dihydropyridines and Albuminuria

The combination of renin-angiotensin system blockers with calcium channel blockers appears to be one of the most effective options for treating hypertension and diabetes.Nevertheless, not all calcium blockers behave in the same manner. Manidipine, unlike other third-generation dihydropyridine derived drugs, blocks T-type calcium channels present in the efferent glomerular arterioles, reducing intraglomerular pressure and microalbuminuria. In addition,T-type channels are related to proliferation, inflammation,fibrosis, vasoconstriction and activation of the renin-angiotensin system. The inhibition of these factors could explain the non-haemodynamic effects of manidipine as compared to other blockers.

Topics: Albuminuria; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Humans; Insulin Resistance; Nitrobenzenes; Oxidative Stress; Piperazines

Microalbuminuria is an issue of great concern in hypertensive patients owing to its close relation with cardiovascular morbidity and mortality. Treatment should aim to reduce microalbuminuria to the normal range. Drugs that block the renin-angiotensin system have specific antiproteinuric properties, but more than one drug is needed to achieve blood pressure control in most cases. The aim of this study was to compare the effects of adding manidipine to the treatment of patients with essential hypertension and persistent albuminuria, despite full-dose treatment with a renin-angiotensin system blocker on urinary albumin excretion (UAE) after 24 weeks of therapy. Patients with diabetes and renal insufficiency were excluded. At baseline, blood pressure and UAE were 155.1 +/- 12/87.76 +/- 11 mmHg and 293.19 +/- 285 mg/g, respectively. At study end, blood pressure was 137.1 +/- 13.1/77.24 +/- 10.4 mmHg (p < 0.001 vs baseline). UAE was reduced by 45% to 161.52 +/- 163 mg/g (p < 0.001 vs baseline). No correlations were found between systolic blood pressure reduction and UAE reduction (Pearson's R = -0.034; p = not significant) nor between estimated glomerular filtration rate and UAE reduction (Pearson's R = -0.0056; p = not significant). No patient withdrew from the study owing to side effects. In conclusion, treatment with manidipine resulted in a large reduction in UAE rates, and this reduction appeared to be independent of the degree of blood pressure reduction or changes in estimated glomerular filtration rate. Our data supports the added value of manidipine in the treatment of patients with hypertension and microalbuminuria.

Topics: Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Renin-Angiotensin System

The main effects of classic calcium antagonists are mediated by the inhibition of L-type calcium channels broadly distributed within the renal vascular bed. Calcium antagonists act predominantly on the afferent arterioles, and dihydropyridines can favour the increase in glomerular hypertension and progression of kidney diseases, in particular when systemic blood pressure remains uncontrolled.. Calcium antagonists have been widely used in clinical practice because of their antihypertensive capacity. The prevention of renal damage is a very important aim of antihypertensive therapy. This is particularly so taking into account the high prevalence of chronic kidney disease in the general population. Non-dihydropyridines such as verapamil have been shown to possess an antiproteinuric effect that could be particularly relevant.. Recent data from clinical trials have confirmed that, in hypertensive patients with preserved renal function or with chronic kidney disease, calcium antagonists are effective antihypertensive drugs to be considered alone or in combination with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. In those patients presenting with proteinuric kidney disease, non-dihydropyridines could reduce proteinuria to a greater degree than dihydropyridines.

Topics: Albuminuria; Angiotensins; Animals; Antihypertensive Agents; Blood Pressure; Calcium; Calcium Channel Blockers; Clinical Trials as Topic; Dihydropyridines; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Proteinuria

Topics: Albuminuria; Calcium Channel Blockers; Dihydropyridines; Endothelium, Vascular; Humans; Hypertension; Inflammation; Insulin Resistance; Metabolic Syndrome; Nitrobenzenes; Oxidation-Reduction; Piperazines; Thrombosis

The aim of this study was to assess the effects of irbesartan alone and combined with amlodipine, efonidipine, or trichlormethiazide on blood pressure (BP) and urinary albumin (UA) excretion in hypertensive patients with microalbuminuria (30≤UA/creatinine (Cr) ratio [UACR] <300 mg/g Cr) and upper-normal microalbuminuria (10≤UACR<30 mg/g Cr). This randomized controlled trial enrolled 175 newly diagnosed and untreated hypertensive patients (home systolic blood pressure [SBP]≥135 mmHg; 10≤UACR<300 mg/g Cr of casual spot urine at the first visit to clinic). All patients were treated with irbesartan (week 0). Patients who failed to achieve home SBP ≤125 mmHg on 8-week irbesartan monotherapy (nonresponders, n = 115) were randomized into three additional drug treatment groups: trichlormethiazide (n = 42), efonidipine (n = 39), or amlodipine (n = 34). Irbesartan monotherapy decreased home SBP and first morning urine samples (morning UACR) for 8 weeks (p < 0.0001). At 8 weeks after randomization, all three additional drugs decreased home SBP (p < 0.0002) and trichlormethiazide significantly decreased morning UACR (p = 0.03). Amlodipine decreased morning UACR in patients with microalbuminuria based on casual spot urine samples (p = 0.048). However, multivariate analysis showed that only higher home SBP and UACR at week 8, but not any additional treatments, were significantly associated with UACR reduction between week 8 and week 16. In conclusion, crucial points of the effects of combination therapy on UACR were basal UACR and SBP levels. The effect of trichlormethiazide or amlodipine treatment in combination with irbesartan treatment on microalbuminuria needs to be reexamined based on a larger sample size after considering basal UACR and SBP levels.

Topics: Aged; Albuminuria; Amlodipine; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dihydropyridines; Drug Therapy, Combination; Essential Hypertension; Female; Humans; Irbesartan; Male; Middle Aged; Nitrophenols; Organophosphorus Compounds; Tetrazoles; Trichlormethiazide; Urinalysis

It has been suggested that renoprotection with calcium channel blockers (CCBs) may differ. This study aimed to compare the anti-proteinuric effect of different CCBs in patients with type 2 diabetes (T2D).. A multicentre, randomized, open-label, active-controlled study was performed in seven centres in Korea. A total of 74 patients with T2D and microalbuminuria treated with renin-angiotensin system (RAS) blockers were randomized to a cilnidipine 10 mg treatment (n=38) or amlodipine 5 mg treatment (n=36).. Urine albumin to creatinine ratio (ACR) reduction was similar between the two groups at 12 weeks (-53.0±123.2 mg/g in cilnidipine group and -35.7±83.6 mg/g in amlodipine group, P=.29) or 24 weeks (-57.3±106.9 mg/g in cilnidipine group and -20.0±110.4 mg/g in amlodipine group, P=.24). In a subgroup analysis, cilnidipine treatment showed a larger ACR reduction than amlodipine treatment at 12 weeks (-84.7±106.8 mg/g in cilnidipine group and -9.5±79.2 mg/g in amlodipine group, P=.01) and 24 weeks (-84.0±111.7 mg/g in cilnidipine group and 14.6±119.4 mg/g in amlodipine group, P=.008), particularly in patients with a longer duration of diabetes more than 10 years.. Cilnidipine did not show any additional anti-albuminuric effect compared with amlodipine in patients with T2D and microalbuminuria treated with an RAS blocker. However, the anti-albuminuric effect of cilnidipine might differ according to the duration of diabetes.

Topics: Adult; Aged; Albuminuria; Amlodipine; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Administration Schedule; Female; Humans; Hypertension; Male; Middle Aged; Treatment Outcome

In AMANDHA trial, the addition of manidipine, but not amlodipine, in diabetic patients with uncontrolled hypertension, microalbuminuria and preserved renal function resulted in a large decrease of urinary albumin excretion (UAE) despite similar blood pressure (BP) reductions. Factors associated with the reduction of UAE were analyzed.. For this purpose, a multivariable analysis was performed.. Although after 6 months of treatment, manidipine and amlodipine decreased BP to a similar extent, reductions of UAE were higher with manidipine. The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were associated with changes in UAE.. The assigned treatment, changes in mean BP, sympathetic tone and glycemic control were independently associated with changes in UAE. Compared with amlodipine, manidipine reduced UAE to a higher extent, independently of BP reduction.

Topics: Adult; Aged; Albumins; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Multivariate Analysis; Nitrobenzenes; Piperazines

Although calcium channel blockers (CCB) are expected to improve the augmentation index (AI) in CKD patients, the potential effect of benidipine on AI has been poorly studied.The present study aimed to compare the effect of benidipine and amlodipine in the treatment of CKD patients as measured through AI and urinary albumin excretion (UAE). Eligible patients with CKD were randomized to either the benidipine group or amlodipine group. Changes in UAE and AI were compared with target blood pressure level set at < 130/80 mmHg. A total of 108 patients were enrolled; 88 patients who were followed up were included in the analysis. Although no significant change in renal function was noted in either group, there was a significant improvement in AI only in the benidipine group (85.7 ± 13.3% to 81.4 ± 15.2%; P = 0.021) A subgroup analysis of 64 patients who achieved SBP < 140 mmHg at the end of follow-up (31 on amlodipine and 33 on benidipine) was carried out. Significant improvement in AI was noted only in the benidipine group (84.5 ± 13.6% to 79.5 ± 15.2%; P = 0.0138). In another subgroup of patients with UAE ≥ 300 mg/g Cr, a significant improvement in UAE in the benidipine group was found compared with the amlodipine group (-25 ± 46, 51 ± 60%, P = 0.031, respectively).These results suggest that benidipine might reduce significantly AI and might have potentially greater improvements in UAE than amlodipine in advanced CKD patients receiving RAS inhibitors.

Topics: Aged; Albuminuria; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Male; Prospective Studies; Renal Insufficiency, Chronic

The RED LEVEL study (REnal Disease: LErcanidipine Valuable Effect on urine protein Losses) directly compares, in an explorative fashion, the effects of lercanidipine + enalapril and amlodipine + enalapril combinations on renal parameters in hypertensive subjects.. This was a 1 year, prospective, multi-center, randomized, open-label, blinded-endpoint (PROBE) study in hypertensive patients with albuminuria.. Renal function (albuminuria, serum creatinine, creatinine clearance, estimated glomerular filtration rate and proteinuria); blood pressure.. Albuminuria was significantly reduced, compared with baseline values, with the lercanidipine + enalapril combination over the entire study period; at month 3, month 6 and month 12, changes from baseline were: -162.5 (p-value = 0.0439), -425.8 (p-value = 0.0010), -329.0 (p-value = 0.0011) mg/24 h), respectively. On the other hand, this improvement was not observed with enalapril + amlodipine. Other parameters of renal function such as serum creatinine, creatinine clearance, estimated glomerular filtration rate and proteinuria did not change over the study. Both lercanidipine + enalapril and amlodipine + enalapril significantly reduced systolic and diastolic blood pressure values from baseline all over the study period with no significant differences between groups. Safety outcomes were comparable between the two groups.. Overall, the results of this explorative study lend support to the anti-albuminuric effect of the lercanidipine + enalapril combination and to the long term renal-protective effects of this combination in patients with hypertension.

Topics: Aged; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Prospective Studies

This study evaluated the non-inferiority of renoprotection afforded by benidipine versus hydrochlorothiazide in hypertensive patients with chronic kidney disease (CKD).. In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of benidipine and hydrochlorothiazide were examined in renin-angiotensin system (RAS) inhibitor-treated patients with blood pressure (BP) readings of ≥ 130/80 mmHg and ≤ 180/110 mmHg, a urinary albumin to creatinine ratio (UACR) of ≥ 300 mg/g, and an estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73m(2). Patients received benidipine (n = 176, final dose: 4.8 mg/day) or hydrochlorothiazide (n = 170, 8.2 mg/day) for 12 months.. Benidipine and hydrochlorothiazide exerted similar BP- and eGFR-decreasing actions. The UACR values for benidipine and hydrochlorothiazide were 930.8 (95% confidence interval: 826.1, 1048.7) and 883.1 (781.7, 997.7) mg/g at baseline, respectively. These values were reduced to 790.0 (668.1, 934.2) and 448.5 (372.9, 539.4) mg/g at last observation carried forward (LOCF) visits. The non-inferiority of benidipine versus hydrochlorothiazide was not demonstrated (benidipine/hydrochlorothiazide ratio of LOCF value adjusted for baseline: 1.67 (1.40, 1.99)).. The present study failed to demonstrate the non-inferiority of the antialbuminuric effect of benidipine relative to that of hydrochlorothiazide in RAS inhibitor-treated hypertensive patients with macroalbuminuria.

