dihydropyridines and Obesity

The majority of patients with hypertension, and in particular high-risk patients or those with diabetes mellitus or renal dysfunction, are likely to require combination therapy with at least two antihypertensive agents (from different classes) to achieve their blood pressure (BP) target. The delapril/manidipine fixed-dose combination consists of two antihypertensive agents with different, yet complementary, mechanisms of action. Delapril/manidipine has demonstrated short- and long-term antihypertensive efficacy in a number of clinical studies in patients with hypertension with an inadequate response to monotherapy. Comparative studies have demonstrated that delapril/manidipine is as effective as enalapril/hydrochlorothiazide (HCTZ) in patients with hypertension with an inadequate response to monotherapy, and as effective as irbesartan/HCTZ, losartan/HCTZ, olmesartan medoxomil/HCTZ, ramipril/HCTZ and valsartan/HCTZ in reducing BP in patients with hypertension and diabetes, or in obese patients with hypertension. Therapy with delapril/manidipine also appears to exert beneficial effects that extend beyond a reduction in BP, including nephroprotective activity and an improvement in fibrinolytic balance, supporting its value as a treatment option in these patient populations at high or very high cardiovascular risk because of the presence of organ damage, diabetes or renal disease.

Topics: Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Clinical Trials as Topic; Diabetes Complications; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Indans; Irbesartan; Losartan; Nitrobenzenes; Obesity; Olmesartan Medoxomil; Piperazines; Ramipril; Tetrazoles; Valine; Valsartan

Obesity is becoming one of the leading risk factors of coronary heart disease, hypertension, cerebrovascular disease. Despite the presence of a large number of antihypertensive agents and scientific substantiation of antihypertensive treatment principles it would be wrong to assume that the problem is completely solved. Development of endothelial dysfunction is one of the key pathogenic mechanisms in hypertension. This process is proven to have contributed by immune inflammation activation which is mediated by pro-inflammatory cytokines and oxidative stress.. To investigate the additional benefits of the combined antihypertensive therapy with lacidipine and candesartan on the basis of studying their antioxidant properties, impact on endothelial function and pro-inflammatory cytokines activity in hypertensive patients with overweight and obesity.. A combination of a calcium channel blocker and angiotensin receptor blocker (lacidipine 2 mg, 4 mg, and candesartan 4mg, 8mg, 16mg) was prescribed to 30 patients with essential hypertension of grades 1-3, 30 to 65 years old (mean age - 54.7 ± 5.8 years), who previously have not been receiving regular antihypertensive therapy.. During the course of combined antihypertensive therapy with lacidipine and candesartan, a significant reduction in i-NOS activity, TNF-α to its type I soluble receptor ratio (TNF- α/sTNF-αRI), and oxidative stress marker - 8-iso-PgF2α has been observed. Activity of e-NOS, levels of SOD and catalase, in contrast, have increased by the end of observation period.. The improvement of endothelial function due to lower level of oxidative stress and a significant decrease of immune activation has been observed in hypertensive patients with overweight and obesity under the influence of combined antihypertensive therapy with lacidipine and candesartan.

Topics: Adult; Aged; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Case-Control Studies; Dihydropyridines; Dinoprost; Drug Therapy, Combination; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Tetrazoles; Tumor Necrosis Factor-alpha

Scanty information is available on the effects of combination drug treatment based on an ACE inhibitor and a calcium channel blocker on the neurometabolic alterations characterizing obesity-related hypertension (OHT). After 2-week run-in with enalapril (20 mg), 36 OHTs were randomized according to a double-blind crossover design to a combination therapy with either lercanidipine 10 mg (L) or felodipine extended release 5 mg (F), each lasting 8 weeks. Measurements included clinic and ambulatory blood pressure (BP) and heart rate, homeostasis model assessment index, plasma norepinephrine, and muscle sympathetic nerve activity. Patients with uncontrolled BP were then uptitrated to 20 mg/d (L) and 10 mg/d (F) combined with enalapril 20 mg, respectively, for further 8 weeks. For similar BP reductions, enalapril-lercanidipine (EL) caused norepinephrine and MSNA increases significantly less pronounced than those seen with enalapril-felodipine, the lesser sympathoexcitation observed with EL being coupled with a significant improvement in homeostasis model assessment index. This was the case also when L and F were uptitrated in the combination. In OHT, at variance from enalapril-felodipine, EL combination is almost entirely devoid of any major sympathoexcitatory effect and is associated with an improvement in insulin sensitivity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Enalapril; Felodipine; Female; Heart Rate; Humans; Hypertension; Insulin Resistance; Male; Metabolome; Middle Aged; Norepinephrine; Obesity; Random Allocation; Sympathetic Nervous System

