Effects Of Manidipine Research Articles

Factors associated with the reduction of albumin excretion in diabetic hypertensive patients: differential effect of manidipine versus amlodipine.

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.

Effects of Manidipine and Delapril in Hypertensive Patients With Type 2 Diabetes Mellitus: The Delapril and Manidipine for Nephroprotection in Diabetes (DEMAND) Randomized Clinical Trial

Effects of Manidipine and Delapril in Hypertensive Patients With Type 2 Diabetes Mellitus: The Delapril and Manidipine for Nephroprotection in Diabetes (DEMAND) Randomized Clinical Trial

Effects of Manidipine and Delapril in Hypertensive Patients With Type 2 Diabetes Mellitus

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m(2) (IQR: 0.16-0.50 mL/min per 1.73 m(2)) on combined therapy, 0.36 mL/min per 1.73 m(2) (IQR: 0.18-0.53 mL/min per 1.73 m(2)) on delapril, and 0.30 mL/min per 1.73 m(2) (IQR: 0.12-0.50 mL/min per 1.73 m(2)) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.

Effects of Manidipine and its Combination with an ACE Inhibitor on Insulin Sensitivity and Metabolic, Inflammatory and Prothrombotic Markers in Hypertensive Patients with Metabolic Syndrome

Metabolic syndrome is common in patients with hypertension and increases the risk of developing diabetes mellitus. The objective of this study (the MARCADOR study) was to compare the effects of manidipine 20 mg with the extemporary combination of manidipine 10 mg/lisinopril 10 mg, amlodipine 10 mg and telmisartan 80 mg on insulin sensitivity, as well as metabolic, inflammatory and prothrombotic markers, in hypertensive non-diabetic patients with metabolic syndrome. This study had a prospective, randomized, open-label, blinded endpoint (PROBE) design. A total of 120 patients aged 35-75 years with stage I-II essential hypertension (systolic blood pressure [BP] 140-179 mmHg, diastolic BP 90-109 mmHg) and metabolic syndrome were recruited from general practitioner clinics in Northern Gran Canaria Island, Spain and randomized to receive amlodipine 10 mg (n = 30), telmisartan 80 mg (n = 30), manidipine 20 mg (n = 30) or (low-dose) manidipine 10 mg/lisinopril 10 mg (n = 30), all administered once daily. At baseline and after 14 weeks of treatment, BP, insulin sensitivity, lipid profile, and albumin and metanephrin excretion as well as several other metabolic, inflammatory, prothrombotic and growth/adhesion markers were measured. The primary endpoint was the change in insulin sensitivity. A total of 115 patients completed the study. All treatments significantly lowered BP from baseline. Compared with amlodipine, manidipine had significantly superior effects (p < 0.05) on insulin resistance (-26.5% vs -3.0%), albumin/creatinine ratio (-28.2% vs -3.6%), low-density lipoprotein (LDL) cholesterol (-6.8% vs +1.7%), and several other metabolic, inflammatory and prothrombotic markers. Manidipine was associated with a slightly greater increase in insulin sensitivity than manidipine/lisinopril, but manidipine/lisinopril was significantly more effective than manidipine and telmisartan for improving a number of metabolic, inflammatory, prothrombotic and growth/adhesion markers. Amlodipine was associated with a significantly greater incidence of adverse effects compared with telmisartan, manidipine and manidipine/lisinopril (26.7% vs 3.3%, 3.3% and 13.3%, respectively). In patients with hypertension and metabolic syndrome, manidipine, both alone and in combination with the ACE inhibitor lisinopril, is significantly superior to amlodipine for improving insulin sensitivity as well as several metabolic, inflammatory and prothrombotic markers. Furthermore, the combination of manidipine and lisinopril appears to have greater efficacy than manidipine alone and telmisartan with respect to the improvement of metabolic, inflammatory and prothrombotic markers.

