Dose-effect relationship of perindopril 10, 14 and 20mg assessed by urine and plasma AcSDKP levels in mildly sodium-depleted healthy volunteers.

BACKGROUND: We describe a pharmacodynamic study of the dose-effect relationship of perindopril arginine at 10, 14, and 20mg with in vivo angiotensin-converting enzyme (ACE) activity, assessed by urine and plasma AcSDKP levels, as well as the effect on plasma active renin concentrations and blood pressure. METHODS: This randomized, double-blind, four-period, crossover study involved single-dose administration of perindopril arginine (10, 14, and 20mg or placebo) to 32 healthy male normotensive mildly sodium-depleted volunteers. Blood and urine were collected over 48h for AcSDKP, ACE activity, and plasma active renin measurements. RESULTS: There were dose-related increases in urinary AcSDKP excretion and plasma AcSDKP concentration after administration of perindopril, with significant between-period differences (estimate of the median difference in urinary excretion over 48h of AcSDKP, 49.1 [95% CI: 15.3-82.0] nmol for 14 versus 10mg, and 73.2 [95% CI: 44.9-106.3] nmol for 20 versus 14mg). Consequently, a dose-dependent increase in plasma active renin concentration was observed. Even though each dose of perindopril 10 to 20mg was associated with a significant 24-h ambulatory blood pressure reduction versus placebo, no dose-dependency was detected in these normotensive subjects. CONCLUSIONS: Administration of perindopril arginine 10, 14, or 20mg to mildly sodium-depleted healthy volunteers is associated with a dose-dependent inhibition of in vivo ACE activity with significant between-dose differences. This effect was associated with a dose-dependent increase in plasma active renin concentration, indicating a dose-dependent blockade of the renin angiotensin system.

Inflammation and oxidative stress markers by pentoxifylline treatment in rats with chronic renal failure and high sodium intake.

BACKGROUND: Inflammation is a risk factor for mortality in patients with chronic renal failure (CRF). Prevention of extracellular fluid volume expansion and the use of certain drugs such as pentoxifylline (PF) may reduce inflammation and oxidative stress. The aim of this study is to analyze the effect of dietary sodium and PF treatment on the levels of inflammation and oxidative stress markers in rats with CRF. METHODS: CRF was induced in rats by 5/6 nephrectomy. Different groups of rats with CRF received low sodium (LNa, 0.01% sodium chloride [NaCl] in the diet), normal sodium (NNa, 0.05% NaCl in the diet), or high sodium diet (HNa, as in NNa plus 0.015% NaCl in the drinking water). An additional group received HNa plus PF treatment (25 mg/kg in the drinking water) for 60 days. Circulating creatinine, tumor necrosis factor alpha (TNF-alpha), nitrites, thiols, malondialdehyde (MDA), and advanced oxidation protein products (AOPP) were measured. RESULTS: Higher sodium intake was associated with higher serum creatinine levels (median; interquartile range), LNa, 1.255; 0.715, NNa, 1.305; 0.495, HNa, 2.015; 1.115 mg/dL (p < 0.05), TNF-alpha levels, LNa, 2.7; 23.6, NNa, 36.7; 47.7, HNa, 263.7; 126.5 pg/mL, and AOPP, LNa, 31.72; 7.55, NNa, 45.89; 9.38, HNa, 60.41; 37.42 microg/mL. MDA was not modified by sodium intake. PF treatment decreased serum TNF-alpha (151.7 pg/mL, p < 0.5) and AOPP (49.83 micromol/L, p < 0.03), and increased nitrites and thiols levels when compared with HNa rats. CONCLUSIONS: High sodium intake increases the serum concentration of inflammation and oxidative stress markers; these changes are prevented by PF treatment.

High dietary calcium attenuates the enhanced vasoconstrictor effects of serum from salt-loaded rats.