To compare the effect of delapril/manidipine vs olmesartan/hydrochlorothiazide (HCTZ) combination on insulin sensitivity and plasma fibrinogen in obese hypertensive patients.. After a 4-week placebo period, 88 obese, hypertensive (DBP >95 and <110 mmHg) outpatients were randomized to delapril 30 mg/manidipine 10 mg combination or to olmesartan 20 mg/HCTZ 12.5 mg combination for 24 weeks according to a prospective, randomized, open-label, blinded endpoint, parallel group design. At the end of the placebo period and treatment period, clinical BP, fasting plasma glucose (FPG), plasma insulin, insulin sensitivity (by euglycemic hyperinsulinemic clamp) and plasma fibrinogen were evaluated. Insulin sensitivity was expressed as the amount of glucose infused during the last 30 minutes (glucose infusion rate, GIR) in mg/Kg/min. The total glucose requirement (TGR) to maintain a steady-state blood glucose level in response to a defined increase in plasma insulin concentration was also evaluated.. Both combinations significantly reduced SBP/DBP values (-22.3/16.4 mmHg and -22.6/17.2 mmHg, respectively, all p <0.001 vs placebo). GIR was significantly increased only by delapril/manidipine (+3.01 mg/min/Kg, p=0.038 vs placebo), the difference between treatments being significant (p <0.05). TGR was significantly increased by delapril/manidipine (+9.7 g, p=0.034), while it was unaffected by olmesartan/HCTZ. Plasma insulin as well as fibrinogen were significantly reduced by delapril/manidipine (-17.8 pmol/l, p=0.047 and -67.5 mg/dl, p=0.021, respectively), but not by olmesartan/HCTZ, the difference between the two treatments being statistically significant (p <0.05).. In obese hypertensive patients the delapril/manidipine combination but not the olmesartan/HCTZ combination significantly decreased insulin resistance and plasma fibrinogen levels, despite the similar BP lowering efficacy.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Female; Fibrinogen; Glucose Clamp Technique; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Indans; Insulin Resistance; Male; Middle Aged; Nitrobenzenes; Obesity; Piperazines; Tetrazoles

Topics: Adult; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Nifedipine; Obesity; Treatment Outcome; Verapamil

To demonstrate that calcium channel blockers can improve insulin resistance clinically, we investigated the effects of the calcium channel blockers, amlodipine, manidipine and cilnidipine on serum levels of steroid hormones and insulin.. Thirty hypertensive obese patients [15 men and 15 women; mean age 55.9 years, mean body mass index (BMI) 27.6] were divided into three groups and treated with either 5 mg of amlodipine, 20 mg of manidipine or 10 mg of cilnidipine. Blood pressure (BP), fasting plasma glucose (FPG), HbA1c, fasting serum immunoreactive insulin (F-IRI), insulin resistance index [as assessed by the homeostasis model assessment (HOMA-R)], serum DHEA, serum DHEA-S, plasma ACTH, serum cortisol, plasma renin activity (PRA), and serum aldosterone, were measured before and after 1, 2, 3 and 6 months of treatment.. In all three groups, BP decreased significantly after 1 month and F-IRI and HOMA-R decreased significantly after 2-3 months. A concurrent rise in serum DHEA and DHEA-S levels was also observed, however, the differences were not significant. No changes in FPG, HbA1c, ACTH, cortisol, PRA or aldosterone levels were observed during treatment.. We conclude that amlodipine, manidipine and cilnidipine all improve insulin resistance and consequently increase serum levels of DHEA and DHEA-S.

