Effects of efonidipine, an L- and T-type calcium channel blocker, on the renin-angiotensin-aldosterone system in chronic hemodialysis patients.

Components of the renin-angiotensin-aldosterone system such as angiotensin II and aldosterone are believed to contribute to the development and progression of cardiovascular tissue and organ injuries. We compared the effects of two calcium channel blockers, efonidipine and amlodipine, on the renin-angiotensin-aldosterone system in patients with end-stage renal diseases on maintenance hemodialysis. Twenty hypertensive patients on chronic hemodialysis were given efonidipine 20-60 mg twice daily and amlodipine 2.5-7.5 mg once daily for 12 weeks each in a random crossover manner. The average blood pressure was comparable between the efonidipine and amlodipine periods (151 + or - 15/77 + or - 8 versus 153 + or - 15/76 + or - 8 mmHg). The pulse rate did not change significantly during the administration periods. Although the plasma renin activity and plasma angiotensin II were not significantly different between the efonidipine and amlodipine periods, plasma aldosterone was significantly lower in the efonidipine period than in the amlodipine period (123 + or - 118 versus 146 + or - 150 pg/mL, P = 0.027). The findings suggest that efonidipine reduces plasma aldosterone levels in patients on maintenance hemodialysis, and this seems to be an additional benefit to the cardiovascular protection by antihypertensive therapy with efonidipine in patients with end-stage renal disease.

Protective effects of an angiotensin II receptor blocker and a long-acting calcium channel blocker against cardiovascular organ injuries in hypertensive patients.

The purpose of this study is to compare the long-term effects of an angiotensin II receptor blocker (ARB) and a long-acting calcium channel blocker (CCB) on left ventricular geometry, hypertensive renal injury and a circulating marker of collagen synthesis in hypertensive patients. Patients with essential hypertension (24 men and 19 women; age, 37-79 years) were treated with a long-acting CCB, amlodipine (AML; 2.5-7.5 mg once daily) for 6 months. Then, AML was switched to an ARB, candesartan (CS; 4-12 mg once daily), in 22 patients (CS group), while AML was continued in the remaining 21 patients for another 6 months (AML group). At the end of each treatment period, ambulatory blood pressure monitoring (ABPM), echocardiography and sampling of blood and urine were performed. The average office blood pressure during the latter period was comparably controlled in the AML and the CS groups (AML: 130 +/- 8/87 +/- 7 mmHg; CS: 133 +/- 11/ 88 +/- 7 mmHg), while the average systolic blood pressure of 24-h ABPM was significantly lower in the AML than in the CS group (127 +/- 9 vs. 133 +/- 14 mmHg, p<0.05). Consequently, the left ventricular mass index was significantly decreased in the AML group (102 +/- 18 to 92 +/- 12 g/m2, p<0.05), while the change was insignificant in the CS group (103 +/- 25 to 98 +/- 21 g/m2). On the other hand, plasma procollagen I C-terminal peptide (PICP), a marker of collagen synthesis, was lowered by CS (86 +/- 21 to 70 +/- 21 ng/ml, p<0.01), but was not significantly affected by AML (80 +/- 127 to 74 +/- 91 ng/ml). CS reduced urinary albumin excretion (57 +/- 123 to 26 +/- 33 mg/g creatinine, p<0.05), but AML did not bring about significant changes (85 +/- 27 to 73 +/- 19 mg/g creatinine). The results suggested that long-acting CCBs are effective in improving left ventricular hypertrophy by controlling 24-h blood pressure, while ARBs possess protective effects against cardiovascular fibrosis and renal injury beyond their antihypertensive effects.

Urinary excretion of liver fatty acid-binding protein in health-check participants.

BACKGROUND: Messenger RNA of liver fatty acid-binding protein (L-FABP) is expressed in proximal tubules of the kidney, and a certain amount is excreted into urine. We analyzed factors relating to the urinary L-FABP excretion in health-check participants. METHODS: We measured L-FABP in the first morning urine by ELISA in 715 men and 193 women 30-79 years of age who entered a 2-day hospitalized health checkup program. In addition to the routine physical examination and laboratory tests, plasma high-sensitivity C-reactive protein (HSCRP) was assayed. RESULTS: In 150 healthy subjects, urinary L-FABP averaged 3.6 +/- 0.2 microg/g creatinine, whereas the values were significantly increased in patients with hypertension (5.2 +/- 0.4, P = 0.010), diabetes mellitus (5.5 +/- 0.5, P < 0.001), and chronic hepatitis (5.8 +/- 1.0, P = 0.022). Urinary L-FABP excretion was significantly greater in women than in men when the value was related to creatinine. In regression analysis in men, urinary L-FABP was positively correlated with fasting plasma glucose (r = 0.103, P = 0.033) and plasma HSCRP (r = 0.135, P = 0.006). CONCLUSIONS: It is suggested that renal production and urinary excretion of L-FABP are increased in situations in which arteriosclerosis is promoted, such as hypertension, diabetes mellitus, and cardiovascular inflammation.

Effects of valsartan on the progression of chronic renal insufficiency in patients with nondiabetic renal diseases.