Manidipine in hypertensive patients with metabolic syndrome: the MARIMBA study

Objectives: To evaluate the effects of manidipine versus amlodipine on blood pressure, albuminuria, insulin sensitivity, adiponectin, TNF-α and C-reactive protein in nondiabetic subjects with metabolic syndrome (ATP-III definition), including impaired fasting glucose (>5.6 mmol/l) and hypertension. Methods: In total, 64 patients were recruited and randomly assigned to manidipine 20 mg versus amlodipine 10 mg (for 12 ± 2 weeks). Results: 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-α 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). Conclusion: 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.

Metabolic Effects of Manidipine

The calcium channel antagonists (CCAs) were originally introduced as vasodilators for the treatment of coronary heart disease, but are now also noted for their clinical efficacy in the management of hypertension. Data from large clinical studies have shown that CCAs are not associated with the undesirable metabolic effects (e.g. worsening of dyslipidemia and reduction of insulin sensitivity) seen with older agents such as thiazide diuretics and beta-adrenoceptor antagonists (beta-blockers) that are used to treat hypertension. Indeed, reductions in cardiovascular risk and rates of onset of new cases of diabetes mellitus have been reported in trials in patients with hypertension treated with CCAs. These beneficial effects extend beyond those expected to accompany reductions in BP. Until recently, the biochemical effects underlying these metabolic changes were only poorly understood, but pharmacologic studies have now started to shed more light on these issues. Of particular interest are studies with manidipine, some of which suggest that this agent may be associated with greater improvements in insulin sensitivity and may have better renal protective properties than other CCAs. Confirmation of potential differences among CCAs in terms of the relative magnitude of any beneficial metabolic effects requires further study. Ongoing research is expected to clarify further the action of these agents at the cellular level and to assist with the optimization of antihypertensive therapy, particularly in patients with elevated cardiovascular risk profiles.

Effect of Manidipine as Compared to Atenolol on Platelet Aggregation in Elderly Patients with Isolated Systolic Hypertension and Type II Diabetes Mellitus

This study was done to evaluate the effect of treatment with manidipine as compared with atenolol on thrombin-mediated platelet aggregation in elderly patients with isolated systolic hypertension and type II diabetes mellitus. After a 2-week washout placebo period, 60 elderly patients (aged 65-80 years) with isolated systolic hypertension (SBP > 140 mm Hg and DBP < 90 mm Hg) were randomly assigned to manidipine 10 mg or atenolol 50 mg 6-week treatment according to a double-blind, crossover design. Thirty patients had a concomitant well-controlled type 2 diabetes mellitus (HbA1c < or = 6.5%). At the end of the washout and of each treatment period, blood pressure (BP) (by mercury sphygmomanometer) and platelet aggregation (by Born-type aggregometer) were evaluated. Blood samples were collected using sodium citrate as anticoagulant, and platelet aggregation was induced by 2 different concentrations of ADP and collagen. Manidipine and atenolol produced a significant BP reduction in both diabetic and nondiabetic patients, with no difference between treatments. Despite the similar BP effect, in diabetic patients manidipine produced a significant reduction in platelet aggregation induced by both doses of either ADP or collagen. In nondiabetic hypertensives, manidipine inhibited platelet aggregation only at the highest doses of both inducers. The difference in the platelet inhibitory effect of manidipine between diabetic and nondiabetic subjects was statistically significant (P < 0.05) at both inducer concentrations. No changes in platelet aggregation were observed in the atenolol group. These data indicate that, unlike atenolol, manidipine inhibits platelet aggregation in elderly hypertensive patients, expecially in those with associated type II diabetes mellitus. The clinical impact of this positive effect in terms of prevention of cardiovascular complications in these high-risk patients remains to be clarified.