Topics: Adult; Aged; Albuminuria; Amlodipine; Blood Pressure; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Renal Insufficiency, Chronic; Renin-Angiotensin System

This study assessed the urinary albumin/creatinine ratio (ACR) and uric acid metabolism in 70 hypertensive patients with chronic kidney disease in whom urinary ACR had remained ≥30 mg/g under the treatment of the L-type calcium channel blocker amlodipine. Three months after switching to the N/L-type calcium channel blocker cilnidipine, blood pressure (BP) did not change; however, urinary ACR significantly decreased with cilnidipine. Serum uric acid levels showed no significant change. In cases where uric acid production had been high (urinary uric acid/creatinine ratio ≥0.5), the urinary uric acid/creatinine ratio decreased significantly after cilnidipine treatment, suggesting that cilnidipine can suppress excessive uric acid formation. These results suggest that switching from amlodipine to cilnidipine results in a significant reduction in urinary ACR as well as significant reduction in uric acid production. Thus, cilnidipine is more useful than amlodipine in improving albuminuria and uric acid metabolism in hypertensive patients with chronic kidney disease.

Topics: Aged; Aged, 80 and over; Albuminuria; Amlodipine; Blood Pressure; Calcium Channel Blockers; Creatinine; Cross-Over Studies; Diabetic Nephropathies; Dihydropyridines; Dose-Response Relationship, Drug; Drug Substitution; Female; Humans; Hypertension, Renal; Japan; Kidney Failure, Chronic; Male; Middle Aged; Nephrosclerosis; Uric Acid

Albuminuria and a high plasma aldosterone concentration (PAC) are prognosis factors predicting a poor outcome for cardiovascular disease. We examined here the effects of benidipine, a T/L-type calcium channel blocker (CCB), on albuminuria and PAC.Thirty-one patients with essential hypertension who received an L-type CCB and achieved the target blood pressure (BP) indicated by the Treatment Guidelines of the Japan Society of Hypertension (JSH2009) were investigated. The Ltype CCB under treatment was switched to benidipine at a dose in which equivalent BP reduction was expected. BP and estimated glomerular filtration rate at 6 months after switching to benidipine were not significantly different from those at baseline. The urinary-albumin-creatinine ratio (UACR) decreased significantly by 36.9% (P = 0.001). No significant change was observed in plasma renin activity (P = 0.063). The PAC of all patients decreased significantly by 11.8% (P = 0.002). When analyzed by daily doses of benidipine, the PAC appeared to have decreased in patients who received 4 mg per day of benidipine (n = 14), although statistical significance was not reached (P = 0.096). The PAC in patients who received 8 mg per day of benidipine (n =17) was significantly reduced by 13.2% (P = 0.017).In hypertensive patients whose BP is controlled by L-type CCB, switching to the T/L-type CCB benidipine maintained BP control and reduced UACR. In addition, the high dose of benidipine reduced the PAC independent of BP control. These results suggest the T/L-type CCB benidipine may contribute to cardio-renal protection in addition to lowering BP.

Topics: Aged; Albuminuria; Aldosterone; Blood Pressure; Calcium Channel Blockers; Creatinine; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Pilot Projects; Prospective Studies; Renin

A thiazide diuretic used in combination with benazepril is superior to amlodipine plus benazepril in reducing albuminuria in hypertensive patients with diabetes. However, calcium channel blockers have diverse characteristics. Thus, we investigated whether combining an angiotensin receptor blocker with either azelnidipine or a thiazide diuretic produced similar reductions in albuminuria in hypertensive diabetic patients for the same levels of blood pressure achieved.. Hypertensive patients with type 2 diabetes and albuminuria (30-600 mg/g creatinine) under antihypertensive treatment (mean age 67.0±7.6 years) were instructed to stop all antihypertensive treatment and take a combination of olmesartan (20 mg/day) and amlodipine (5 mg/day) for 3 months (run-in period). Then, patients were randomly assigned to receive either olmesartan plus azelnidipine (16 mg/day; n=71) or olmesartan plus trichlormethiazide (1 mg/day; n=72) for an additional 6 months. The primary end point was urinary excretion of albumin at 6 months after randomization.. At the time of randomization, urinary albumin was 116.0 and 107.8 mg/g creatinine (geometric mean) in the azelnidipine and diuretic arms, respectively, and was reduced to a similar extent [79.8 (95% confidence interval 66.4-96.0) and 89.7 (74.6-107.7) mg/g creatinine, respectively, after adjustment for baseline values]. Blood pressure did not differ between the two groups throughout the study period.. Azelnidipine is equally effective as a thiazide diuretic in reducing urinary albumin when used in combination with olmesartan.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diabetes Complications; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Imidazoles; Kidney Diseases; Male; Middle Aged; Prognosis; Prospective Studies; Risk Factors; Tetrazoles; Young Adult

To clarify whether the L-/N-type calcium channel blocker (CCB) cilnidipine is more renoprotective than the L-type CCB amlodipine in patients with early-stage diabetic nephropathy.. In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of cilnidipine and amlodipine were examined in renin-angiotensin system (RAS) inhibitor-treated patients with hypertension (blood pressure [BP]: 130-180/80-110 mmHg), type 2 diabetes, and microalbuminuria (urinary albumin to creatinine [Cr] ratio [UACR]: 30-300 mg/g).. Patients received cilnidipine (n = 179, final dose: 10.27 ± 4.13 mg/day) or amlodipine (n = 186, 4.87 ± 2.08 mg/day) for 12 months. Cilnidipine and amlodipine equally decreased BP. The UACR values for the cilnidipine and amlodipine groups were 111.50 ± 138.97 and 88.29 ± 63.45 mg/g, respectively, before treatment and 107.93 ± 130.23 and 89.07 ± 97.55 mg/g, respectively, after treatment. The groups showed similar changes for the natural logarithm of the UACR, serum Cr, and estimated glomerular filtration rate.. Cilnidipine did not offer greater renoprotection than amlodipine in RAS inhibitor-treated hypertensive patients with type 2 diabetes and microalbuminuria.

Topics: Aged; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Renin-Angiotensin System

At the intervention for cardiovascular disease (CVD), albuminuria is a new pivotal target. Calcium channel blocker (CCB) is one of the most expected agents. Currently CCBs have been classified by delivery system, half-life and channel types. We tested anti-albuminuric effect among 4 types of CCBs.. Subjects were 50 hypertensives (SBP/DBP 164.7±17.1/92.3±12.2mmHg, s-Cr 0.81±0.37mg/dl, urinary albumin excretion (UAE) 69.4 (33.5-142.6) mg/gCr). Four CCBs were administered in a crossover setting: nifedipine CR, a long biological half-life L type by controlled release; cilnidipine, an N/L type; efonidipine, a T/L type; and amlodipine, a long biological half-life L type.. Comparable BP reductions were obtained. UAE at endpoints ware as follows (mg/gCr, *P<0.01): nifedipine CR 30.8 (17.3-81.1),* cilnidipine 33.9 (18.0-67.7),* efonidipine 51.0 (21.2-129.8), amlodipine 40.6 (18.7-94.7). By all agents, significant augmentations were observed in PRA, angiotensin I and angiotensin II (AngII). AngII at cilnidipine was significantly lower than that at amlodipine. PAC at cilnidipine and efonidipine was significantly lower than that at amlodipine. Nifedipine CR significantly reduced ANP concentration.. It is revealed that only nifedipine CR and cilnidipine could reduce albuminuria statistically. Thus, it is suggested that the 2 CCBs might be favorable for organ protection in hypertensives.

Topics: Aged; Aged, 80 and over; Albuminuria; Biomarkers; Calcium Channel Blockers; Cardiovascular Diseases; Cross-Over Studies; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Nifedipine

Cilnidipine inhibits both L- and N-type calcium channels and has been shown to dilate efferent arterioles as effectively as afferent arterioles. We conducted an open-label, randomized trial to compare the effects of cilnidipine against those of amlodipine on blood pressure (BP), albuminuria, and plasma aldosterone concentration in hypertensive patients with mild- to moderate-stage chronic kidney disease. Patients with BP ≥130/80 mmHg, an estimated glomerular filtration rate of 90-30 ml/min/1.73 m(2), and albuminuria ≥30 mg/g, despite treatment with the maximum recommended dose of angiotensin II receptor blockers, were randomly assigned to two groups. Patients received either 10 mg/day cilnidipine (increased to 20 mg/day; n = 35) or 2.5 mg/day amlodipine (increased to 5 mg/day; n = 35). After 48 weeks of treatment, a significant and comparable reduction in systolic and diastolic BP was observed in both groups. The percent reduction in the urinary albumin to creatinine ratio and liver-type fatty acid binding protein (L-FABP) in the cilnidipine group was significantly greater than in the amlodipine group. Although plasma renin activity did not differ between the two groups, the plasma aldosterone level was significantly decreased in the cilnidipine group. Cilnidipine therefore appears to reduce albuminuria, urinary L-FABP, and plasma aldosterone levels more than amlodipine, and these effects are independent of BP reduction.

Topics: Aged; Albuminuria; Aldosterone; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Biomarkers; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Creatinine; Dihydropyridines; Down-Regulation; Fatty Acid-Binding Proteins; Female; Humans; Hypertension; Japan; Linear Models; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome

Intraglomerular pressure is one of the main drivers of progression of renal failure. Experimental data suggest that there are important differences between calcium channel blockers (CCBs) in their renal haemodynamic effects: manidipine reduces, whereas amlodipine increases intraglomerular pressure. The aim of this study was to investigate the effects of manidipine and amlodipine treatment on intragomerular pressure (P(glom)) in patients with mild to moderate essential hypertension.. In this randomized, double-blind, parallel group study, hypertensive patients were randomly assigned to receive manidipine 20 mg (n = 54) or amlodipine 10 mg (n = 50) for 4 weeks. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined by constant-infusion input-clearance technique with p-aminohippurate (PAH) and inulin. P(glom) and resistances of the afferent (R(A)) and efferent (R(E)) arterioles were calculated according to the model established by Gomez.. P(glom) did not change in the manidipine group (P = 0.951), whereas a significant increase occurred in the amlodipine group (P = 0.009). There was a significant difference in the change of P(glom) by 1.2 mmHg between the manidipine and amlodipine group (P = 0.042). In both treatment arms, R(A) was reduced (manidipine P = 0.018; amlodipine P < 0.001). The reduction of R(A) was significantly more pronounced with amlodipine compared with manidipine treatment (P < 0.001). R(E) increased in both treatment arms (manidipine P = 0.012; amlodipine P = 0.002), with no difference between the treatment arms. Both CCBs significantly reduced systolic and diastolic blood pressure (BP) (both P < 0.001). However, amlodipine treatment resulted in a significantly greater decrease of BP compared with manidipine (P < 0.001).. In accordance with experimental data after antihypertensive treatment of 4 weeks, intraglomerular pressure was significantly lower with the CCB manidipine than with amlodipine, resulting and explaining their disparate effects on albuminuria.

Topics: Adult; Aged; Albuminuria; Amlodipine; Creatinine; Dihydropyridines; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension; Kidney; Male; Middle Aged; Nitrobenzenes; Piperazines

Angiotensin II receptor blockers (ARB) are often co-administered with a calcium channel blocker (CCB) for treating hypertension. In this open-label randomised study, untreated diabetic hypertensive patients were randomised to receive either olmesartan 20 mg/day or candesartan 8 mg/day for 12 weeks. Patients with blood pressure exceeding 130/80 mm Hg received add-on 16 mg/day azelnidipine to ongoing olmesartan (OL group) or 5 mg/day amlodipine to ongoing candesartan (CA group) for 24 weeks. Home-measured and clinic-measured blood pressure decreased in both groups. Fasting blood glucose, haemoglobin A1c (HbA1c) and urinary albumin levels decreased significantly in the OL group but not in the CA group. In conclusion, this study revealed clinically relevant differences between two combinations of an ARB+CCB in diabetic hypertensive patients. Olmesartan and azelnidipine had a more persistent early morning antihypertensive effect and produced greater decreases in heart rate, fasting blood glucose and HbA1c (National Glycohemoglobin Standardization Program values) levels, and microalbuminuria than did candesartan and amlodipine.