The present study tested the effects of valsartan, an angiotensin II receptor blocker, on the progression of renal insufficiency in patients with nondiabetic renal diseases. The study subjects were 22 patients with nondiabetic renal diseases whose serum creatinine (Cr) ranged from 1.5 to 3.0 mg/dl. Valsartan (40-80 mg) or placebo was given once daily for 1 year each in a random crossover manner. In both periods, antihypertensive medications were titrated when the blood pressure was not lower than 140/90 mmHg. Blood sampling and urinalysis were performed bimonthly throughout the study periods. The average blood pressure was comparable between the valsartan and the placebo periods (130 +/- 9/86 +/- 6 vs. 131 +/- 8/86 +/- 6 mmHg). Serum Cr significantly increased from 1.9 +/- 0.5 to 2.3 +/- 0.8 mg/dl (p < 0.001) during the placebo period, but the change was insignificant in the valsartan period (2.1 +/- 0.6 to 2.2 +/- 0.9 mg/dl). The slope of decrease in the reciprocal of serum Cr was steeper in the placebo period than in the valsartan period (-0.064 +/- 0.070/year vs. -0.005 +/- 0.050/year, p < 0.01). During the valsartan period, urinary protein excretion was less than that during the placebo period (0.75 +/- 0.73 vs. 1.24 +/- 0.92 g/g Cr, p < 0.001). Serum K was significantly higher in the valsartan period than in the placebo period (4.6 +/- 0.5 vs. 4.4 +/- 0.5 mEq/l, p < 0.05); however, no patients discontinued taking valsartan as a result of hyperkalemia. It is possible that long-term treatment with an angiotensin II receptor blocker, valsartan, is effective at retarding the deterioration of renal function in patients with nondiabetic renal disease by a mechanism independent of blood pressure reduction.

[Angiotensin type 1 receptor blocker reduced proteinuria in patients of focal glomerular sclerosis].

We report three cases of focal glomerular sclerosis (FGS) with proteinuria that improved with the administration of angiotensin type 1 receptor blocker (ARB, losartan or valsartan). These three patients were a 41-year-old male (case 1), a 22-year-old male (case 2) and a 47-year-old male (case 3), who showed proteinuria, renal dysfunction, and hyperlipidemia. In case 1, proteinuria and renal dysfunction were improved by losartan administration and low protein diet therapy. In case 2, losartan with steroid and immunosuppressant led to the complete remission of proteinuria, improvement of renal dysfunction and reduction of the glomerular injury score from repeat biopsy specimen by approximately 20%. In case 3, proteinuria was reduced by valsartan administration with steroid and immunosuppressant therapy. ARB treatment with steroid and immunosuppressant might be more effective on the reduction of proteinuria in FGS patients.

Increased cardiovascular risk in long-term hemodialysis patients carrying deletion allele of ACE gene polymorphism.

BACKGROUND: Controversy continues about the relation of insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene to the genetic predisposition to develop such cardiovascular diseases as myocardial infarction, stroke, and other arteriosclerotic disorders. METHODS: To examine the relation of ACE gene polymorphism to risk for developing cardiovascular diseases in long-term hemodialysis patients, we followed up 534 patients on long-term hemodialysis therapy for 3 years after determining ACE genotype. RESULTS: Numbers of patients with the II, ID, and DD genotypes were 208, 245, and 81, and frequencies of the I and D alleles were 0.62 and 0.38, respectively. Background characteristics, such as age, sex, causative diseases of renal failure, and preexistence of cardiovascular diseases at the time of study entry, were similar among the 3 genotype groups. Serum ACE activity was significantly greater in the DD and ID groups than the II group; however, plasma angiotensin II concentrations were not significantly different among the 3 groups. During the 3 years of follow-up, 46 fatal and 167 nonfatal cardiovascular events occurred. The incidence of these cardiovascular events was significantly associated with older age (P < 0.001), diabetes (P < 0.001), preexistence of cardiovascular diseases (P < 0.001), systolic blood pressure (P = 0.009), high cardiothoracic ratio on chest roentgenogram (P < 0.001), electrocardiographic abnormalities (P < 0.001), and low serum sodium level (P < 0.001). In addition, the incidence of cardiovascular events was greater in patients carrying the D allele (II, 22.1%; ID, 31.8%; DD, 38.3%; P = 0.010). CONCLUSION: It is suggested that the D allele of ACE gene polymorphism is a risk factor for cardiovascular complications in hemodialysis patients.

Nipradilol prevents L-NAME-exacerbated nephrosclerosis with decreasing of caspase-3 expression in SHR.

The proliferative cell nuclear antigen (PCNA) is an auxiliary protein of DNA polymerase delta and appears to be required for both DNA synthesis and repair. Previously, we showed that prolonged NO synthase (NOS) inhibition produced severe nephrosclerosis with an increase of glomerular cell DNA fragmentation (apoptosis), glomerular ischemia and hypertension in spontaneously hypertensive rats (SHR). The objective of the present study was to investigate the effects of the vasodilating, nonselective, NO-releasing beta-adrenoceptor blocker nipradilol on DNA fragmentation and synthesis/repair of glomerular cells in this prolonged NOS blockaded SHR. Twenty-week-old SHR were administered an NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 80 mg/l in drinking water) or co-treated with the same dose of L-NAME and nipradilol (20 mg/kg/day) for 3 weeks. After this treatment, expression of apoptosis was histologically examined using caspase-3, an apoptosis inducer, in addition PCNA (DNA synthesis/repair), and examination of glomerular morphometric changes, including cell number and tuft area. Nipradilol reduced blood pressure and preserved creatinine clearance reduction in L-NAME/SHR. These effects were associated with normalization of the glomerular cell apoptosis index and caspase-3 score, an increase in PCNA index, and increases in glomerular cell numbers and glomerular tuft area, resulting in a decreased glomerular injury score. Thus, in SHR administered an NOS inhibitor, nipradilol improved nephrosclerosis in association with a decrease in apoptosis and an increase in DNA synthesis/repair of glomerular cells. These findings may provide important insights into DNA repair/repair and apoptosis in nephrosclerosis.