Antihypertensive Effect of Manidipine

Manidipine is a lipophilic, third-generation, highly vasoselective, dihydropyridine (DHP) calcium channel antagonist, which, when given on a once-daily basis, effectively reduces blood pressure (BP) in patients with mild-to-moderate essential hypertension. Manidipine has a gradual onset and a long duration of action, effectively maintaining reduced BP levels throughout the 24-hour dosing period, and is effective in the long term with no evidence of intolerance. The BP-lowering capacity of manidipine is similar to that of other established DHPs and of angiotensin-converting enzyme inhibitors. Diabetic patients and very elderly patients with mild-to-moderate hypertension also respond favourably to treatment with manidipine. Manidipine has neutral effects on glucose and lipid metabolism and is generally well tolerated. Manidipine thus represents a first-line option for lowering BP in patients with mild-to-moderate hypertension.

DIFFERENT EFFECTS OF MANIDIPINE AND LERCANIDIPINE ON BLOOD PRESSURE, PERIPHERAL CIRCULATION AND ANKLE OEDEMA IN HYPERTENSIVE PATIENTS

P2.330; Citation: Journal of Hypertension Volume 22, Supplement 2, June 2004, page S244 DIFFERENT EFFECTS OF MANIDIPINE AND LERCANIDIPINE ON BLOOD PRESSURE, PERIPHERAL CIRCULATION AND ANKLE OEDEMA IN HYPERTENSIVE PATIENTS V. Tikhonoff, A. Mazza, E. Casiglia, A.C. Pessina Department of Clinical and Experimental Medicine, University of Padua, Via Giustiniani 2, 35128 Padua, Italy Objectives: To evaluate the oedemigenous effect and the anti-hypertensive efficacy of two newgeneration dihydropyridine calcium channel blockers, manidipine and lercanidipine. Design and Methods: The study was a randomized, controlled, parallel group trial. After a 2-week placebo run-in, 53 mild-to-moderate hypertensive patients aged 18-75 years were treated for 12 weeks with either manidipine (10 mg/day) or lercanidipine (10 mg/day) by oral route in the morning. 24-hour blood pressure (BP) and heart rate were recorded with a TM-2430 device (Takeda, Tokyo, Japan). Leg arterial flow (ml⋅min−1⋅dl−1) was measured with strain-gauge plethysmography (Angioflow, Microlab, Padova, Italy) both at rest and after ischemia, at baseline as well as at the end of treatment. Peripheral resistances (mmHg⋅min⋅dl⋅ml−1) were calculated as the mean BP/flow ratio; minimal arterial resistance calculated from peak flow was taken as an indirect measure of arterial wall thickness. Ankle volume was assessed with water-displacement plethysmography, and ankle oedema calculated for each drug as difference between baseline and post-treatment volume. Results: In comparison to baseline, daytime BP decreased from 147±15/85±7 to 139±16/80±10 mmHg with manidipine (systolic and diastolic: p<0.001) and from 147±12/85±9 to 141±12/79±6 mmHg with lercanidipine (systolic and diastolic: p<0.001). Normalization of BP (<140 and <90 mmHg) was observed in 35% of cases after manidipine and in 18% after lercanidipine (p<0.005 between treatments). HR remained unchanged with both drugs. Rest and post-ischaemic vascular peripheral resistance significantly decreased after manidipine (−30%, p<0.005) but not after lercanidipine. Ankle volume significantly increased (+6.6%) after lercanidipine, whereas no significant increase was observed after manidipine. Conclusions: Both manidipine and lercanidipine were effective in reducing BP; however, the rate of normalization was double with manidipine with respect to lercanidipine. Compared to lercanidipine, manidipine was more potent as a vasodilator and, despite the short-term treatment, reduced arteriolar wall thickness as shown by the reduced maximal arterial resistance. Finally, vasodilatory edema was less pronounced with manidipine than with lercanidipine treatment.

Effect of manidipine on gene expression and protein level of oxidative stress-related proteins: p22phox and HO-1: relevance for antihypertensive and anti-remodeling effects.