Topics: Aged; Amlodipine; Analysis of Variance; Body Mass Index; Calcium Channel Blockers; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Delayed-Action Preparations; Dihydropyridines; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Nitrobenzenes; Obesity; Piperazines; Probability; Reference Values; Risk Assessment; Severity of Illness Index; Treatment Outcome

To determine the efficacy and tolerability of a long-acting dihydropyridine in the clinical settings of general practice.. 110 essential hypertensives were included (age 62.3 +/- 10.8 years, 51 men and 53 women, 38/ obese -IMC >30 kg/m2, ten diabetics). 104 patients ended the followup. Patients were treated with lercanidipine 10 mg once daily in the morning. Follow-up lasted 6 months. When blood pressure was not controlled (BP < 140/90 mmHg) in any visit, a second drug was added, excluding calcium channel blockers. Antiadrenergic drugs were recommended. If patients were not controlled ittwo consecutive visits they were excluded from follow-up.. Significant reductions in both systolic (baseline 157.4 +/- 11.7 vs 131.1 +/- 6.8 mmHg, p < 0,001) and diastolic BP (baseline 94.7 +/- 5.8 vs 80.0 +/- 5.5 mmHg, p < 0,001) were attained at six months. Mean SBP decrease was 26.7 mmHg and mean DBP reduction was 15.6 mmHg. At the study end, 84.3/ of the patients achieved a BP < 140/90 mmHg. Thirty patients needed a second drug to become controlled (26 at the study end). The overall incidence of adverse effects was 4,4/ (n=6) and just three patients withdrew the treatment due to untoward effects. Plasmatic cholesterol lowered from 225.3 +/- 41.0 to 216.7 +/- 25.3 mg/dl (p = 0,03) and urate decreased from 5.6 +/- 1.6 to 5.1 +/- 1.4 mgldl, p = 0,03).. Lercanidipine is a calcium channel blockers of high efficacy and low incidence of adverse effects in the clinical settings of general practice. It seems to have a positive metabolic effects on plasmatic levels of cholesterol and urate.

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Cholesterol; Diabetes Complications; Dihydropyridines; Family Practice; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Obesity; Treatment Outcome; Uric Acid

To evaluate the efficacy, metabolic effects and tolerability of manidipine used in the treatment of stage I and II essential hypertensive patients with overweight or android obesity.. By an open-label, non comparative protocol in 11 Brazilian clinical research centers 102 hypertensive patients of both sexes with over weight or central obesity were treated with manidipine 10 to 20mg once daily for 12 weeks. Blood pressure, heart rate and adverse events were monitored. Fasting plasma glucose, total, HDL and LDL-cholesterol and triglicerides were determined at both placebo period and end of active treatment. Also in 12 patients, insulin sensitivity index was evaluated during placebo and manidipine treatment.. Blood pressure was reduced from 159+/-15 / 102+/-5mmHg to 141+/-15 / 90+/-8mmHg with the treatment without any noticeable change in heart rate. Manidipine-efficacy rate was 71.9% with 51.1% of blood pressure normalization. No significant changes in metabolic parameters were noticed. Tolerability to manidipine was very high and at the last visit 87.1% of the treated patients were free of any adverse event.. Manidipine is an adequate, highly effective, exempt of metabolic effects and safe option for treatment of stage I and II essential hypertensive patients with overweight or android obesity.

Topics: Adult; Antihypertensive Agents; Blood Glucose; Brazil; Dihydropyridines; Female; Humans; Hypertension; Lipid Metabolism; Lipids; Male; Middle Aged; Nitrobenzenes; Obesity; Piperazines; Treatment Outcome

The aim of the present study is to examine the effects of the antihypertensive drug cilnidipine on glucose metabolism and adipocytokines, including adiponectin, in diet-induced obese (DIO) mice. The effects of cilnidipine on insulin sensitivity and the levels of adiponectin in DIO mice were examined after the mice had been treated with cilnidipine dissolved in water at a dose of 0.2 g l(-1) for 14 days. As expected, treatment with cilnidipine decreased the systolic and diastolic blood pressures in DIO mice, compared with control mice (P<0.05 for each parameter). Cilnidipine treatment improved glucose and insulin sensitivity in DIO mice. In addition, cilnidipine treatment dramatically increased the level of adiponectin in white adipose tissue (P<0.05) and the circulating levels of total and high-molecular weight (HMW) adiponectin in DIO mice (P<0.01 for each parameter). Furthermore, the secretion of HMW adiponectin and the ratio of HMW adiponectin/total adiponectin were both increased after cilnidipine treatment. Finally, the secretion of adiponectin from adipocytes was increased after cilnidipine treatment. Taken together, these results indicate that cilnidipine improves insulin tolerance and adiponectin levels, especially high-molecular type adiponectin, in DIO mice.