Topics: Aged; Albuminuria; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Azetidinecarboxylic Acid; Benzimidazoles; Biomarkers; Biphenyl Compounds; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Chi-Square Distribution; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Glycated Hemoglobin; Heart Rate; Humans; Hypertension; Imidazoles; Japan; Male; Middle Aged; Tetrazoles; Time Factors; Treatment Outcome

Cilnidipine, an L/N-type calcium channel blocker (CCB), has been reported to have more beneficial effects on proteinuria progression in hypertensive patients than amlodipine, an L-type CCB. The N-type calcium channel blockade that inhibits renal sympathetic nerve activity might reduce glomerular hypertension by facilitating vasodilation of the efferent arterioles. However, the precise mechanism of the renoprotective effect of cilnidipine remains unknown. Because cilnidipine exerted significantly higher antioxidant activity than amlodipine in cultured human mesangial cells, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing oxidative stress. A total of 35 hypertensive patients receiving a renin-angiotensin system inhibitor were randomly assigned to a cilnidipine (n=18; 10 mg per day cilnidipine titrated to 20 mg per day) or amlodipine (n=17; 5 mg per day amlodipine titrated to 10 mg per day) group; the target blood pressure (BP) was set at 130/85 mmHg. After 6 months of treatment, systolic and diastolic BPs were significantly reduced in both of the groups, without any significant difference between the groups. The urinary albumin, 8-hydroxy-2'-deoxyguanosine (OHdG) and liver-type fatty-acid-binding protein (L-FABP) to creatinine ratios significantly decreased in the cilnidipine group (P<0.05) compared with those in the amlodipine group. The reductions in urinary albumin, 8-OHdG and L-FABP were not correlated with the change in systolic BP. In conclusion, cilnidipine, but not amlodipine, ameliorated urinary albumin excretion and decreased urinary 8-OHdG and L-FABP in the hypertensive patients. Cilnidipine probably exerts a greater renoprotective effect through its antioxidative properties.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Albuminuria; Amlodipine; Antihypertensive Agents; Antioxidants; Blood Pressure; Calcium Channel Blockers; Deoxyguanosine; Dihydropyridines; Fatty Acid-Binding Proteins; Female; Heart Rate; Humans; Hypertension; Incidence; Male; Middle Aged; Oxidative Stress; Prospective Studies; Renal Insufficiency, Chronic

Benidipine inhibits both L- and T-type Ca channels, and has been shown to dilate the efferent arterioles as effectively as the afferent arterioles. In this study, we conducted an open-label and randomized trial to compare the effects of benidipine with those of amlodipine on blood pressure (BP), albuminuria and aldosterone concentration in hypertensive patients with mild-to-moderate stage chronic kidney disease (CKD). Patients with BP ≥ 130/80 mm Hg, with estimated glomerular filtration rate (eGFR) of 30-90 ml min(-1) per 1.73 m(2), and with albuminuria>30 mg per g creatinine (Cr), despite treatment with the maximum recommended dose of angiotensin II receptor blockers (ARBs) were randomly assigned to two groups. Patients received either of the following two treatment regimens: 2 mg per day benidipine, which was increased up to a dose of 8 mg per day (n=52), or 2.5 mg per day amlodipine, which was increased up to a dose of 10  mg per day (n=52). After 6 months of treatment, a significant and comparable reduction in the systolic and diastolic BP was observed in both groups. The decrease in the urinary albumin to Cr ratio in the benidipine group was significantly lower than that in the amlodipine group. Although plasma renin activity was not different in the two groups, plasma aldosterone levels were significantly decreased in the benidipine group. Moreover, urinary Na/K ratio was significantly decreased in the benidipine group but remained unchanged in the serum. It may be concluded that benidipine results in a greater reduction of plasma aldosterone and albuminuria than amlodipine, and that these effects are independent of BP reduction.

Topics: Aged; Albuminuria; Aldosterone; Amlodipine; Angiotensin Receptor Antagonists; Blood Pressure; Calcium Channel Blockers; Chronic Disease; Diabetic Nephropathies; Dihydropyridines; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Hypertension; Male; Middle Aged; Nephrosclerosis; Potassium; Severity of Illness Index; Sodium

We aimed to test the hypothesis that the angiotensin II receptor blocker (ARB)/diuretic combination decreases the urinary albumin/creatinine ratio (UACR) to a greater extent than treatment with the ARB/calcium-channel blocker (CCB) combination through a mechanism related to a greater reduction of sleep blood pressure (BP).. We conducted a prospective, randomized, open-label, blinded end-point trial in hypertensive patients. Patients received olmesartan monotherapy for 12 weeks, followed by an additional use of hydrochlorothiazide (HCTZ) (n = 104) or azelnidipine (n = 103) for 24 weeks after randomization. The measurements of central and ambulatory BP, and laboratory tests were performed at baseline and the end of the study.. The adjusted percent reduction in UACR in the olmesartan/HCTZ group was significantly greater than that in the olmesartan/azelnidipine group (-43.2 vs. -24.0%, P = 0.0014), although the olmesartan/azelnidipine group showed greater decreases in central systolic BP (SBP; P = 0.04), oxidative stress (urinary 8-isoprostane; P = 0.02), inflammation (high-sensitivity C-reactive protein; P = 0.04), and insulin resistance (the homeostasis model assessment insulin resistance index (HOMA(IR)); P < 0.001) than the olmesartan/HCTZ group. In multivariate regression analyses, the significant determinants of change in UACR in the olmesartan/HCTZ group were changes in sleep SBP (P < 0.001), central SBP (P = 0.01), estimated glomerular filtration rate (eGFR) (P = 0.02), and HOMA(IR) (P = 0.03), and those in the olmesartan/azelnidipine group were changes in central SBP (P = 0.001) and urinary 8-isoprostane (P = 0.02).. These data showed that the ARB/diuretic combination decreased UACR significantly more than the ARB/CCB combination, and this decrease in UACR was associated with a greater magnitude reduction in sleep SBP.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin Receptor Antagonists; Azetidinecarboxylic Acid; Blood Pressure; C-Reactive Protein; Calcium Channel Blockers; Creatinine; Dihydropyridines; Dinoprost; Diuretics; Female; Humans; Imidazoles; Male; Middle Aged; Sleep; Tetrazoles

Calcium channel blockers (CCBs) are recommended second-line antihypertensives for renin-angiotensin system (RAS) inhibitor-treated patients with chronic kidney disease (CKD), but they do not always ameliorate the progression of CKD. However, small clinical studies suggest that sympatholytic CCBs may protect against kidney injury. Therefore, a clinical trial was designed to test whether the sympatholytic CCB azelnidipine decreases the urinary albumin levels of CKD patients treated with the angiotensin receptor blocker olmesartan more potently than the widely-used non-sympatholytic CCB amlodipine.. A multi-center, open-labeled, randomized clinical intervention trial was designed to compare the antialbuminuric effect of azelnidipine (8-16 mg/day) and amlodipine (2.5-5 mg/day) in olmesartan-treated hypertensive (blood pressure 130-180/80-110 mmHg) patients with type 2 diabetes (fasting blood sugar ≥126 mg/dL or treatment with antidiabetic agents) and albuminuria (urinary albumin/creatinine ratio ≥30 mg/g). The primary study endpoint is the change in the urinary albumin/creatinine ratio after 12 months of treatment.. The present trial is expected to clarify whether the sympatholytic CCB azelnidipine is a beneficial second-line choice for RAS inhibitor-treated hypertensive patients with CKD, such as diabetic nephropathy.

Topics: Adult; Aged; Albuminuria; Amlodipine; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diabetic Nephropathies; Dihydropyridines; Drug Therapy, Combination; Humans; Hypertension; Imidazoles; Middle Aged; Research Design; Sympatholytics; Tetrazoles

Recently, it has been demonstrated that L-/N-type calcium channel blockers (CCBs), cilnidipine, but not L-type CCB, decreased urinary protein in renin-angiotensin system (RAS), inhibitor-treated hypertensive patients with macroproteinuria. However, the antiproteinuric effect of cilnidipine was weaker in diabetic patients than in nondiabetic patients with macroproteinuria. This may be due to the fact that diabetic neuropathy was also developed in patients with advanced diabetic nephropathy because L-/N-type CCB has been considered to exert its renoprotetive effects through sympatholytic action. If so, the antiproteinuric effect of cilnidipine may be potent in patients with early stages of diabetic nephropathy. To elucidate our hypothesis, we designed a multi-center, open-labeled, randomized trial to compare the antialbuminuric effect between cilnidipine and amlodipine in RAS inhibitor-treated hypertensive (blood pressure [BP]: 130-180/80-110 mmHg) patients with type 2 diabetes and microalbuminuria (urinary albumin/creatinine [Cr] ratio: 30-300 mg/g). The primary study endpoint is the change in the urinary albumin/Cr ratio after a 1-year treatment. Enrollment began in April 2008 and was completed in March 2010. A total of 367 patients were randomly allocated to receive cilnidipine or amlodipine. At baseline, study subjects had 63.3± 8.5 years of age, 145.9 ± 12.2/80.8 ± 10.0 mmHg of BP, 101.0 ± 111.6 mg/g of urinary albumin/Cr. The trial is expected to show whether cilnidipine can exert an antialbuminuric effect in RAS inhibitor-treated hypertensive patients with early stages of diabetic nephropathy.

Topics: Aged; Albuminuria; Amlodipine; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Clinical Protocols; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Kidney Function Tests; Male; Middle Aged; Renin-Angiotensin System

The present study aimed to determine whether either of two calcium channel blockers affected urinary albumin excretion or urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein (L-FABP) in hypertensive diabetic patients with chronic kidney disease (CKD) who were already being treated with maximum doses of the angiotensin II receptor blocker olmesartan. We conducted an open-label, randomized, parallel-controlled study on type 2 diabetic patients with stable glycemic control who were receiving fixed doses of antidiabetic agents. The patients received either 8 mg per day azelnidipine, which was increased up to 16 mg per day (azelnidipine group; n=34), or 2.5 mg per day amlodipine, which was increased up to 5 mg per day (amlodipine group; n=33), over a 24-week period. Mean systolic and diastolic blood pressure decreased significantly in both groups, but there was no significant difference between the two groups at the end of the study. Serum creatinine levels and estimated glomerular filtration rate did not differ significantly between the two groups, whereas the urinary albumin/creatinine ratio and 8-OHdG and L-FABP levels decreased significantly in the azelnidipine group compared with the amlodipine group. Plasma aldosterone level was significantly decreased in the azelnidipine group, and its changes correlated significantly with those of urinary 8-OHdG and L-FABP. Our results suggest that the addition of azelnidipine to the maximal recommended dose of olmesartan was more effective in reducing albuminuria and oxidant stress in hypertensive diabetic patients with CKD than the addition of amlodipine.

Topics: Aged; Albuminuria; Aldosterone; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Male; Middle Aged; Tetrazoles

Anti-hypertensive medication with an angiotensin II receptor blocker (ARB) is effective in slowing the progression of chronic kidney disease. The present study was designed to investigate whether calcium channel blockers (CCBs) in combination with an ARB differentially affect kidney function. Elderly hypertensive patients with chronic kidney disease (n = 17, 72 +/- 6 years old) were instructed to self-measure blood pressure. They were randomly assigned to receive either benidipine (4-8 mg/day) or amlodipine (5-10 mg/day) combined with olmesartan (10 mg/day). After 3 months, CCBs were switched in each patient and the same protocol was applied for another 3 months. At baseline, significant correlation was obtained between urine albumin (22.8 +/- 16.7 (median +/- median absolute deviation) mg/g creatinine) and self-measured blood pressure (170 +/- 23/87 +/- 10 (mean +/- SD) mmHg, r = 0.65, p < 0.01). Both regimens reduced blood pressure to a similar extent (139 +/- 22/75 +/- 11 mmHg and 133 +/- 17/72 +/- 10 mmHg, respectively; both p < 0.001), while urine albumin decreased only after combination therapy including benidipine (11.7 +/- 6.1 mg/g creatinine, p < 0.05). Benidipine, but not amlodipine, in combination with olmesartan, reduced urinary albumin excretion in elderly hypertensive patients with chronic kidney disease. The results suggest the importance of selecting medications used in combination with ARB in hypertensive patients with chronic kidney disease.

