dihydropyridines and Heart-Diseases

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Antihypertensive Agents; Calcium Channel Blockers; Cardiology; Dihydropyridines; Drug Therapy, Combination; Education, Medical, Continuing; Heart Diseases; Humans; Hypertension; Nitroprusside; Renin; Renin-Angiotensin System; Vasoconstriction

During the past 20 years the number of subclasses of calcium channel blockers has increased from one to four. Three classes have only a single clinically approved compound: verapamil, diltiazem, and mibefradil. The fourth class, dihydropyridines, contains numerous compounds. All agents are effective in lowering blood pressure in short-term studies, and side effects that trouble the patient are infrequent. Long-term studies in hypertensive patients are limited. Short-acting agents such as nifedipine have been associated with an increased cardiovascular risk in some, but not all studies. These agents also probably create a compliance problem for hypertensive patients because of the need for multiple daily doses and their unpleasant side effects, e.g., ankle edema, palpitations, and flushing. Therefore, they are not useful or indicated for the treatment of hypertensive patients. No data have suggested that long-acting dihydropyridines or nondihydropyridine calcium channel blockers share the same fate. Indeed, several lines of evidence suggest the opposite: they have a cardioprotective effect. However, definitive information will require the completion of several long-term trials, including ALLHAT, CONVINCE, HOT, INSIGHT and NORDIL. Finally, it is important to reflect on the lessons learned from the controversy associated with the potential risks of calcium channel blockers. First, disagreements are common when one uses case-controlled studies and are reflective of the poor precision of the methods used. What is statistically relevant in one study may not hold true for another and may have no clinical relevance, particularly if the relative risk is less than 2. Investigators need to temper their enthusiasm to reflect this reality. Second, at the cutting edge of science there is probably relatively little agreement about what is correct among equally competent scientists. All have bias in their positions and should both recognize and admit so to themselves and their colleagues. Inferring that those who disagree have an unstated secondary agenda that will bring personal financial rewards or government accolades is inappropriate and counterproductive. Third, the randomized clinical trial, despite all its imperfections, is still the best tool to establish common ground on controversial issues. Finally, what may seem best from the public health perspective may not be in the best interest of the individual patient--a possibility that physicians have to constantly c

Topics: Antihypertensive Agents; Benzimidazoles; Blood Pressure; Calcium Channel Blockers; Case-Control Studies; Clinical Trials as Topic; Dihydropyridines; Diltiazem; Heart Diseases; Humans; Hypertension; Longitudinal Studies; Mibefradil; Nifedipine; Public Health; Randomized Controlled Trials as Topic; Risk Factors; Tetrahydronaphthalenes; Vasodilator Agents; Verapamil

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was conducted to compare the effects of regimens combining the dihydropyridine calcium-channel blocker benidipine with each of 3 secondary agent types (an angiotensin-receptor blocker (ARB), a β-blocker and a thiazide) in Japanese hypertensive outpatients who did not achieve target blood pressure (<140/90 mmHg) with benidipine 4 mg/day alone. The analysis included 3,293 patients (ARB, 1,110; β-blocker, 1,089; thiazide, 1,094) with a median follow-up of 3.61 years. The main results of the COPE trial demonstrated that the incidences of hard cardiovascular composite endpoints and fatal or non-fatal strokes were significantly higher in the benidipine/β-blocker group than in the benidipine/thiazide group.Methods and Results:We further evaluated the treatment effects on different cardiac events among the 3 benidipine-based regimens.We observed a total of 50 cardiac events, 4.2 per 1000 person-years. The incidences of total cardiac events and each cardiac event were similarly low among the 3 treatment groups. Unadjusted and multi-adjusted hazard ratios for total cardiac events showed no significant difference among the 3 treatment groups.. This subanalysis of the COPE trial demonstrated that blood pressure-lowering regimens combining benidipine with an ARB, β-blocker or thiazide diuretic were similarly effective for the prevention of cardiac events in Japanese hypertensive outpatients.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Heart Diseases; Humans; Hypertension; Male; Middle Aged; Thiazides; Treatment Outcome

Visit-to-visit blood pressure (BP) variability is an important predictor of stroke. However, which antihypertensive drug combination is better at reducing visit-to-visit BP variability and therefore at reducing stroke incidence remains uncertain. We have previously reported that the dihydropyridine calcium channel blocker benidipine combined with a β-blocker appeared to be less beneficial in reducing the risk of stroke than a combination of benidipine and thiazide. Here, we further compare the visit-to-visit BP variability among three benidipine-based regimens, namely angiotensin receptor blocker (ARB), β-blocker and thiazide combinations. The present post hoc analysis included 2983 patients without cardiovascular events or death during the first 18 months after randomization. We compared the BP variability (defined as the s.d. and the coefficient of variation (CV)), maximum systolic BP (SBP) and diastolic BP (DBP) of the clinic mean on-treatment BPs obtained at 6-month intervals, starting 6 months after the treatment initiation, among the 3 treatments (ARB, n=1026; β-blocker, n=966; thiazide, n=991). During the first 6-36 months after randomization, both the s.d. and CV-BPs were lower in the benidipine-thiazide group than in the benidipine-β-blocker group (s.d.-SBP, P=0.019; s.d.-DBP, P=0.030; CV-SBP, P=0.012; CV-DBP, P=0.022). The s.d. and CV in the ARB group did not reach statistical significance compared with the other two groups. The maximum BPs did not differ among the three treatments. These findings suggest that the benidipine-thiazide combination may reduce visit-to-visit BP variability more than the benidipine-β-blocker combination.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Diuretics; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Heart Diseases; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Risk Factors; Stroke; Thiazides