The effect of calcium supplementation and salt loading on blood pressure, serum electrolytes, and vasoconstrictor response to serum and vascular prostaglandin synthesis were studied in Sprague Dawley rats. The mean arterial pressure of salt-loaded rats was higher (P < 0.05) than the mean arterial pressure of normal rats, salt-loaded-calcium-fed rats, or calcium-fed rats. Serum from salt-loaded rats had lower serum potassium (4.47 +/- 0.39 Meq/L) and salt-loaded-calcium-fed rats (5.14 +/- 0.47 Meq/L). The vasoactivity of serum from the salt-loaded rats (1116.67 +/- 160.13 mg) was higher than the contraction produced by sera from normal rats (643.80 +/- 37.50 mg) or from salt-loaded-calcium fed rats (562.47 +/- 37.50 mg). Indomethacin did not alter the contractile response of aortae from normal rats and salt-loaded rats to noradrenaline, but it significantly enhanced the contractile response of aortae from salt-loaded-calcium-fed and calcium-fed rats. The results suggest that dietary calcium may lower blood pressure by reducing the circulating levels of some plasma vasoactive factors induced by salt loading and by enhancing the synthesis of vasodilator prostaglandins.

Benidipine counteracts sodium-induced alterations in systemic and regional hemodynamics.

We compared hemodynamic and humoral responses to benidipine and nifedipine during different sodium intakes in essential hypertensives. The study had a single-blind crossover design. Doppler flowmetry and laboratory examinations were performed. During low sodium intake, both benidipine and nifedipine significantly reduced mean arterial pressure to the same extent. Benidipine increased cardiac index, superior mesenteric and renal flows, whereas nifedipine had no effect on either cardiac index or regional blood flows. In the salt-sensitive patients whose mean arterial pressure increased more than 5 mmHg during high sodium intake, sodium loading increased cardiac index and terminal aortic flow, but decreased superior mesenteric and renal flows, while plasma noradrenaline concentrations remained unchanged and plasma arginine vasopressin increased significantly. These hemodynamic responses to sodium in the salt-sensitive patients were more effectively inhibited by benidipine than by nifedipine, although neither of them had any influence on sodium-induced changes in plasma noradrenaline or arginine vasopressin concentration.

DuP 753 increases survival in spontaneously hypertensive stroke-prone rats fed a high sodium diet.

We studied the effects of the nonpeptide angiotensin II receptor antagonist, DuP 753, on blood pressure, body weight, plasma renin activity, sodium excretion, and mortality in male stroke-prone spontaneously hypertensive rats (SHRsp) fed a 4% NaCl diet for 12 weeks. The rise in blood pressure, due to high sodium intake, was blunted in the first 8 weeks of the study in the DuP 753-treated group; however, it started slowly to rise in the following weeks. In the untreated group, blood pressure rose steadily and it was significantly higher than that of the treated group during the whole experimental period. DuP 753-treated rats gained weight continuously during the study in contrast to the untreated group, where weight gain was arrested after 4 weeks. Plasma renin activity rose significantly after 4 weeks of treatment with DuP 753; by week 6 its values returned to baseline values and remained at these lower values until week 12. In the untreated group, plasma renin activity was not suppressed by high sodium intake after 4 weeks; it continued to rise and it was significantly elevated by 8 and 12 weeks. Survival at 12 weeks was 84% in DuP 753-treated group and 26% in the untreated group. The data demonstrate that DuP 753 decreased mortality and dramatically blunted the blood pressure rise in SHRsp fed a high sodium diet.

Angiotensin II receptor antagonist markedly reduces mortality in salt-loaded Dahl S rats.

We investigated the effect of blockade of the renin-angiotensin system (RAS) on morbidity and hypertension in salt-loaded Dahl salt-sensitive (Dahl S) rats. Six-week-old male Dahl S rats (n = 198) were fed a high sodium diet (8% NaCl) for 10 weeks. One group of rats (n = 91) was treated with 30 mg/kg/day of the nonpeptide angiotensin II receptor antagonist, DuP 753, whereas the control group (n = 107) was left untreated. Blood pressure rose steeply in both groups, reaching levels above 200 mm Hg by week 6. DuP 753-treated animals were less hypertensive than controls between weeks 3 and 5 of the study, but had similar blood pressure before and after that time. Although the angiotensin II antagonist had only a transient effect on blood pressure it markedly prolonged survival. After 10 weeks, 68.3% of rats receiving DuP 753, but only 30.1% of controls, were still alive (P less than .0001). Higher morbidity in controls than in DuP 753-treated rats was also suggested by body weights. Following 6 weeks of high salt diet, untreated rats progressively lost weight while DuP 753-treated animals maintained a steady body weight. These results show that the angiotensin II receptor antagonist DuP 753 greatly enhanced survival in salt-loaded Dahl S rats although it reduced blood pressure only transiently. Our data are consistent with a contribution of the RAS to morbidity in this model of hypertension.