Curcumin and enalapril ameliorate renal failure by antagonizing inflammation in 5/6 nephrectomized rats: role of phospholipase and cyclooxygenase.

Previously, we showed that curcumin prevents chronic kidney disease (CKD) development in ⅚ nephrectomized (Nx) rats when given within 1 wk after Nx (Ghosh SS, Massey HD, Krieg R, Fazelbhoy ZA, Ghosh S, Sica DA, Fakhry I, Gehr TW. Am J Physiol Renal Physiol 296: F1146-F1157, 2009). To better mimic the scenario for renal disease in humans, we began curcumin and enalapril therapy when proteinuria was already established. We hypothesized that curcumin, by blocking the inflammatory mediators TNF-α and IL-1ß, could also reduce cyclooxygenase (COX) and phospholipase expression in the kidney. Nx animals were divided into untreated Nx, curcumin-treated, and enalapril-treated groups. Curcumin (75 mg/kg) and enalapril (10 mg/kg) were administered for 10 wk. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was comparably reduced by curcumin and enalapril, with only enalapril significantly lowering blood pressure. Compared with controls, Nx animals had higher plasma/kidney TNF-α and IL-1ß, which were reduced by curcumin and enalapril treatment. Nx animals had significantly elevated kidney levels of cytosolic PLA(2), calcium-independent intracellular PLA(2), COX 1, and COX 2, which were comparably reduced by curcumin and enalapril. Studies in mesangial cells and macrophages were carried out to establish that the in vivo increase in PLA(2) and COX were mediated by TNF-α and IL-1ß and that curcumin, by antagonizing the cytokines, could significantly reduce both PLA(2) and COX. We conclude that curcumin ameliorates CKD by blocking inflammatory signals even if it is given at a later stage of the disease.

Pharmacokinetics and blood pressure response of losartan in end-stage renal disease.

BACKGROUND: Losartan is a selective angiotensin AT1 receptor antagonist currently employed in the management of essential hypertension. This compound is in common use in populations with renal failure and end-stage renal disease (ESRD). OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of losartan in patients with ESRD in order to establish administration guidelines. METHODS: Patients were administered losartan 100 mg/day for 7 days, and after the seventh and final dose pharmacokinetic parameters were determined for both losartan and its active metabolite E-3174. During the study, the haemodialytic clearances of losartan and E-3174 were measured during a standard 4-hour dialysis session. Neurohumoral and biochemical changes were assessed during losartan administration. RESULTS: The pharmacokinetics of losartan and E-3174 in haemodialysis patients did not alter to a clinically significant level. Losartan administration was accompanied by a decline in plasma aldosterone level as well as by an increase in plasma renin activity. Losartan administration resulted in a decline in plasma uric acid level, despite the fact that the study participants had no residual renal function. Losartan and E-3174 were not dialysable. CONCLUSIONS: The pharmacokinetics of losartan and E-3174 are minimally altered in ESRD; thus, dosage adjustment is not required in the presence of advanced dialysis-dependent renal failure. In addition, postdialysis supplementation is not required for losartan because of the negligible dialysability of losartan and E-3174.

Effects of potassium on blood pressure in salt-sensitive and salt-resistant black adolescents.

This study examined the effects of increasing dietary potassium on ambulatory blood pressure nondipping status (<10% decrease in blood pressure from awake to asleep) and cardiovascular reactivity in salt-sensitive and salt-resistant black adolescents. A sample of 58 normotensive (blood pressure, 101/57+/-9/4 mm Hg) black adolescents (aged 13 to 16 years) participated in a 5-day low sodium diet (50 mmol/24 h) followed by a 10-day high sodium diet (150 mmol/24 h NaCl supplement) to determine salt-sensitivity status. Participants showed a significant increase in urinary sodium excretion (24+/-19 to 224+/-65 mmol/24 h) and were identified as salt-sensitive if their mean blood pressure increase was >/=5 mm Hg from the low to high sodium diet. Sixteen salt-sensitive and 42 salt-resistant subjects were then randomly assigned to either a 3-week high potassium diet (80 mmol/24 h) or usual diet control group. Urinary potassium excretion significantly increased in the treatment group (35+/-7 to 57+/-21 mmol/24 h). At baseline, a significantly greater percentage of salt-sensitive (44%) compared with salt-resistant (7%) subjects were nondippers on the basis of diastolic blood pressure classifications (P<0.04). After the dietary intervention, all of the salt-sensitive subjects in the high potassium group achieved dipper status as a result of a drop in nocturnal diastolic blood pressure (daytime, 69 versus 67 mm Hg; nighttime, 69 versus 57 mm Hg). No significant group differences in cardiovascular reactivity were observed. These results suggest that a positive relationship between dietary potassium intake and blood pressure modulation can still exist even when daytime blood pressure is unchanged by a high potassium diet.

The influence of gender and emotional versus instrumental support on cardiovascular reactivity in African-American adolescents.

Research suggests that females seek out, prefer, and are more receptive to emotional support (encouragement), and that males seek out, prefer, and are more receptive to instrumental support (problem-solving). Thus, we hypothesized that boys would show lower blood pressure (BP) reactivity in response to instrumental than emotional or no support, and that girls would show lower BP reactivity in response to emotional than instrumental or no support. Forty-eight healthy African-American adolescents (50% males) participated in a role play conflict task and were randomized to receive either emotional, instrumental, or no support (presence only) from a confederate. Boys showed lower systolic blood pressure (SBP) reactivity in the instrumental than in the emotional or no support conditions and lower recovery SBP as compared to boys in the emotional or no support conditions. A similar pattern of results was demonstrated for diastolic blood pressure (DBP) reactivity. Girls, however, did not demonstrate lower BP reactivity in response to emotional as compared to instrumental support. These findings suggest that instrumental and emotional support differentially influence cardiovascular (CV) reactivity in African-American boys versus girls.

Variability in salt sensitivity classifications in black male versus female adolescents.

Salt sensitivity (changes in blood pressure in response to alterations in salt intake) may be a risk factor for hypertension. In the present study, we examined the prevalence of salt sensitivity based on two different classifications in healthy black male and female adolescents (aged 13 to 16 years). A total of 135 black adolescents participated in a 50 mmol/24 h low sodium diet for 5 days and a 150 mmol/24 h NaCl supplement for 10 days. Dietary compliance was defined as sodium excretion less than or equal to 50 mmol/24 h for the low sodium diet and greater than or equal to 165 mmol/24h for the high NaCl supplement. Salt sensitivity was defined by two classifications: (1) as a decrease in mean blood pressure greater than or equal to 5 mm Hg from baseline to the low sodium diet, and (2) as an increase in mean blood pressure greater than or equal to 5 mm Hg from the low sodium diet to the high NaCl supplement. With classification 1, 14% of boys were identified as salt sensitive compared with 22% of girls. With classification 2, however, 31% of boys were identified as salt sensitive compared with 18% of girls. Analyses based on changes in systolic pressure demonstrated similar findings across sex, although overall classifications based on systolic pressure yielded a greater percentage of salt-sensitive subjects. These sex differences in classification patterns were not due to differences in other important variables, such as changes in sodium excretion, potassium excretion, or Quetelet index. These results suggest that the prevalence of salt sensitivity differs by sex depending on the type of protocol used for the classification of salt sensitivity in a black pediatric population.