Cilnidipine is an L/N-type calcium channel blocker (CCB). The effects of cilnidipine on N-type channels give it unique organ-protective properties via the suppression of hyperactivity in the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS). In the present study, we compared the effects of cilnidipine and amlodipine (an L-type CCB) on cardiac and renal functions in spontaneously-hypertensive rats injected with adriamycin (ADR). After the weekly administration of ADR for 3 weeks, spontaneously-hypertensive rats were orally administered cilnidipine (20 mg/kg per day), amlodipine (3 mg/kg per day), or vehicle once daily for 4 weeks. A control group received saline rather than ADR, followed by vehicle for 4 weeks. Cilnidipine and amlodipine produced similar reductions in blood pressure after 4 weeks. Cilnidipine ameliorated ADR-induced heart and kidney damage, whereas amlodipine slightly improved cardiac echocardiographic parameters, but did not protect against ADR-induced renal damage. Cilnidipine (but not amlodipine) suppressed the reflex SNS and RAAS hyperactivity caused by their antihypertensive effects. Furthermore, cilnidipine and amlodipine treatment decreased the urinary levels of adrenocortical hormones. The protective effects of cilnidipine against ADR-induced renal and cardiac dysfunction might be associated with its blockade of N-type calcium channels, in addition to its pleiotropic actions, which include the inhibition of the RAAS.

Topics: Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Calcium Signaling; Dihydropyridines; Disease Models, Animal; Doxorubicin; Fibrosis; Heart Diseases; Hypertension; Kidney; Kidney Diseases; Male; Myocardium; Rats, Inbred SHR; Renin-Angiotensin System; Sympathetic Nervous System

Azelnidipine (AZL), a long-acting dihydropyridine-based calcium antagonist, has been recently approved and used for treating ischemic heart disease and cardiac remodeling after myocardial infarction, however, its effect on hyperglycemia-induced cardiac damage has not been studied.. This study examined the effect of AZL on circulating markers of cardiac damage, altered lipid and cytokines profile and markers of oxidative stress including homocysteine in diabetic rats.. STZ induced diabetes caused a significant increase in blood glucose levels. It also resulted in an increase in the levels of homocysteine and cardiac damage markers, like Troponin-1, CK-MB, CK-NAC, uric acid, LDH and alkaline phosphatase. Moreover, there was an increase in the levels of proinflammatory cytokines like TNF-α, IFN-γ, and TGF-β and decrease in the levels of IL-4 and IL-10. Additionally, there was increase in the levels of cholesterol, triglycerides, LDL, VLDL and a decrease in HDL in these animals. There was an altered antioxidant enzyme profile which resulted in a notable increase in the levels of oxidative stress markers like lipid peroxides, nitric oxide and carbonylated proteins. Compared with the untreated diabetic rats, AZL treatment significantly reduced the levels of troponin-1 (P < 0.05), CK-MB (P < 0.05), CK-NAC (P < 0.05), uric acid (P < 0.05), LDH (P < 0.05) and alkaline phosphatase (P < 0.05). It also reduced the levels of the TNF-α (P < 0.05), IFN-γ (P < 0.05), and TGF-β (P < 0.05) and increased the levels of IL-4 (P < 0.05). A significant decrease in the serum cholesterol (P < 0.05), triglycerides (P < 0.05), LDL (P < 0.05), VLDL (P < 0.05) and a significant rise in levels of HDL (P < 0.05) was also observed. Treatment with AZL corrected the distorted antioxidant enzyme profile resulting in a significant decrease in the levels of lipid peroxides, nitric oxide and carbonylated proteins.. Our results indicate that AZL treatment can reduce the risk of hyperglycemia induced metabolic disorders and its role can be further extended to explore its therapeutic potential in diabetic patients with cardiac complications.