Topics: Aged; Aged, 80 and over; Albuminuria; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Imidazoles; Male; Renal Insufficiency, Chronic; Tetrazoles

Calcium channel blocker (CCB) is one of the most useful antihypertensive agents. However, the activation of the renin-angiotensin system (RAS) is an unfavorable characteristic. N-type calcium channel is thought to be involved in catecholamine's release. Accordingly, N/L-type CCB has a probability of less activation of the RAS. We substantiated the hypothesis that N/L-type CCB, cilnidipine, leads to less activation of the RAS compared with conventional L-type CCB, amlodipine.. Randomized, cross-over study.. Outpatient study.. Participants were 110 hypertensive patients [male/female 46/64, age 66.3 ± 10.8 years, systolic blood pressure (SBP)/diastolic blood pressure (DBP) 161.8 ± 16.9/92.9 ± 12.4 mmHg, s-Cr 0.77 ± 0.32 mg/dl, plasma renin activity (PRA) 0.65 ± 0.63 ng/ml per h, angiotensin I (AngI) 70.5 ± 77.3 pg/ml, angiotensin II (AngII) 5.2 ± 3.9 pg/ml, plasma aldosterone concentration (PAC) 76.3 ± 35.9 pg/ml, urinary albumin excretion (UAE) 108.1 ± 284.2 mg/gCr]. Amlodipine besilate or cilnidipine was administered for 12 weeks in a cross-over manner as a monotherapy with an intention-to-treat fashion by titrating doses. Final doses of amlodipine besilate and cilnidipine were 6.6 ± 2.7 and 13.7 ± 5.1 mg/day, respectively.. Changes in blood pressure, PRA, AngI, AngII, PAC, UAE of baseline and each end of amlodipine besilate and cilnidipine administration.. Results were as follows (amlodipine vs. cilnidipine): SBP/DBP (mmHg): 135.2 ± 11.7/79.8 ± 9.6 vs. 136.7 ± 13.2/79.5 ± 10.9, P = 0.22/0.74; PRA (ng/ml per h): 1.16 ± 1.03 vs. 0.95 ± 0.78, P < 0.01; AngI (pg/ml): 155.0 ± 306.4 vs. 101.8 ± 92.0, P < 0.05; AngII (pg/ml): 12.0 ± 12.3 vs. 7.1 ± 4.5, P < 0.001; PAC (pg/ml): 81.6 ± 37.9 vs. 74.3 ± 36.2, P < 0.05; UAE (mg/gCr): 145.4 ± 424.5 vs. 58.8 ± 125.1, P < 0.05. Thus, in spite of the comparable blood pressure reductions, each level of components of the RAS at cilnidipine administration was significantly lower than those at amlodipine. Apart from this, UAE at cilnidipine administration was also significantly lower than that at amlodipine.. It is suggested that cilnidipine leads to less activation of the RAS compared with amlodipine for the first time in human clinical patients and therefore cilnidipine might be expected to be superior in organ protection in addition to the antialbuminuric effect.

Topics: Aged; Albuminuria; Aldosterone; Amlodipine; Angiotensin I; Angiotensin II; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Male; Middle Aged; Renin; Renin-Angiotensin System

High-normal urinary albumin excretion has been reported to have clinical significance with respect to progression of proteinuria and hypertension.. We analysed the effect of cilnidipine (10 mg/day) on morning systolic blood pressure (SBP) and urine albumin-creatinine ratio (UACR) in 16 non-diabetic hypertensive patients with a normal to marginally elevated UACR (mean +/- SD 29.4 +/- 21.7; range 7.5-72.9 mg/g creatinine).. Sequential home BP and UACR data were fitted to a simple exponential function as follows: where y is SBP (mmHg) or UACR (mg/g creatinine); alpha is the extent of the SBP (mmHg)- or UACR (mg/g creatinine)-lowering effect; beta (days) is the time-constant for SBP or UACR decrease; t is the number of days after the start of cilnidipine administration; and gamma is the finally stabilized SBP (mmHg) or UACR (mg/g creatinine).. Mean +/- SD morning SBP and UACR decreased by 20.4 +/- 11.4 mmHg and 15.2 +/- 13.1 mg/g creatinine, respectively, as determined by coefficient alpha. The mean +/- SD time-constant for UACR decrease was significantly longer than that for BP decrease (43.5 +/- 22.9 vs 15.4 +/- 7.1 days). UACR reduction correlated with pre-treatment UACR values (correlation coefficient [R] = 0.88, p < 0.01) but not with BP decrease.. The present study demonstrated that cilnidipine reduced UACR in hypertensive patients with normal to marginally elevated UACR independent of its BP-lowering effect.

Topics: Albuminuria; Antihypertensive Agents; Biomarkers; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Creatinine; Dihydropyridines; Humans; Hypertension; Models, Statistical; Nephelometry and Turbidimetry; Time Factors; Treatment Outcome

Patients with diabetes complicated by hypertension and microalbuminuria have elevated cardiovascular risk, and controlling blood pressure in these patients is an urgent clinical priority. The present study aimed to examine the effects of a fixed-dose combination of antihypertensives on blood pressure and microalbuminuria.. Patients with type 2 diabetes, mild-to-moderate hypertension (diastolic blood pressure 85-105 mmHg, systolic blood pressure <160 mmHg, and 24-hour mean systolic blood pressure >130 mmHg), and microalbuminuria were randomized to 1 year of doubleblind treatment with fixed-dose manidipine/delapril (n=54) or losartan/hydrochlorothiazide (HCTZ) (n=56).. Blood pressure was significantly reduced at 1 year in both groups (-22.2/-14.6 mmHg and -19.5/-14.3 mmHg, for systolic and diastolic blood pressure respectively, P<0.001 for each), with no significant between-group difference. Reductions in microalbuminuria occurred in both groups, with mean changes at 1 year of -3.9 mg/mmol creatinine (95% CI -5.3, -2.5) for manidipine/delapril (P<0.001 vs. baseline) and -2.7 mg/mmol creatinine (95% CI -4.0, -1.3) for losartan/HCTZ (P<0.001 vs. baseline and P=0.199 between groups). Glycemia over the 1-year study was largely unaffected; the blood glucose concentration was reduced from baseline with manidipine/delapril, although not statistically significant (mean change -0.2 mmol/L, P=0.064). Both treatments were well tolerated, with discontinuation for adverse events for one (1.9%) patient in the manidipine/delapril group and two (3.6%) in the losartan/HCTZ group.. A fixed-dose manidipine/delapril combination represents a useful addition to the treatment options available to control hypertension complicated by diabetes and microalbuminuria.

Topics: Aged; Aged, 80 and over; Albuminuria; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Combinations; Female; Humans; Hydrochlorothiazide; Hypertension; Indans; Losartan; Male; Middle Aged; Nitrobenzenes; Piperazines

To evaluate the effects of manidipine versus amlodipine on blood pressure, albuminuria, insulin sensitivity, adiponectin, TNF-alpha and C-reactive protein in nondiabetic subjects with metabolic syndrome (ATP-III definition), including impaired fasting glucose (>5.6 mmol/l) and hypertension.. In total, 64 patients were recruited and randomly assigned to manidipine 20 mg versus amlodipine 10 mg (for 12 +/- 2 weeks).. Blood pressure was reduced to a similar extent (p < 0.001) by both treatments. Albuminuria was significantly reduced by manidipine (-37.3%; p = 0.003), but not by amlodipine. C-reactive protein was reduced similarly (p < 0.01) by both treatments. Plasma adiponectin was increased (32.9%; p = 0.011) and plasma TNF-alpha was reduced by manidipine (-37.1%; p = 0.019), but neither was significantly changed by amlodipine. The HOMA insulin resistance index was significantly reduced by manidipine (-21.3%; p = 0.007), but not by amlodipine (-8.3%; p = 0.062). Tolerability with manidipine was superior to that with amlodipine (p = 0.04).. These data support the added value of manidipine in renal and metabolic protection beyond blood pressure reduction in the treatment of hypertensive patients with metabolic syndrome.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Albuminuria; Amlodipine; Antihypertensive Agents; Blood Pressure; C-Reactive Protein; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Nitrobenzenes; Piperazines; Prospective Studies; Single-Blind Method; Tumor Necrosis Factor-alpha

To achieve the target blood pressure recommended by the latest guidelines, multiple antihypertensive drugs are needed in most patients. In this study, the efficacy of treatment using an angiotensin II receptor antagonist (ARB) combined with a calcium channel blocker (CCB) or a diuretic was compared from multiple perspectives in patients with hypertension. Twenty-nine patients with essential hypertension, who had failed to achieve their target blood pressure (<130/85 mm Hg for patients <65 years old and <140/90 mm Hg for those >/=65 years) when treated with the ARB olmesartan at 20 mg day(-1), were additionally given 8-16 mg day(-1) of the CCB azelnidipine or 1-2 mg day(-1) of trichlormethiazide (a thiazide diuretic) in a randomized crossover manner for 4 months each. At the end of each combination therapy period, blood and urine samples were collected and arterial stiffness was evaluated by measuring the cardio-ankle pulse wave velocity. Compared with monotherapy, the blood pressure was reduced similarly by adding azelnidipine (-12/-10 mm Hg) or trichlormethiazide (-14/-9 mm Hg). The heart rate was decreased with the CCB by 4 b.p.m. (P<0.05), whereas it was unchanged with the thiazide. Serum K, lipids and blood glucose were not significantly changed with either combination, whereas serum uric acid was increased with the thiazide (P<0.01) but was unchanged with azelnidipine. Plasma levels of renin, angiotensin II and aldosterone were also increased with the thiazide period, whereas high-sensitivity C-reactive protein and oxidized low-density lipoprotein were decreased with azelnidipine. In addition, the cardio-ankle vascular index, a parameter of arterial stiffness, was decreased with the azelnidipine period but was unchanged with the thiazide period (P<0.01). It is suggested that the combination of olmesartan and azelnidipine has advantages over the combination of olmesartan and a thiazide with respect to avoiding hyperuricemia, sympathetic activation, renin-angiotensin-aldosterone system stimulation, inflammation, oxidative stress, and increased arterial stiffness in patients with moderate hypertension. These properties may provide cardiovascular protection in addition to the hypotensive effect.

Topics: Adult; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Ankle Brachial Index; Azetidinecarboxylic Acid; Blood Pressure; C-Reactive Protein; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Hypertension; Imidazoles; Lipoproteins, LDL; Male; Middle Aged; Sodium Chloride Symporter Inhibitors; Tetrazoles; Trichlormethiazide

The aim of this study was to compare the efficacy and safety of adding manidipine 20 mg versus amlodipine 10 mg to the treatment of diabetic patients with uncontrolled hypertension and microalbuminuria despite full-dose treatment with a renin-angiotensin system blocker for at least 6 months. Patients were randomized to receive manidipine (n = 61) or amlodipine (n = 30) in a 2:1 ratio for 6 months and monitored for microalbuminuria for an additional extension phase of 18 months. Manidipine and amlodipine decreased blood pressure values to a similar extent. Urinary albumin excretion was reduced by 65.5% with manidipine versus 20% with amlodipine (p < 0.01) at 6 months and 62.7 versus 16.6% (p < 0.01) at the end of the extension phase. Manidipine was better tolerated than amlodipine. Thus, the addition of manidipine, but not amlodipine, resulted in a large reduction in the urinary albumin excretion rate despite similar blood pressure reductions.

Topics: Adult; Aged; Albuminuria; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Prospective Studies; Renin-Angiotensin System

Benidipine (CAS 105979-17-7) is a dihydropyridine calcium channel blocker used in the treatment of hypertension and angina pectoris.. To examine the efficacy and safety of therapy with benidipine in elderly hypertensive patients.. Chinese patients >60 years of age with mild to moderate essential hypertension were enrolled. The patients were prescribed benidipine at the dose of 8 mg once daily for 12 weeks. Detailed laboratory examinations and 24-h ambulatory blood pressure monitoring were performed before and after the treatment.. One hundred and sixty-four of the 180 patients enrolled completed the 12-week active treatment phase. Sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) reductions at the end of treatment were 21.50 +/- 12.83 and 10.60 +/- 8.04 mmHg, respectively; the proportion of patients showing a good treatment response was 95.1% for SBP and 96.9% for DBP. Benidipine significantly reduced the mean 24-h ambulatory blood pressure (p < 0.001 vs. baseline) exhibiting smooth, sustained effects and high trough-to-peak ratios (T/P ratio) (0.87 for SBP and 0.72 for DBP). Moreover, benidIpine significantly reduced the systolic morning blood pressure surge and urinary albumin, and it was well tolerated. No serious adverse events were noted.. Benidipine was welltolerated and effective in elderly Chinese patients with essential hypertension.

Topics: Aged; Albuminuria; Antihypertensive Agents; Arteries; Blood Pressure; China; Dihydropyridines; Female; Humans; Hypertension; Male

In hypertensive patients with chronic renal disease, angiotensin receptor blockers (ARBs) are among the first-line drugs, and calcium channel blockers (CCBs) are recommended as a second line. We examined the effects of two therapeutic strategies using ARBs and benidipine, a CCB, on blood pressure (BP), urinary albumin excretion (UAE), and cost-effectiveness in hypertensive patients with albuminuria. Patients whose BP was 140/90 mmHg or higher despite treatment with low- or medium-dose ARBs were assigned randomly to two groups. In Group A (n=14), the ARB dose was maximized and then benidipine was added until BP targets were reached (<130/85 mmHg). In Group B (n=18), benidipine was administered first and then the ARB dose was increased until BP targets were reached. The BP targets were achieved by ARB alone in 36% of Group A patients and by the addition of benidipine in 83% of Group B patients. Finally, BP decreased in each group, reaching the targets in 93% of Group A patients and 94% of Group B patients after a 4-month therapeutic period. UAE was decreased in both groups after a 4-month therapeutic period compared to the allocation period (-33+/-6% in Group A, -31+/-6% in Group B; p<0.001, respectively). The monthly drug cost was higher (11,426+/-880 vs. 8,955+/-410 yen, p=0.012) and the cost-effectiveness of antihypertensive treatment was lower (p=0.003) in Group A than in Group B. We conclude that the addition of benidipine to low- or medium-dose ARB is, in light of the renal protection and the cost-effectiveness of this approach, a useful therapeutic strategy for controlling BP in hypertensive patients with albuminuria.