Oxidative stress (OxSt) is a major damaging factor in arterial hypertension and its long-term complications. This is why considerable attention is paid to the possible effects of antihypertensive drugs on OxSt. Manidipine is a dihydropiridine calcium channel blocker with reported nephroprotective activities, but no information is available on its effect on OxSt and related mechanisms. This study assessed the effect of manidipine on normal subjects' monocyte gene and protein expression of OxSt-related proteins such as p22(phox), a NAD(P)H oxidase system subunit, critical in generating O2-, and heme oxygenase-1 (HO-1), induced by and protective from OxSt, and compared manidipine with the ACE inhibitor captopril and the calcium channel blocker nifedipine, in the presence and absence of sodium arsenite (NaAsO2) as an inducer of OxSt.Co-incubation of manidipine with NaAsO2 dose-dependently decreased p22(phox) mRNA production from basal: 0.87 +/- 0.1 d.u., 0.69 +/- 0.06 and 0.66 +/- 0.09 at 100, 300 and 500 nM respectively versus 0.99 +/- 0.2, P < 0.04, while HO-1 mRNA production was increased by the same concentrations of the drug: 0.87 +/- 0.1 d.u., 0.92 +/- 0.1, 0.98 +/- 0.1 respectively versus 0.63 +/- 0.07; P < 0.03. Monocyte p22(phox) mRNA production was reduced both by manidipine and captopril: 0.48 +/- 0.04 d.u. and 0.43 +/- 0.08, respectively versus 0.58 +/- 0.07, P < 0.006, while no changes were induced by nifedipine (0.61 +/- 0.07, P = ns). Manidipine increased monocyte HO-1 mRNA production (1.6 +/- 0.4 versus 1.2 +/- 0.4, P < 0.008), while nifedipine and captopril showed no effect (1.2 +/- 0.3 and 1.1 +/- 0.3, respectively). The effects of M on p22(phox) and HO-1 gene expression in the presence of OxSt were also paralleled by the same effects at protein level. In conclusion, manidipine decreases p22(phox) and increases HO-1 mRNA production and protein level. The manidipine-induced increase of HO-1 gene and protein expression seems to be a peculiar effect of this drug since it is not observed with captopril and nifedipine. This effect, together with the reduction of p22(phox) mRNA production, could play a role in its protective mechanism against OxSt.

Effects of Manidipine and Nifedipine on Blood Pressure and Renal Function in Patients with Chronic Renal Failure: A Multicenter Randomized Controlled Trial

Several studies suggest the distinctive advantages of ACE-inhibitors and calcium-channel blockers in protecting the residual renal function in hypertensive patients. Pre-clinical and clinical studies have shown rare adverse events in the treatment with manidipine, which is commonly used as antihypertensive drug. We therefore decided to compare the effects of manidipine and nifedipine, on blood pressure, and renal function. One hundred and one hypertensive patients with chronic renal failure were randomly assigned to receive either manidipine 20 mg daily or nifedipine 60 mg daily, respectively. Patients were assessed every two weeks during the active treatment period with the final follow-up after three months. The primary endpoint was the achievement of DBP ≤90 mmHg or a 10 mmHg DBP reduction from the baseline values, whilst the secondary endpoints was the improvement of the renal function assessed through the creatinine clearance, creatinine blood levels, protein and sodium urine excretion. Significant reduction in SBP (p<0.001) and DBP (p<0.001), compared to the baseline values, was reached in both treatments. Creatinine blood levels (p<0.05) and creatinine clearance (p<0.01) significantly increased in the manidipine group. Protenuria did not significantly change in the manidipine group but increased in the nifedipine group (p<0.05). The number of patients with severe adverse reactions differed significantly (p<0.01) between the groups with the highest frequency for nifedipine (14.5%) compared to manidipine (8.5%). The withdrawal rate was not significantly different between the groups. Manidipine is equally safe and effective as nifedipine and it may have more activity on renal function and less severe side effects compared to nifedipine.

Effect of manidipine and lisinopril on albuminuria and ventricular mass in diabetic hypertensive patients with microalbuminuria

Effect of manidipine and lisinopril on albuminuria and ventricular mass in diabetic hypertensive patients with microalbuminuria

Manidipine: a review of its use in hypertension.

