hypertension.

The established associations between blood pressure (BP) and electrolytes are mostly based on either dietary intake or urinary excretion data. We measured office BP, ambulatory BP (ABP) using the automated oscillometric ABPM-630 device, and plasma electrolytes in 82 essential hypertensive patients to examine the relation between BP and plasma electrolytes. Significant negative correlations were observed between plasma potassium concentration and 24-h systolic BP (r = -0.336) and diastolic BP (r = -0.298) in our patients. Plasma potassium concentration inversely correlated also with both daytime and nighttime systolic and diastolic BPs. There was no relation between office BP and plasma potassium concentration. These findings indicate that in essential hypertensives plasma potassium concentration is inversely related to ABP including daytime and nighttime BPs and suggest that potassium may be a factor determining the whole day BP in essential hypertension.