Topics: Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Calcium Channel Blockers; Cost-Benefit Analysis; Dihydropyridines; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Kidney; Male; Middle Aged

Recent studies have shown that metabolic syndrome is associated with an increased risk for chronic kidney disease. We recently found that the prevalence of sodium-sensitive hypertension in patients with metabolic syndrome was significantly higher than that in patients with essential hypertension but without metabolic syndrome. We therefore assessed the effects of benidipine, a long-acting calcium channel blocker, on the sodium sensitivity of blood pressure and renal hemodymamics in 5 patients with metabolic syndrome. Glomerular hemodynamics were assessed using pressure-natriuresis curves, which were constructed by plotting the urinary excretion of sodium as a function of the mean arterial pressure, which was calculated as the mean of 48 values based on 24-h monitoring, during the intake of low (3 g NaCl daily) and relatively high (10 g NaCl daily) sodium diets. Under the relatively high sodium diet condition, benidipine significantly lowered systolic and diastolic blood pressure. The pressure-natriuresis curve was steeper after the administration of benidipine. Benidipine lowered glomerular capillary hydraulic pressure (P(GC)) levels (from 54.4+/-7.5 to 47.0+/-7.0 mmHg, p=0.0152) and reduced both the resistance of the afferent arterioles (from 10,338+/-2,618 to 9,026+/-2,627 dyn.s/cm5, p=0.047) and the resistance of the efferent arterioles (from 4,649+/-2,039 to 2,419+/-2,081 dyn.s/cm(5), p=0.003). The urinary albumin excretion rate also decreased after the administration of benidipine. These findings indicated that benidipine may be effective for reducing the risk of developing chronic kidney disease in patients with metabolic syndrome.

Topics: Albuminuria; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension, Renal; Kidney Glomerulus; Male; Metabolic Syndrome; Middle Aged; Renal Circulation; Treatment Outcome

Cilnidipine is a calcium channel blocker that blocks both L and N-type calcium channels. L/N-type calcium channel blockers exhibit sympatholytic action and a renal protective effect via dilation of afferent and efferent arterioles of the renal glomerulus, and afford more potent protection against hypertension-related organ damage than L-type calcium channel blockers. Few studies, however, have directly compared the organ protective effects of L-type calcium channel blocker monotherapy and L/N-type calcium channel blocker monotherapy. This study compares the effects on renal and vascular endothelial functions and arterial stiffness of monotherapy regimens of amlodipine, an L-type calcium antagonist, and cilnidipine, in patients with essential hypertension.. Fifty patients with untreated essential hypertension were randomized to receive 5 mg of amlodipine (n = 25) or 10 mg of cilnidipine (n = 25) once daily in the morning for 24 weeks. The patients were evaluated before and after the therapy to assess changes in renal function, flow-mediated vasodilation (a parameter of vascular endothelial function), and brachial-ankle pulse wave velocity (a parameter of arterial stiffness).. Before treatment, the above parameters showed no significant differences between groups. After treatment, urinary albumin excretion was decreased significantly in the cilnidipine group compared with the amlodipine group, and the decrease of brachial-ankle pulse wave velocity was significantly larger in the cilnidipine group than in the amlodipine group.. These results suggest that cilnidipine is more effective than amlodipine at improving renal function and arterial stiffness in patients with essential hypertension.

Topics: Albuminuria; Amlodipine; Antihypertensive Agents; Arteries; Calcium Channel Blockers; Dihydropyridines; Endothelium, Vascular; Female; Humans; Hypertension; Kidney; Male; Middle Aged; Safety; Vasodilation

We sought to compare the effect of manidipine versus hydrochlorothiazide (HCTZ) in addition to candesartan on the urinary albumin excretion rate (UAER) in hypertensive patients with type II diabetes and microalbuminuria.. After a 2-week washout and run-in period, and 8-week monotherapy with candesartan 16 mg every day, 174 microalbuminuric diabetic hypertensive patients with uncontrolled blood pressure (BP) (>130/80 mm Hg) were randomized to addition of manidipine 10 mg every day (n = 87) or HCTZ 12.5 mg every day (n = 87) for 24 weeks, with a titration after 4 weeks (manidipine or HCTZ dose-doubling) in nonresponder patients. Blood pressure, UAER, creatinine clearance, serum electrolytes, fasting plasma glycemia, and glycosylated hemoglobin were evaluated at baseline (end of run-in period), after candesartan monotherapy, and at the end of the combination treatment period.. Both combinations produced greater systolic BP/diastolic BP reduction than candesartan monotherapy (-28/21 mm Hg versus -16/11 mm Hg and -28/20 mm Hg versus -15/11 mm Hg, respectively; all P < .05 versus monotherapy), with no significant difference between the two combinations. The addition of manidipine produced a greater reduction in UAER than candesartan monotherapy (-55.4 mg/24 h v -36.1 mg/24 h, P < .05), whereas the addition of HCTZ did not significantly modify UAER; the difference between the two combinations was statistically significant (P < .05). Similarly, the percentage of patients moving to a normoalbuminuric state (UAER <30 mg/24 h) was increased by the addition of manidipine to candesartan (from 35% to 64%, P < .05), but not by the addition of HCTZ (from 34% to 39%, NS), with a statistical difference between the two combinations (P < .05).. These findings show that, despite equivalent reduction in BP, the addition of manidipine to candesartan further reduced the UAER, whereas the addition of HCTZ did not modify the UAER. This suggests that the antiproteinuric effect of manidipine is partially independent of BP reduction, and is attributable to mechanisms different from those mediated by angiotensin receptor blockade.

Topics: Adult; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Nitrobenzenes; Piperazines; Prospective Studies; Proteinuria; Single-Blind Method; Tetrazoles

Cilnidipine, an L-/N-type calcium channel blocker, dilates the efferent glomerular arterioles in an experimental model and shows a renoprotective effect, but its clinical benefits and safety have not yet been assessed in type II diabetics with albuminuria. The objective of this trial was to evaluate the effect of reducing albuminuria in type II diabetic patients with a combination therapy consisting of valsartan plus cilnidipine versus monotherapy with valsartan. An open-label, randomized controlled trial was conducted from April 2002 to October 2003 in 87 Japanese patients aged 31-90 years with type II diabetes showing albuminuria (urinary albumin/creatinine ratio: 10-300 mg/g). The patients were randomized to receive either valsartan (n=41) or valsartan plus cilnidipine (n=46) once daily for 1 year. The primary end point was the percent change in the albumin/creatinine ratio. The secondary end points were the progression/regression of albuminuria, blood pressure (BP), renal function, and safety. After 1 year, the albumin/creatinine ratio was found to have decreased more markedly in the valsartan plus cilnidipine group than in the valsartan group (reduction rate -44+/-11% (s.e.) versus -9+/-7% (s.e.); P=0.014 by analysis of covariance). Although a significant reduction was observed in the systolic and diastolic BP of both groups from baseline to 1 year (P<0.0001, respectively), there was no significant difference in the change in the BP between the two groups (systolic BP, P=0.066; diastolic BP, P=0.391). There were also no significant differences in the side effects between the two groups. Cilnidipine was thus found to show an additive effect with valsartan and thereby caused a reduction in albuminuria in type II diabetics.

Topics: Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Tetrazoles; Treatment Outcome; Valine; Valsartan

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypertension; Indoles; Treatment Outcome; Verapamil

The aim of this open-labelled, randomised, parallel-group study was to evaluate the effect of long-term monotherapy with manidipine or lisinopril on albumin excretion rate (AER) and left ventricular mass index (LVMI) in hypertensive patients with type-2 diabetes and microalbuminuria.. After a 4-week wash-out period, 174 patients with essential hypertension [diastolic blood pressure (DBP) >80 mmHg and <100 mmHg], type-2 diabetes and microalbuminuria were randomised to manidipine 10 mg o.d. or lisinopril 10 mg o.d.; after 8 weeks, the dose was doubled in non-responders (DBP >80 mmHg); after 3 months, treatment was discontinued in the non-responder patients and in those complaining of side effects; the remaining 121 patients continued their therapy with manidipine or lisinopril, and 99 completed the 2-year study. At the end of the wash-out period, of the titration period and after 6, 12, 18 and 24 months of treatment, BP was measured, AER, creatinine clearance, glycosylated haemoglobin (HbA1c) and body mass index (BMI) were evaluated and an echocardiographic evaluation was performed.. The 99 patients who completed the study were statistically analysed according to a per-protocol evaluation. Manidipine and lisinopril significantly reduced systolic blood pressure (SBP) and DBP levels (at 24 months, --22.3/15.5 mmHg, P<0.001 versus baseline and --21.4/15.7 mmHg, P<0.01 versus baseline, respectively). Both drugs provided a significant decrease in AER, but it was significantly more pronounced with lisinopril (at 24 weeks, --37.2 mg/24 h, P<0.001 versus baseline) than with manidipine (--29.9 mg/24 h, P<0.05 versus baseline) and became evident earlier in the lisinopril group (after 3 months versus 6 months of treatment). Manidipine produced a greater reduction of LVMI than lisinopril (--14.9 g/m(2) versus --10.8 g/m(2) at 24 months). The effect was more pronounced in patients with left ventricular hypertrophy at baseline (--19.8 g/m(2) versus --12.8 g/m(2), P<0.05).. These data suggest that, despite similar BP lowering, non-haemodynamic factors play an important role in the pharmacological reduction of AER and LVMI in diabetic hypertensive patients.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Heart Ventricles; Humans; Hypertension; Lisinopril; Male; Middle Aged; Nitrobenzenes; Piperazines

Microalbuminuria and hypertension are risk factors for diabetic nephropathy in Type 2 diabetic patients. Recent data suggest that blockade of the renin-angiotensin system slows the progression of diabetic nephropathy; in contrast, the results on the renoprotective effect of calcium channel antagonists are conflicting. We evaluated the effectiveness of lercanidipine, in comparison with ramipril, on the reduction in albumin excretion rate (AER) and blood pressure in mild-to-moderate hypertensive patients with Type 2 diabetes and persistent microalbuminuria. A total of 277 patients were enrolled in a multicentric, randomized, double-blind, active-controlled, parallel-group trial; 180 were randomized to receive 10-20 mg/day of lercanidipine or 5-10 mg/day of ramipril and followed up for 9-12 months. The primary outcome was the change in AER from baseline. After 9-12 months of follow-up, a reduction in AER of -17.4+/-65 microg/min (p<0.05) and -19.7+/-52.5 (p<0.05) in the lercanidipine and ramipril group, respectively, was observed, without differences between the groups. A significant reduction in systolic and diastolic blood pressure was observed in both the lercanidipine and ramipril-based treatment groups (p<0.0001 for both). This study demonstrated that treatment with lercanidipine 10-20 mg/day does not worsen albuminuria in microalbuminuric Type 2 diabetic patients with hypertension. Indeed, both lercanidipine and ramipril treatments resulted in a significant reduction in AER without a statistically significant difference between the two groups.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Ramipril; Treatment Outcome

The importance of measuring microalbuminuria is well established. However, only scanty data are available concerning the biological variability of albumin excretion in type 2 diabetic subjects. We report our experience from a large clinical trial of a new antihypertensive drug (Lercanidipine) designed to reduce albumin excretion and blood pressure in type 2 diabetic patients with hypertension and microalbuminuria. Eighty seven patients with persistent microalbuminuria were studied within 1 year of the clinical trial. The measurements were performed on blood and timed urine samples frozen at -80 degrees C and shipped to a central laboratory unit. Preliminary experiments were performed to assess albumin stability in urine under various conditions (4 degrees C, -20 degrees C and -80 degrees C), particularly with regard to the albumin/creatinine ratio. Urine samples can be stored up to 3 weeks at 4 degrees C or up to 2 months at -80 degrees C. The biological variability of the albumin excretion rate was 25.7%, while that of the albumin/creatinine ratio was 13.4%. These data are useful in defining the analytical goals of imprecision for microalbuminuria (CV = 13% for albumin, and CV = 6% for albumin/creatinine ratio). No correlation between albumin/creatinine ratio and HbA1c was found in the cohort of 61 microalbuminuric patients who completed the trial. The results of this study confirm that the albumin/ creatinine ratio is much more suitable for monitoring albumin excretion in longitudinal studies than the albumin excretion rate.