Manidipine is a dihydropyridine calcium antagonist, which causes systemic vasodilation by inhibiting the voltage-dependent calcium inward currents in smooth muscle cells. The resulting reduction in blood pressure (BP) in patients with hypertension is maintained over 24 hours. Manidipine 10 to 40 mg once daily for 4 weeks significantly lowered office BP from baseline and compared with placebo, and significantly reduced 24-hour BP compared with placebo in patients with essential hypertension in a well controlled trial. The decline in BP was maintained over 24 hours (trough to peak BP ratios were >50%) without disturbing the circadian BP pattern. BP reductions with therapeutic dosages of manidipine were maintained for up to 1 year in noncomparative trials. The BP-lowering capacity of manidipine 5 to 20 mg/day appears to be similar to that of other calcium antagonists with which it has been compared in randomised double-blind and nonblind trial. In a well controlled short term trial, manidipine 10 mg daily significantly decreased trough sitting BP compared with placebo in elderly patients with mild to moderate essential hypertension. Decreases in BP were maintained for up to 3 years of treatment. The drug (10 or 20 mglday) also significantly lowered sitting BP from baseline in patients with hypertension and type 2 diabetes mellitus in randomised, long term comparative trials. In general, the observed reduction in BP with manidipine was similar to that observed with amlodipine, enalapril or delapril. The effects of manidipine on urinary albumin excretion (UAE) have not been clearly demonstrated in clinical trials in this patient group. BP was also reduced with manidipine in patients with impaired glucose tolerance. Manidipine was well tolerated in clinical trials, with most adverse effects related to vasodilation. Commonly reported events included ankle oedema, headache. palpitation. flushing, dizziness, rash and fatigue. Manidipine appears to have less potential for pedal oedema than amlodipine. Manidipine has shown antihypertensive efficacy and appears to be well tolerated in adult and elderly patients with mild or moderate essential hypertension. The BP-lowering effects of the drug in patients with hypertension and type 2 diabetes mellitus or impaired glucose tolerance were not associated with any adverse metabolic effects. The effects of manidipine on UAE in this patient group remain unclear. Manidipine provides an additional treatment option for patients for whom dihydropyridine calcium antagonists are appropriate. Manidipine is a dihydropyridine calcium antagonist, which causes systemic vasodilation by inhibiting the voltage-dependent calcium inward currents in smooth muscle cells. The resulting reduction in blood pressure (BP) in patients with hypertension is maintained over 24 hours. Manidipine 10 to 40mg once daily for 4 weeks significantly lowered office BP from baseline and compared with placebo, and significantly reduced 24-hour BP compared with placebo in patients with essential hypertension in a well controlled trial. The decline in BP was maintained over 24 hours (trough to peak BP ratios were >50%) without disturbing the circadian BP pattern. BP reductions with therapeutic dosages of manidipine were maintained for up to 1 year in non-comparative trials. The BP-lowering capacity of manidipine 5 to 20 mg/day appears to be similar to that of other calcium antagonists with which it has been compared in randomised double-blind and nonblind trial. In a well controlled short term trial, manidipine 10 mg daily significantly decreased trough sitting BP compared with placebo in elderly patients with mild to moderate essential hypertension. Decreases in BP were maintained for up to 3 years of treatment. The drug (10 or 20 mg/day) also significantly lowered sitting BP from baseline in patients with hypertension and type 2 diabetes mellitus in randomised, long term comparative trials. In general, the observed reduction in BP with manidipine was similar to that observed with amlodipine, enalapril or delapril. The effects of manidipine on urinary albumin excretion (UAE) have not been clearly demonstrated in clinical trials in this patient group. BP was also reduced with manidipine in patients with impaired glucose tolerance. Manidipine was well tolerated in clinical trials, with most adverse effects related to vasodilation. Commonly reported events included ankle oedema, headache. palpitation. flushing, dizziness, rash and fatigue. Manidipine appears to have less potential for pedal oedema than amlodipine. Manidipine has shown antihypertensive efficacy and appears to be well tolerated in adult and elderly patients with mild or mo