Topics: Adipocytes; Adiponectin; Administration, Oral; Animals; Blood Pressure; Calcium Channel Blockers; Cells, Cultured; Diet, High-Fat; Dihydropyridines; Disease Models, Animal; Glucose; Insulin; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Obesity; Resistin; Tumor Necrosis Factor-alpha

It has been suggested that increased dietary calcium intake can attenuate obesity. Calcium antagonists, such as benidipine, also have been shown to have an anti-obesity effect. However, the mechanism for calcium-related anti-obesity effect has not yet been established. A defective brown adipose tissue thermogenesis has been shown in obese rodents. This study was designed to examine the direct effects of calcium channel blocker benidipine and calmodulin antagonist W7 administration on the adaptive thermogenesis in brown adipose tissue taken from the genetically obese mice and their lean controls. The GDP binding to brown-fat cell mitochondria was used as a brown adipose tissue thermogenic index. The results show that benidipine treatment had no marked effect on brown-fat cell GDP-binding capacities in both obese and lean mice. However, GDP-binding capacities were significantly reduced in both obese and lean mice after the W7 administration. The results of this study support the previous finding that benidipine did not have direct thermogenic effect on brown adipose tissue and suggest that the change in intracellular calmodulin availability might contribute to the adaptive thermogenesis in brown adipose tissue.

Topics: Adipose Tissue, Brown; Animals; Calcium Channel Blockers; Calmodulin; Dihydropyridines; Enzyme Inhibitors; Female; Guanosine Diphosphate; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Sulfonamides; Thermogenesis

Anti-obesity effects of calcium antagonists such as benidipine and nifedipine have been described in rodent obesity models, but the mode of action of the calcium antagonists as anti-obesity agents has not been established.. To examine whether the anti-obesity effects of calcium antagonists (here benidipine) could be ascribed to a direct stimulation of brown adipose tissue (BAT) thermogenesis.. Examination of the ability of benidipine to induce thermogenesis (increased rate of oxygen consumption) in isolated brown-fat cells from rats, mice and hamsters--and in intact cold-acclimated rats.. Benidipine itself, or in combination with any dose of noradrenaline (NA), was totally unable to induce or augment thermogenesis in isolated brown-fat cells of any species tested. However, it markedly induced thermogenesis in intact animals (approx 60% increase over resting metabolic rate). This effect could be fully inhibited by propranolol.. Benidipine is itself without thermogenic effect. The thermogenic response in-vivo (and thus presumably the anti-obesity effect) is probably secondary to a previously described general side-effect of calcium antagonists: a release of NA from sympathetic nerves, here most likely directly from nerves in the BAT. The anti-obesity effect of benedipine is thus probably not due to its calcium channel blocking effect.. It is probable that the anti-obesity effects of calcium antagonists reported in several models of genetically obese rodents (MSG-obese and agouti mice, SHHF/Mcc-fa(cp) and JCR:LA-corpulent rats) are mediated via an indirect stimulation of BAT. To what extent calcium antagonists may induce similar effects in a clinical situation, is currently unknown.

Topics: Adipose Tissue, Brown; Adrenergic beta-Antagonists; Animals; Body Temperature Regulation; Calcium Channel Blockers; Cricetinae; Dihydropyridines; Male; Mice; Norepinephrine; Obesity; Propranolol; Rats; Rats, Sprague-Dawley

Benidipine hydrochloride, a dihydropyridine calcium antagonist, decreases body weight and also has a hypotensive effect. The mechanism of its inhibitory effect on body weight is unclear, although this agent increases blood flow in brown adipose tissue, which functions as a main thermogenic organ. The hypothesis that benidipine hydrochloride activates brown adipose tissue to induce body weight loss was tested on mice made obese by pretreatment with monosodium-L-glutamate (MSG). When benidipine hydrochloride was incorporated in the diet (1.0 mg per gram of food) for 4 weeks, binding of guanosine-5'-diphosphate in brown adipose tissue mitochondria was significantly increased. Body weight and body fat decreased in both MSG obese mice and in lean controls. Results support the hypothesis and suggest the possibility that benidipine hydrochloride may be useful for treating obese hypertensive patients.

Topics: Adipose Tissue, Brown; Analysis of Variance; Animals; Body Weight; Calcium Channel Blockers; Dihydropyridines; Eating; Female; Mice; Mice, Inbred ICR; Obesity