Topics: Albuminuria; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Humans; Hypertension; Protein Denaturation; Sensitivity and Specificity; Serum Albumin; Temperature

This study was carried out to assess whether with a similar degree of blood pressure reduction, Lisinopril compares favorably or otherwise with lacidipine in respect of effects on urinary albumin excretion and renal function as assessed by creatinine clearance, plasma creatinine, urea and electrolytes. Thirty hypertensive diabetic nephropathy patients with moderate hypertension were studied. After a 2-week washout period, they were allocated into two groups matched at baseline for age, sex, weight, blood pressure, and urinary albumin excretion rate as well as creatinine clearance. There were 8 males and 7 females in each group. One group received lisinopril (with furosemide if needed to control BP) and the other group received lacidipine. Staged increases in doses of antihypertensives were used until BP was controlled or maximum dose of 40 mg/day lisinopril or 8 mg/day lacidipine was reached. Furosemide was added to lisinopril if BP was not controlled at 40 mg/day. These medications were given for 12 weeks at the end of which measurements done at baseline were repeated. Comparison of baseline and end of study values of these parameters within the groups and between the two groups were made. Lisinopril group and lacidipine group achieved similar and highly significant reduction in blood pressure levels P < 0.001. There was reduction in urinary albumin excretion rate in both groups but this only reached statistical significance in the lisinopril group [480] [269] mg/day vs. 315 [202] mg/day P < 0.05] while for the lacidipine group it was not significant [491] [257] mg/day vs. 335 [182] mg/day P > 0.05]. However, comparison of albumin excretion rate between both groups at baseline and at end of the study did not show any significant difference, P > 0.1. With both drugs there is a tendency for creatinine clearance to increase and plasma creatinine to drop while plasma potassium tended to rise more with lisinopril than lacidipine but differences within and between both groups, did not reach statistical significance P > 0.05. In conclusion, blood pressure reduction was comparable in both drugs; both drugs reduced albuminuria but lisinopril appeared superior. Treatment with both drugs tended to increase creatinine clearance but both had no significant effects on blood sugar.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Disease Progression; Female; Humans; Hypertension; Lisinopril; Male; Metabolic Clearance Rate; Middle Aged; Potassium; Prospective Studies; Treatment Outcome; Urea

Microalbuminuria (MA) is associated with increased cardiovascular risk and lipid abnormalities in people with type 2 diabetes. ACE inhibitors and calcium channel blockers (CCBs) reduce MA and are neutral on total cholesterol and triglycerides. The effect of ACE inhibitors and CCBs on lipid subfractions such as Lp(a), apolipoprotein (apo) A1, apo B, and others, however, is unclear. The current study tests the hypothesis that a fixed-dose combination of an ACE inhibitor, benazepril (B) with the dihydropyridine CCB, amlodipine (A), will further reduce arterial pressure and reduce atherogenic lipid fractions compared to either agent alone.. A multicentre, randomised, open-label, parallel group design was used to study 27 participants with type 2 diabetes. Measurements for total cholesterol, high- and low-density lipoprotein (HDL and LDL), triglycerides, apo A1, apo B, Lp(a), MA, arterial pressure and creatinine clearance were obtained at baseline and at 12-week intervals during the 36 week study.. Arterial pressure was significantly reduced at 36 weeks in all three groups (P = 0.0078 for A, P = 0.0039 for B, and P = 0.0313 for A+B). MA was lowered in all groups with relatively greater reductions in the B (P < 0.05) and A+B groups (P < 0.03) vs A. An increase in mean HDL-cholesterol from baseline was noted in the B and A+B groups; P < 0.05), but not in the A group. A trend was also observed between the rise in HDL-cholesterol and the reduction in MA in the B and A+B groups. Additionally, only the B group exhibited a decrease in the median value of Lp(a) (P < 0.05).. These data support the concept that ACE inhibition with B reduces the atherogenic profile by decreasing Lp(a) and increasing HDL-cholesterol, the latter being correlated with reductions in MA. While A+B exhibited similar trends in lipid subfractions and MA as B, this group had the greatest reduction in systolic blood pressure of the three groups. Thus, use of A+B offers the benefits of a decreased atherogenic profile with a higher probably of achieving goal blood pressure as recommended by national guidelines.

Topics: Aged; Albuminuria; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Apolipoproteins; Apoprotein(a); Benzazepines; Calcium Channel Blockers; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Lipoprotein(a); Male; Middle Aged; Pilot Projects; Triglycerides

This study was designed to investigate the effect of delapril, an ACE inhibitor, and manidipine, a long action calcium antagonist, on persistent microalbuminuria in normotensive type 2 diabetic patients. Sixty type 2 diabetic patients were randomized to take delapril 30 mg/day or manidipine 10 mg/day for 48 weeks, in an open label design. Twenty eight of thirty subjects in the delapril group and twenty nine of thirty in the manidipine group completed the study. Urine albumin excretion as measured by the urinary albumin creatinine ratio decreased significantly in both groups (112.0+/-60.9 to 95.3+/-64.9 mg/g and 108.5+/-51.0 to 96.4+/-53.5 mg/g in the delapril and manidipine group respectively, p < 0.05, by paired t-test). Systolic and diastolic blood pressure were not significantly changed after treatment in the delapril group but significantly decreased in the manidipine group (130.9+/-7.1/80.2+/-6.1 to 127.2+/-7.1/78.0+/-5.3 mm/Hg, p < 0.05, by student's paired t-test). After 48 weeks of treatment, two patients in the delapril group and one patient in the manidipine group converted to normoalbuminuria (urinary albumin:creatinine ratio < 30 mg/g) and one patient in each group progressed to overt nephropathy (urinary albumin:creatinine ratio > 300 mg/g). There were no significant changes in fasting plasma glucose, HbA1c, serum fructosamine, creatinine, potassium and lipid profiles after 48 weeks of treatment in both groups. Two cases in the delapril group were withdrawn during the study because of an intolerable cough and one case in the manidipine group because of intolerable dizziness and headache. In conclusion, both delapril and manidipine are effective in the reduction of microalbuminuria in normotensive type 2 diabetic patients with persistent microalbuminuria.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Diabetic Nephropathies; Dihydropyridines; Humans; Indans; Kidney; Middle Aged; Nitrobenzenes; Piperazines

To investigate the beneficial effects of cilnidipine, a calcium channel blocker that shows high selectivity for N-type receptors, on the progression of chronic renal insufficiency, we compared the efficacy of cilnidipine to that of benazepril, an angiotensin-converting enzyme (ACE) inhibitor with known renal protective effects, in a one-year trial evaluating hypertensive control, serum creatinine, and albuminuria in a cohort of patients. Given the seeming importance of the etiology of chronic renal insufficiency in determining drug efficacy, we limited our study to 20 patients with a single common condition, benign nephrosclerosis. The average age of the patients was 62+/-4 years old. The changes in systolic and diastolic blood pressure over the course of the study year revealed a similar reduction with cilnidipine and benazepril. Both cilnidipine and benazepril induced similar reductions in systolic and diastolic blood pressure over the course of the study year. The baseline levels of serum creatinine were 1.40+/-0.2 mg/dl and urinary excretion of albumin was 168+/-10 mg daily. The levels of serum creatinine were not significantly changed throughout the study in either group, although the levels of urinary excretion of albumin were significantly decreased in both groups. There were no significant differences in either of these values between the two groups. In conclusion, both cilnidipine and benazepril equally and effectively reduced blood pressure and albuminuria in hypertensive patients with benign nephrosclerosis in a one-year trial.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Blood Pressure; Calcium Channel Blockers; Cohort Studies; Creatinine; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Nephrosclerosis; Proteinuria

There are few studies on the use of dihydropyridine calcium antagonists in hypertensive patients with moderate renal insufficiency. We undertook an open study on the effects on renal function, albumin excretion and blood pressure of the slow-onset, long-acting dihydropyridine calcium antagonist, lacidipine, in 14 patients with stable, chronic renal insufficiency (mean assessed GFR 0.78 ml/s, range 0.50-1.17 ml/s) and moderate hypertension. Following a 2 week washout phase, lacidipine was administered for 24 weeks in a dose of 2 mg/day with the dose being titrated at 2 weekly intervals to a maximum of 6 mg/day in order to achieve adequate blood pressure control. Frusemide was introduced if blood pressure was not controlled on the maximum lacidipine dose. Blood pressure, creatinine clearance, 24 h urinary albumin excretion and plasma creatinine and albumin concentrations were measured at regular intervals throughout the study. Isotopic GFR was determined at the end of the washout period and at week 24. Lacidipine was not very effective in controlling blood pressure and had an adverse effect on renal function. In 3 patients with an incipient nephrotic syndrome this necessitated withdrawal from the study. Mean GFR of the 10 patients who completed the study decreased from 0.69 ml/s/1.73 m2 at baseline to 0.56 ml/s/1.73 m2 at week 24 (p = 0.006) with a decline in GFR being observed in 9 of these patients. The decrease in GFR was greatest in patients with poorly controlled blood pressure. An insignificant increase in mean urinary albumin excretion occurred during the study with this increase being observed only in patients with albuminuria > 1 g/24 h at baseline. These findings indicated that systemic hypertension altered glomerular hemodynamics and that the vasodilatation of pre-glomerular vessels which followed introduction of the calcium antagonist may have exacerbated this situation. The withdrawal of an angiotensin converting enzyme inhibitor during the washout period may have contributed to these changes. We suggest that renal function should be monitored closely in patients with renal insufficiency when a calcium antagonist is being used to control blood pressure, particularly in those with either marginal blood pressure control, significant albuminuria or an incipient nephrotic syndrome.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Furosemide; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Renal Insufficiency; Serum Albumin

Sixteen middle-aged men with primary hypertension were treated with the calcium antagonist isradipine over a 9-week period in a randomized, placebo-controlled, double-blind cross-over manner. At the end of the intervention period the urinary albumin excretion rate, systemic and renal haemodynamics, haemorheological properties of blood and plasma concentrations of atrial natriuretic peptide, noradrenaline and peripheral renin activity were determined. Treatment with isradipine resulted in a substantial reduction in blood pressure due to a reduction in peripheral resistance. The mean albumin excretion rate was not influenced by the isradipine treatment. In a multivariate analysis, changes in the urinary albumin excretion rate were only related to changes in blood pressure.

Topics: Albuminuria; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Hemodynamics; Humans; Hypertension; Isradipine; Male; Middle Aged; Multivariate Analysis; Renal Circulation; Rheology

The in vivo effectiveness of 4-dihydropyridine (bis-1,4-DHP), a new calcium-channel blocker, as a nephroprotector in isolated perfused kidney was evaluated by determining its effects on parameters associated with renal injury in diabetic rats. Diabetes in male Wistar rats, control, diabetic, control + bis-1,4-DHP, and diabetic + bis-1,4-DHP, was induced by a single administration of STZ (55 mg·kg(-1), i.p.). In the drug-treated groups, treatment with bis-1,4-DHP (10 mg·kg(-1)·day(-1)) started one week before diabetes induction; bis-1,4-DHP was dissolved in DMSO (0.3%) and suspended in drinking water with carboxymethyl cellulose (3%). Parameters evaluated were body weight, blood glucose, albuminuria, proteinuria, creatinine, urea excretion, kidney's weight / body weight ratio, and kidney perfusion pressure in all rat groups at different times of diabetes (2, 4, 6, and 10 weeks). Kidney weight of diabetic rats significantly increased vs. control, control + bis-1,4-DHP, and diabetic + bis-1,4-DHP rats at different times of diabetes. The ratios % kidney weight / 100 g body weight were different between control, control + bis-1,4-DHP, and diabetic + bis-1,4-DHP rats vs. diabetic rats (P < 0.05). Kidney perfusion pressure was decreased by diabetes, while it was partially recovered by bis-1,4-DHP treatment in response to phenylephrine. Bis-1,4-DHP had a tendency to decrease hyperglycemia vs. diabetic rats, even though glycemia was too high as compared with controls, and it ameliorated albuminuria, creatinine, and urea excretion, suggesting a favorable effect on renal haemodynamics. Bis-1,4-DHP, by inhibiting Ca(2+) entrance, induced vasodilation in renal vascular bed and thus may have a nephroprotective effect against diabetes-induced renal dysfunction, but does not have significant impact on hyperglycemia.