Effects of manidipine and nitrendipine enantiomers on the plateau phase of K +-induced intracellular Ca 2+ increase in GH 3 cells

The aim of the present study was to investigate whether the chirality and type of substitution at position 3 of the dihydropyridine ring influences the pattern of voltage-gated Ca 2+ channel blockade. For this purpose, the effect of R- and S-enantiomers of manidipine and nitrendipine, separated by chiral High-Pressure-Liquid-Chromatography columns, were investigated by fura-2 microfluorimetry during the plateau phase of the intracellular Ca 2+ ([Ca 2+] i) increase induced by 55 mM K + and by patch-clamp recording of Ca 2+ channel activity in GH 3 cells. R- and S-enantiomers of both nitrendipine and manidipine produced a [Ca 2+] i decay of the K +-induced plateau phase that followed a biexponential pattern with a `fast' and a `slow' phase. The S-configuration of both nitrendipine and manidipine produced a larger [Ca 2+] i decrease during the `fast phase', and a faster and smaller [Ca 2+] i decrease in the `slow phase' than did the R-enantiomers. The S- and R-enantiomers of manidipine, which possess a longer and more lipophilic side chain at position 3 of the dihydropyridine ring, induced a slower [Ca 2+] i decrease than that observed with the respective nitrendipine enantiomers. Accordingly, patch-clamp experiments revealed that the S-enantiomers of both dihydropyridines displayed a faster onset of action and produced a greater blockade than the R-enantiomers. These results suggest that the enantiomeric configuration and a small side chain at position 3 of the dihydropyridine ring are factors in the chemical structure which influence the pattern of blockade of voltage-sensitive Ca 2+ channels.

Effect of manidipine and delapril on insulin sensitivity in type 2 diabetic patients with essential hypertension

The open trial was designed to evaluate the effects of long-term antihypertensive treatment with the calcium-channel blocker, manidipine and the angiotensin converting enzyme (ACE) inhibitor, delapril on insulin sensitivity in Japanese non-insulin dependent diabetes mellitus (NIDDM) patients with essential hypertension. We measured the insulin sensitivity index (S I) and the glucose-effectiveness (S G) by the use of Bergman's minimal model method in 18 hypertensive NIDDM patients before and after administration of manidipine (group A) or delapril (group B) for 3 months. Manidipine treatment for 3 months significantly improved S I in group A from 3.35 ± 0.61 (× 10 −4 min −1 μU −1 ml −1) to 4.70 ± 1.34 ( P < 0.05). Delapril treatment for 3 months also significantly improved S I in group B from 3.56 ± 1.04 to 5.00 ± 0.87 ( P < 0.05). Manidipine significantly improved S G in group A from 1.60 ± 0.64 (× 10 −2 min) to 2.19 ± 0.38 ( P < 0.05). Delapril treatment also significantly improved S G in the group B from 1.41 ± 0.56 to 1.91 ± 0.35 ( P < 0.05). Manidipine and delapril did not affect urinary C-peptide excretion for 24 h in the hypertensive NIDDM patients. Treatment with manidipine or delapril significantly reduced systolic and diastolic blood pressures in the hypertensive NIDDM patients. There were no differences between plasma glucose, serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions, heart rate and body weight after 3 months on manidipine or delapril. This study confirmed the improving effects on S I and S G by long-term treatment with manidipine or delapril in the hypertensive NIDDM patients.