Topics: Albuminuria; Animals; Body Weight; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dihydropyridines; In Vitro Techniques; Kidney; Male; Organ Size; Perfusion; Proteinuria; Rats; Rats, Wistar; Streptozocin; Vasodilation

We evaluated the antialbuminuric advantage of cilnidipine, an N/L-type calcium channel blocker (CCB), compared with L-type CCBs in diabetic patients with normoalbuminuria and microalbuminuria. The study was a multicenter, non-randomized crossover trial. Participants were 90 type 2 diabetic patients exhibiting either normo- or microalbuminuria, and undergoing CCB treatment for ≥6 months prior to study entry. The CCB at the time of entry was continued for the first 6 months (Period 1). Treatment was subsequently switched from cilnidipine to an L-type CCB, or vice versa, for the second 6-month observation period (Period 2). During Period 1, the L-type CCB group showed a significant increase of urinary albumin excretion (UAE) over time, while the cilnidipine group showed no significant elevation. During Period 2, switching of the treatment from the L-type CCB to cilnidipine resulted in significant reduction of the UAE, whereas switching from cilnidipine to the L-type CCB resulted in no significant change in the UAE. This study demonstrated that the antialbuminuric effect of Cilnidipine, but not the L-type CCBs, was sustained even in patients treated for a long time. In addition, the antialbuminuric effect can be anticipated after switching from an L-type CCB to cilnidipine, but not vice versa.

Topics: Aged; Albuminuria; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Drug Administration Schedule; Female; Humans; Hypertension; Japan; Male; Treatment Outcome

Topics: Albuminuria; Antihypertensive Agents; Blood Pressure; Combined Modality Therapy; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hypertension; Physical Fitness; Stroke

Topics: Albuminuria; Antihypertensive Agents; Azetidinecarboxylic Acid; Dihydropyridines; Humans; Hydrochlorothiazide; Imidazoles; Tetrazoles

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Azetidinecarboxylic Acid; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Humans; Hypertension; Imidazoles; Male; Tetrazoles

The aims of the present study were to compare the effects of cilnidipine [L-type/N-type calcium channel blocker (CCB)] and amlodipine (L-type CCB) alone or in combination with the angiotensin II receptor blocker (ARB), valsartan, on blood pressure (BP), kidney function in Dahl salt-sensitive (DS) rats. DS rats fed a high-salt diet were divided into six groups; control (n = 13), two CCB (cilnidipine or amlodipine) groups at 1 mg/kg/day (n = 10), ARB (valsartan) at 10 mg/kg/day (n = 12), cilnidipine + valsartan (CV, n = 12), and amlodipine + valsartan (AV, n = 12). BPs were lower in the combination therapy groups than in those given either drug alone, but only CV inhibited the increase in urinary albumin excretion (UAE) and lowered the glomerular sclerosis score. In addition, AV elevated plasma renin activity and the angiotensin II concentration, and thus failed to inhibit increases in UAE and to lower glomerular sclerosis score. In conclusion, combination therapy with CCB and ARB decreases BP more effectively than either drug alone. When used in combination with valsartan, cilnidipine is more effective than amlodipine for preventing kidney injury.

Topics: Albuminuria; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Dihydropyridines; Disease Models, Animal; Drug Therapy, Combination; Glomerulonephritis; Hypertension; Kidney; Kidney Diseases; Male; Organ Size; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Tetrazoles; Time Factors; Valine; Valsartan

Calcium channel antagonists (calcium channel blockers [CCBs]) are often used in the treatment of patients with hypertension to achieve strict blood pressure (BP) targets. In the present study, we compared the antihypertensive effects (determined by home BP [HBP] measurements) and the effects on renal function of benidipine (hydrochloride) and amlodipine (mesylate), a commonly used CCB.. Changes in HBP and urinary albumin excretion (UAE) were investigated in 47 benidipine and 37 amlodipine recipients with essential hypertension and albuminuria between January 2007 and December 2007. Both benidipine and amlodipine significantly reduced morning and evening HBP over a 12-month period.. Both medications also significantly reduced UAE compared with pretreatment values; however, the reduction in UAE observed in the benidipine group occurred independent of the drug's antihypertensive effects, whereas a positive correlation was shown between the reduction in morning systolic BP and UAE in the amlodipine group.. These results demonstrate that benidipine favourably affects renal function in patients with essential hypertension compared with amlodipine, suggesting that the clinical benefits of benidipine as an antihypertensive drug include a renoprotective effect.

Topics: Adult; Aged; Albuminuria; Amlodipine; Blood Pressure; Calcium Channel Blockers; Calcium Channels, T-Type; Dihydropyridines; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Retrospective Studies

The present study was undertaken to examine the effects of a calcium channel blocker, azelnidipine (1 mg/kg/day), an angiotensin converting enzyme (ACE) inhibitor, temocapril (10 mg/kg/day), an angiotensin II type 1 (AT1) receptor blocker (ARB), olmesartan (5 mg/kg/day), and their combination on Dahl salt-sensitive rats (DS rats) developing heart failure with preserved systolic function. DS rats were fed a high-salt diet (8% NaCl) from 7 weeks of age and progressively developed hypertension. Although monotherapy with azelnidipine lowered the blood pressure of DS rats to a greater extent than monotherapy with temocapril or olmesartan, the three drugs had similar effects on cardiac hypertrophy, cardiac fibrosis, the expressions of brain natriuretic peptide, transforming growth factor-beta1, collagen I, collagen III and monocyte chemoattractant protein-1 mRNA (as estimated by Northern blot analysis), and cardiac diastolic dysfunction (as estimated by echocardiography). These results show that ACE and AT1 receptor, as well as hypertension, are involved in the development of heart failure with preserved systolic function in DS rats. The combination of azelnidipine with olmesartan or temocapril produced no additive hypotensive effect in DS rats and no additive effect on cardiac hypertrophy or gene expressions. However, the combination therapy prolonged the survival rate of DS rats more than azelnidipine (p <0.01) or temocapril alone (p <0.05), and this additive beneficial effect by the combination therapy was associated with a greater reduction of cardiac fibrosis, urinary albumin excretion and serum creatinine. Our results thus showed that the combination of a calcium channel blocker with an ARB or an ACE inhibitor had additive preventive effects on a rat model of hypertensive heart failure with preserved systolic function. Thus, combination therapy with these agents seems to be a useful therapeutic strategy for the prevention of hypertensive heart failure.

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Calcium Channel Blockers; Cardiac Output, Low; Creatinine; Dihydropyridines; Drug Combinations; Echocardiography; Gene Expression; Hypertension; Imidazoles; Myocardium; Olmesartan Medoxomil; Organ Size; Rats; Rats, Inbred Dahl; Survival Analysis; Tetrazoles; Thiazepines

We examined the effect of the dihydropyridine calcium channel blocker (CCB) benidipine, the angiotensin II type 1 receptor blocker (ARB) candesartan, and the combination of these drugs on blood pressure and kidney and vascular function in rats with salt-induced hypertension. Dahl salt-sensitive (DS) rats were fed with a high-salt (8% NaCl) diet from 7 weeks of age. Benidipine (1, 3 mg/kg), candesartan (1, 3 mg/kg), benidipine (3 mg/kg) combined with candesartan (3 mg/kg), or vehicle was administered orally after the start of the feeding. Relaxant responses to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator) were measured to examine the vascular function. DS rats fed the high-salt diet showed an increase in systolic blood pressure (SBP), which was accompanied by glomerular sclerosis and an increase in urinary albumin excretion. Relaxant responses to acetylcholine and sodium nitroprusside were impaired in superior mesenteric arterial rings from the hypertensive DS rats. SBP was significantly lower in all of the drug-treated groups than in the vehicle-treated group. The antihypertensive effect of benidipine at 3 mg/kg was more potent than that of candesartan at 3 mg/kg. The albuminuria was significantly decreased in the benidipine and benidipine plus candesartan groups, but not in the candesartan group. The level of SBP in the benidipine plus candesartan group was lower than that by either drug alone. In addition, benidipine alone and benidipine plus candesartan inhibited the glomerular sclerosis and the impairment of relaxant responses in the arteries. These results demonstrate that benidipine is more effective than candesartan in lowering blood pressure and preventing the impairment of kidney and vascular function in salt-sensitive hypertensive rats. In addition, the results suggest that combination therapy with benidipine and an ARB decreases blood pressure more effectively than either drug alone and may be useful for the treatment of hypertension.

Topics: Albuminuria; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Hypertension; Kidney; Male; Mesenteric Artery, Superior; Rats; Rats, Inbred Dahl; Tetrazoles; Vasodilation; Vasodilator Agents

We examined the effects of the angiotensin II type 1 receptor blocker candesartan, the calcium channel blockers benidipine and amlodipine, hydralazine, and the combination of candesartan and benidipine or amlodipine on blood pressure and renal function in Dahl salt-sensitive (DS) hypertensive rats. Male DS rats (5 weeks of age) were fed a high-salt (8% NaCl) diet, resulting in hypertension accompanied by glomerular sclerosis and an increased urinary albumin excretion. Drugs were orally administered from 2 to 6 weeks after the start of the feeding. Although candesartan (1 or 10 mg/kg) had little effect on the blood pressure, benidipine (4 mg/kg), amlodipine (4 mg/kg) and hydralazine (5 mg/kg) had similar hypotensive effects. Benidipine, but not amlodipine, hydralazine, or candesartan, significantly inhibited the increase in the albuminuria and glomerular sclerosis. The combination of candesartan (1 mg/kg) and benidipine (4 mg/kg) lowered the levels of blood pressure and albuminuria more effectively than the combination of candesartan (1 mg/kg) and amlodipine (4 mg/kg). These results indicate that benidipine is effective in preventing the impairment of renal function in DS hypertensive rats, and suggest that additional benefits can be expected by combination therapy with benidipine and an angiotensin II type 1 receptor blocker.

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Body Weight; Calcium Channel Blockers; Creatinine; Dihydropyridines; Drug Therapy, Combination; Hypertension, Renal; Kidney; Male; Rats; Rats, Inbred Dahl; Tetrazoles

Microalbuminuria (30-300 mg 24 h-1) is recognized to be independently associated with renal and cardiovascular risk. Antihypertensives may lower microalbuminuria. We questioned whether the use of different antihypertensive drug classes in general practice influences microalbuminuria as related to blood pressure in nondiabetic subjects.. To study this, we used the data from 6836 subjects of an on-going population based study, focused on the meaning of microalbuminuria (PREVEND). Odds ratios, adjusted for age, sex, blood pressure, cholesterol level, smoking and the use of other antihypertensive or cardiovascular drugs, were calculated to determine the association of drug groups with microalbuminuria. Influence of antihypertensives on the relation between blood pressure and (log) urinary albumin excretion was determined by comparing linear regression lines.. Microalbuminuria was significantly associated with the use of dihydropyridine calcium channel blockers (odds ratio: 1.76 [1.22-2.54]), but not with other antihypertensive drug groups. The linear regression line of the relation between blood pressure and (log) urinary albumin excretion was significantly steeper (P = 0.0047) for users of calcium channel blockers, but not for other antihypertensives, compared with subjects using no antihypertensive. Users of a combination of renin-angiotensin system inhibitors and diuretics however, had a less steep regression line (P = 0.037).. This study suggests a disadvantageous effect of dihydropyridine calcium channel blockers on microalbuminuria compared with other antihypertensive drug groups. Thus, if microalbuminuria is causally related to an increased risk for cardiovascular morbidity and mortality, dihydropyridines do not seem to be agents of choice to lower blood pressure. Furthermore, the combination of renin-angiotensin system inhibition and diuretics seems to act synergistically.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Chi-Square Distribution; Cohort Studies; Diabetes Mellitus; Dihydropyridines; Female; Humans; Hypertension; Logistic Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Prevalence

The molecular mechanism of glomerular injury in hypertension remains to be clarified. In this study, to examine the possible role of platelet-derived growth factor (PDGF) receptors in hypertensive glomerular injury, we specifically measured glomerular PDGF receptor tyrosine phosphorylation in various models of hypertensive rats using immunoprecipitation and Western blot analysis. A high-salt diet significantly enhanced glomerular PDGF beta-receptor tyrosine phosphorylation of Dahl-salt sensitive rats (DS-rats) without an increase in its protein levels, and this enhancement was associated with an elevation of blood pressure and glomerular injury. Stroke-prone spontaneously hypertensive rats (SHRSP) at hypertensive phase also had higher glomerular PDGF beta-receptor tyrosine phosphorylation levels than control Wistar-Kyoto rats (WKY), while SHR did not. Thus, DS-rats and SHRSP, which are well known to represent severe glomerular injury, had the enhanced PDGF beta-receptor tyrosine phosphorylation, while SHR, a hypertensive model without significant glomerular injury had no increased tyrosine phosphorylation. Treatment of DS-rats or SHRSP with benidipine, a calcium channel blocker, significantly lessened the increase in glomerular PDGF beta-receptor tyrosine phosphorylation, reduction of urinary protein and albumin excretion. These results suggest that the enhanced activation of glomerular PDGF beta-receptors may be responsible for the development of hypertensive glomerular injury and that the suppression of this receptor activation by a calcium channel blocker may contribute to its renal protective effects.