Manidipine affects rPDGF-BB-induced gene transcription of low-density lipoprotein receptors and 3-hydroxy-3-methylglutaryl coenzyme A reductase in human mesangial cells

The effects of manidipine, a newly developed Ca 2+ channel blocker, on recombinant platelet-derived growth factor BB (rPDGF-BB)-induced transcription of the low-density lipoprotein receptor and the 3-hydroxy-3-methylglutaryl coenzyme A reductase genes in human mesangial cells are reported. The transcription of the rPDGF-BB-induced gene of the low-density lipoprotein receptor was enhanced and maintained over a longer period, whereas the transcription of the 3-hydroxy-3-methylglutaryl reductase gene was blocked by manidipine at nanomolar concentrations. The results suggest that aside from the ability to block mandipine's potential-operated Ca 2+ channels, manidipine also affects gene transcription of relevant proteins involved in the regulation of cholesterol metabolism at concentrations close to those efficacious for clinical therapies. This may further explain the antiinflammatory and organ-protective activities of the compound.

Effects of manidipine and other calcium antagonists on rat renal arcuate arteries

We investigated the effect of 1,4-dihydropyridine calcium antagonists (nifedipine, nisoldipine, and manidipine) on serotonin (5-hydroxytryptamine [5-HT])- and KCl (120 mmol/L)-induced contractions of rat isolated renal arcuate arteries. The preparation showed the well-known biphasic response to KCl-induced depolarization. All three calcium antagonists were more potent in inhibiting the second phase (tonic) compared with the first phase (transient) of the effect. The inhibitory concentration of 50% (pIC 50) values were 6.92 ± 0.24 8.51 ± 0.08 (nifedipine, n = 32), 7.61 ± 0.10 9.33 ± 0.03 (nisoldipine, n = 28), and 7.61 ± 0.13 9.07 ± 0.06 (manidipine, n = 32) for the suppression of the first and second phases, respectively. In small coronary and renal arteries maximally activated with KCl solution, nifedipine and manidipine concentrations dependently inhibited the calcium concentration response curves. Manidipine was more potent than nifedipine (pIC 50 coronary artery: 9.26 ± 0.14 vs 7.93 ± 0.22; pIC 50 renal artery: 9.14 ± 0.14 vs 7.77 ± 0.21), but both compounds showed the same potency in the two different preparations. Furthermore, the influence of the calcium antagonists on the 5-HT concentration-response curve was investigated. Marked differences were found in the ability of the three compounds to inhibit the 5-HT-induced vasoconstriction of isolated renal arteries. For manidipine, a 93% ± 3% reduction of the maximal 5-HT-induced contraction was observed, which was a significantly stronger inhibition compared with nifedipine (43% ± 4.12%) or nisoldipine (26% ± 0.37%). The pIC 50 values were 7.96 ± 0.15 (nifedipine), 8.17 ± 0.14 (nisoldipine), and 7.84 ± 0.12 (manidipine). Results indicate that all three calcium antagonists are potent and effective dilators of depolarization-induced renal vasospasms. Manidipine, a new 1,4-dihydropyridine, proved to be the most effective compound in inhibiting 5-HT-induced contractions in isolated small renal arteries.

Natriuretic Action of Manidipine Hydrochloride, a New Calcium Channel Blocker, in Spontaneously Hypertensive Rats

Effects of manidipine, a new dihydropyridine derivative, on sodium and water excretion were examined in conscious spontaneously hypertensive rats. Manidipine (3 mg/kg) significantly increased the sodium and water excretion in the urine collected for 3 hr after the calcium antagonist was orally administered, and its natriuretic action was more prominent than those of nifedipine and nicardipine (3 mg/kg). These results suggest that manidipine may be useful for treating hypertension.

Natriuretic action of manidipine hydrochloride, a new calcium channel blocker, in spontaneously hypertensive rats.

Effects of manidipine, a new dihydropyridine derivative, on sodium and water excretion were examined in conscious spontaneously hypertensive rats. Manidipine (3 mg/kg) significantly increased the sodium and water excretion in the urine collected for 3 hr after the calcium antagonist was orally administered, and its natriuretic action was more prominent than those of nifedipine and nicardipine (3 mg/kg). These results suggest that manidipine may be useful for treating hypertension.