Topics: Albuminuria; Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Genetic Predisposition to Disease; Hypertension; Kidney Glomerulus; Male; Phosphorylation; Proteinuria; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Platelet-Derived Growth Factor beta; Stroke; Tyrosine

Through the use of microanatomic techniques, we investigated the effects of treatment with some dihydropyridine-type calcium antagonists (CAs) (ie, lercanidipine, manidipine, and nicardipine) and with the nondihydropyridine-type vasodilator hydralazine on hypertension-dependent glomerular injury and on the morphology of afferent and efferent arterioles in spontaneously hypertensive rats (SHR). Fourteen-week-old male SHR and age-matched normotensive Wistar-Kyoto rats were left untreated (control groups). Four additional groups of 14-week-old SHR were treated for 12 weeks with daily oral doses of 2.5 mg/kg lercanidipine, 5 mg/kg manidipine, 3 mg/kg nicardipine, or 10 mg/kg hydralazine. These treatments decreased systolic blood pressure values to a similar extent in SHR. Signs of glomerular injury, as characterized by glomerulosclerosis, hypertrophy, and an increased number of mesangial cells, were observed in control SHR. The treatment with CAs improved glomerular morphology and decreased the number of mesangial cells. Lercanidipine and manidipine were more effective than nicardipine in countering glomerular injury. In the SHR, both afferent and efferent arterioles revealed luminal narrowing, accompanied by increased wall thickness in efferent arterioles. The dihydropyridine-type derivatives that were tested decreased the luminal narrowing of afferent arterioles. Lercanidipine and manidipine countered the luminal narrowing of efferent arterioles. Hydralazine had no effect on hypertension-dependent glomerular injury or vascular changes. The present data indicate that lercanidipine and manidipine vasodilate afferent and efferent arterioles in SHR. A vasodilatory activity on efferent arteriole, which is not induced by the majority of CAs, may represent an useful property in the treatment of hypertension complicated by renal disease.

Topics: Albuminuria; Animals; Arterioles; Calcium; Calcium Channel Blockers; Dihydropyridines; Hydralazine; Hypertension, Renal; Juxtaglomerular Apparatus; Male; Nicardipine; Nitrobenzenes; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Vasodilator Agents

We investigated the renal protective effect of nifedipine (2-nitrophenyl derivative BAY a 1040) in streptozotocin (STZ)-induced spontaneously hypertensive rats (SHRs, 8 weeks of age). Diabetic SHRs were treated with 40 mg/kg/day of nifedipine or efonidipine as controls for 16 weeks. Dosage of nifedipine or efonidipine was chosen after preliminary studies demonstrated that it showed moderate antihypertensive action (more than a 20% decrease in systemic blood pressure after treatment). In the diabetic SHR, the excretion of urinary albumin was increased and reached 4.41 +/- 0.08 mg/day at 24 weeks. The levels of urinary albumin in the diabetic SHR after treatment with nifedipine were significantly less than those in the diabetic SHR at 24 weeks (p < 0.01). Levels of the ratio of creatinine clearance to body weight were significantly decreased in the diabetic SHR after treatment with nifedipine. In light microscopy, the ratio of glomerular tufts to Bowman's areas was significantly decreased compared with those in the diabetic SHRs (p < 0.05). These findings suggest that nifedipine inhibits the development of albuminuria and glomerular enlargement in STZ-induced diabetic SHRs. There was no significant difference in the changes in antihypertensive or antialbuminuric effects between nifedipine and efonidipine. Thus, nifedipine, as well as efonidipine, may become a useful antihypertensive drug with a renal protective effect.

Topics: Albuminuria; Animals; Antihypertensive Agents; Creatinine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dihydropyridines; Kidney; Male; Nifedipine; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Inbred SHR; Time Factors; Vasodilator Agents

1. We investigated the renal protective effect of efonidipine hydrochloride (efonidipine, NZ-105) in STZ-induced spontaneously hypertensive rats (SHRs, 8 weeks of age). Diabetic SHRs were treated with 15 mg/kg/day of efonidipine for 12 weeks. 2. The dosage of efonidipine was chosen after preliminary studies demonstrated that it showed mild antihypertensive action (within 20% decrease of systemic blood pressure). 3. In the diabetic SHRs, the excretion of urinary albumin was increased (1.78 +/- 0.09 mg/day) at 4 weeks and reached 4.41 +/- 0.12 mg/day at 12 weeks. The levels of urinary albumin in the diabetic SHRs after treatment with efonidipine were significantly less than those in the diabetic SHRs at 8 and 12 weeks (P < 0.01). 4. Levels of creatinine clearance were decreased in the diabetic SHRs after treatment with efonidipine. 5. In light microscopy, the ratio of glomerular tuft to Bowman's areas was significantly decreased compared with those in the diabetic SHRs (P < 0.05). 6. These findings suggest that efonidipine inhibits the development of albuminuria and glomerular enlargement in the streptozotocin-induced diabetic SHRs and may become a useful antihypertensive drug with a renal protective effect.

Topics: Albuminuria; Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Dihydropyridines; Hypertension; Kidney; Male; Nitrophenols; Organophosphorus Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Streptozocin

The contributions of hypertension and diabetes to microvascular dysfunction in the kidney and eye were investigated. Two indices of microvascular dysfunction, urinary albumin excretion rate (AER) and albumin vascular clearance (AVC) in the eye, were studied in control and streptozocin diabetic Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR).. Studies were performed on four groups of untreated rats--nondiabetic and diabetic WKY and nondiabetic and diabetic SHR--and on three groups of diabetic SHR treated with a converting enzyme inhibitor (perindopril), a calcium-channel blocker (lacidipine), or triple therapy (hydrochlorothiazide, reserpine, and hydralazine). In all rats, AER and AVC were measured at 16 weeks.. There was a progressive increase in both parameters in the order WKY, diabetic WKY, SHR, and diabetic SHR. When compared with nondiabetic WKY, diabetic SHR showed an approximately 30-fold increase in AER and an approximately threefold increase in AVC. Treatment of diabetic SHR with perindopril or triple therapy normalized AER compared to an equihypotensive dose of lacidipine, which had no effect. By contrast, the three antihypertensive regimens showed a different order of efficacy in preventing increases in ocular AVC. In diabetic SHR, the increase in retinal AVC was prevented largely by lacidipine, whereas the other two antihypertensive regimens showed lesser effects [AVC expressed as percentage nondiabetic WKY: untreated diabetic SHR 278% +/- 47%, lacidipine 93% +/- 10% (P < 0.001), triple therapy 132% +/- 37% (P < 0.05), and perindopril 167% +/- 9% (P < 0.05)]. Lacidipine also prevented the increase in AVC of the anterior and posterior uvea. By contrast, increases in AVC observed in the diabetic SHR were not prevented by perindopril in the posterior uvea or by triple therapy in the anterior uvea. Thus, hypertension and diabetes increased ocular AVC and AER, and effective antihypertensive therapy substantially prevented changes in both parameters. However, despite equivalent levels of blood pressure control for each regimen, discordant effects were noted on AVC and AER. Perindopril was associated with significantly lower AER than lacidipine, whereas lacidipine was more potent in preventing increases in ocular AVC.. Results of this study suggest that different antihypertensive regimens in the diabetic rat may exert organ-specific effects on the retina and kidney despite equivalent effects on systemic blood pressure. These data also raise the possibility that retinal microvascular dysfunction in diabetes is ameliorated more readily by calcium-channel blockade than by converting-enzyme inhibition, whereas the reverse applies to renal microvascular dysfunction, as reflected by albuminuria.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Capillary Permeability; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Dihydropyridines; Drug Therapy, Combination; Hydralazine; Hydrochlorothiazide; Hypertension, Renal; Indoles; Kidney; Male; Organ Specificity; Perindopril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reserpine; Retina; Serum Albumin

The aim of this study was to compare the renal effects of angiotensin converting enzyme (ACE) inhibition with calcium channel blockade in a model combining genetic hypertension with diabetes. Streptozotocin diabetes was induced in spontaneously hypertensive rats (SHR). The animals were then randomized to receive no treatment, the ACE inhibitor, perindopril, or the dihydropyridine calcium antagonist lacidipine. Body weight, systolic blood pressure, glycemic control, renal function, and albumin excretion rate (AER) were assessed serially over the 32-week study period. At week 32 the animals were killed and glomerular volume was measured. Both antihypertensive regimens significantly reduced systolic blood pressure in diabetic SHR. There was no significant difference in glycemic control, serum creatinine, or glomerular filtration rate among the three groups at week 32. The ACE inhibitor perindopril significantly reduced AER and glomerular hypertrophy over the 32 weeks, whereas the calcium antagonist lacidipine failed to reduce AER or glomerular hypertrophy. Thus, in contrast to the effects of ACE inhibition, calcium channel blockade with lacidipine, despite significantly reducing blood pressure, failed to reduce renal injury in this model. These results support the hypothesis that antihypertensive regimens may differ in their capacity to protect the diabetic kidney, despite similar effects on systemic blood pressure.

Topics: Albuminuria; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Dihydropyridines; Disease Models, Animal; Hypertension; Indoles; Kidney Diseases; Male; Perindopril; Random Allocation; Rats; Rats, Inbred SHR; Renin

We evaluated the effects of a novel calcium antagonist, manidipine, on albuminuria in rats with passive Heymann nephritis (PHN). Treatment with 0.05% manidipine significantly reduced urinary albumin excretion (62.1 +/- 7.5 vs. 46.9 +/- 8.5 mg/urinary creatinine excretion mg, P < 0.05) and attenuated lipid peroxidation of the renal cortices (0.97 +/- 0.08 vs 0.84 +/- 0.11 nM MDA/mg protein, P < 0.05) on day 14 in PHN. Manidipine affected neither the light microscopic, immunofluorescent nor electron microscopic findings. These results indicate that manidipine reduced proteinuria in rats with PHN, and that its antiproteinuric effect was associated with the reduction of lipid peroxidation.

Topics: Albuminuria; Animals; Calcium Channel Blockers; Creatinine; Dihydropyridines; Glomerulonephritis; Kidney Cortex; Lipid Peroxidation; Nitrobenzenes; Piperazines; Rats

1. It has been suggested that hypertension may be an important determinant of the rate of progression of diabetic microangiopathy. 2. Renal microvascular disease as assessed by urinary albumin excretion and glomerular ultrastructure was evaluated in a model in which streptozotocin diabetes was induced in spontaneously hypertensive rats (SHR). 3. Diabetes was associated with increases in urinary albumin excretion, and hypertension resulted in a further increase in albuminuria. 4. Various antihypertensive regimens were administered to diabetic SHR, with the angiotensin-converting enzyme inhibitor perindopril and triple therapy (hydralazine, reserpine and hydrochlorothiazide) being more effective than the calcium antagonist (lacidipine) in retarding the increase in albuminuria in diabetic SHR. 5. Antihypertensive therapy appears to ameliorate the development of diabetic renal disease.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Nephropathies; Dihydropyridines; Hypertension, Renovascular; Indoles; Kidney Glomerulus; Male; Perindopril; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The effects of the calcium channel blocker, isradipine, on BP, urinary albumin excretion, plasma lipoproteins and natriuresis in albuminuric Type 1 (insulin-dependent) diabetic patients were assessed. Fifteen Type 1 diabetic patients aged 22-52 years were studied. All had elevated urinary albumin excretion (more than 30 mg/24h) based on several 24 h urine collections, and BP was normal (below 140/90 mmHg). After a placebo treatment period of eight weeks the patients were randomly assigned to two groups for a double-blind crossover study. Each patient received either 2.5 mg isradipine twice daily or placebo for eight weeks. Then, after 4 weeks (the wash-out period), each patient received the drug he or she had not taken before for another 8 weeks. Systolic blood pressure was lowered by 8 mmHg from 127 (114-139) mmHg (P less than 0.01) and diastolic by 5 mmHg from 81 (70-87) mmHg (P less than 0.03) during isradipine treatment. The 24 h urinary sodium excretion increased and no signs of volume expansion were observed during treatment with isradipine. Urinary albumin excretion and total body exchangeable sodium remained unchanged. During isradipine treatment the plasma concentrations of VLDL cholesterol and triglyceride decreased significantly (P less than 0.01) and the level of HDL cholesterol increased, but not significantly (P = 0.08). In conclusion, treatment of Type 1 diabetic patients, at risk of progressive clinical nephropathy, with the calcium channel blocker, isradipine, had beneficial effects on plasma lipoprotein levels and resulted in a reduction in BP. We did not find any effect of isradipine on urinary albumin excretion.

Topics: Albuminuria; Blood Pressure; Calcium Channel Blockers; Cholesterol; Diabetes Mellitus, Type 1; Dihydropyridines; Humans; Isradipine; Natriuresis; Reference Values