Topics: Animals; Azetidinecarboxylic Acid; Biomarkers; Blood Glucose; Calcium Channel Blockers; Catalase; Cytokines; Diabetes Mellitus, Experimental; Dihydropyridines; Glutathione; Heart Diseases; Homocysteine; Inflammation Mediators; Insulin; Lipid Peroxidation; Lipids; Liver; Male; Myocardium; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Superoxide Dismutase

This study demonstrates the effective protection by compounds of atypical 1,4-dihydropyridine (DHP) series cerebrocrast, glutapyrone and tauropyrone against neuro- and cardiotoxicity caused by the model compound azidothymidine, a well-known mitochondria-compromising anti-HIV drug. In previous in vitro experiments, we have demonstrated distinct effects of these DHP compounds to influence mitochondrial functioning. In the present in vivo experiments, DHP compounds were administered intraperitoneally in mice daily for 2 weeks, per se and in combinations with azidothymidine at doses: azidothymidine 50 mg/kg; cerebrocrast 0.1 mg/kg; glutapyrone 1 mg/kg; and tauropyrone 1 mg/kg. At the end of the experiment, mice were killed, heart and brain tissues were removed and examined ex vivo histopathologically and immunohistochemically. NF-kappaBp65 and caspase-3 were used as the markers indicating inflammatory and apoptotic events, respectively. Cerebrocrast (dicyclic structure) was the most potent DHP, which effectively reduced azidothymidine-induced overexpression of NF-kappaBp65 and caspase-3 in mouse myocardium and brain cortex. Glutapyrone per se increased the number of caspase-3-positive cells in the brain, whereas it reduced NF-kappaBp65 and caspase-3 expression in cardiac tissue caused by azidothymidine. Tauropyrone showed dual action: per se it increased caspase-3 in the brain and NF-kappaBp65 expression in the heart, but it considerably reduced these activations in azidothymidine-treated mice. This study provides the first demonstration of a distinct pharmacological action for atypical DHP compounds in cardiac and brain tissues. The dicyclic structure of cerebrocrast is considered beneficial for neuro- and cardioprotection at least in part via mitochondrial targeting and consequent regulation of inflammatory and apoptotic processes.

Topics: Animals; Anti-HIV Agents; Apoptosis; Caspase 3; Cerebral Cortex; Dihydropyridines; Gene Expression Regulation; Glutamates; Heart Diseases; Inflammation; Male; Mice; Mice, Inbred ICR; Neurotoxicity Syndromes; Taurine; Transcription Factor RelA; Zidovudine

Calcium channel blockers (CCBs) have been reported to reduce the incidence of stroke in hypertensive patients. CCBs are also commonly used to treat patients with angina pectoris (AP). However, there are very few reports on their effects on cardiovascular events, including stroke and end-stage renal disease (ESRD), in patients with AP. This study was designed to assess the differences among CCBs regarding the occurrence of cardiovascular events in patients with AP.. Clinical records of 226 patients with AP who had received treatment with CCBs in hospital from January 1, 1993 to December 31, 2006 were reviwed. The influence of patient characteristics and medication on the occurrence of cardiovascular events was evaluated (median follow-up period: 4.4 years). Of these 226 patients, 155 were treated with benldipine (CAS 91599-74-5), 36 with diltiazem (CAS 33286-22-5), and 35 were treated with nifedipine (CAS 21629-25-4).. Cox proportional hazard regression analysis showed that benidipine was the only CCB that significantly reduced the occurrence of cardiovascular events (HR = 0.39, p < 0.05). Benidipine treatment was associated with higher cardiovascular- and cardiac event-free rates than diltiazem treatment, and higher stroke- and ESRD-free rates than nifedipine.. This study demonstrated that benidipine prevents the occurrence of cardiovascular events in patients with AP, suggesting that benidipine contributes to a favorable long-term prognosis of such patients.

Topics: Aged; Angina Pectoris; Calcium Channel Blockers; Dihydropyridines; Diltiazem; Female; Heart Diseases; Humans; Kidney Failure, Chronic; Male; Nifedipine; Prognosis; Proportional Hazards Models; Retrospective Studies; Stroke; Treatment Outcome

We investigated the role of protein kinase C in adenosine A3 receptor (A3AR)-induced delayed cardioprotection in the mouse heart. Mice were treated with selective A3AR agonist N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA). Twenty-four hours later, hearts were perfused in the Langendorff mode and subjected to 30 min of global ischemia and 30 min of reperfusion. Infarct size was determined by computer morphometry of tetrazolium-stained sections, and ventricular function was monitored by inserting a fluid-filled balloon into the left ventricle (LV). Chelerythrine chloride (CHE, 5.0 mg/kg) and rottlerin (Rot, 0.3 mg/kg) were given 30 min before IB-MECA to block total and PKC-delta isoforms, respectively. IB-MECA caused postischemic reduction in necrosis and improvement in ventricular function, which was abolished by CHE. Western blot analysis demonstrated translocation of the PKC-delta isoform but not the alpha, epsilon, xi, eta isoform(s) from cytoplasm to the membrane fraction after 30 min of IB-MECA administration. A3AR antagonist MRS-1191 and CHE blocked the translocation of PKC-delta. Furthermore, IB-MECA-induced increase in nuclear factor-kappaB binding was diminished by CHE. These results provide direct evidence of an essential role of PKC, and more specifically, PKC-delta in A3AR-induced delayed cardioprotection.

Topics: Adenosine; Alkaloids; Animals; Benzophenanthridines; Blotting, Western; Cell Nucleus; Cytosol; Dihydropyridines; Electrophoretic Mobility Shift Assay; Enzyme Inhibitors; Heart Diseases; Heart Function Tests; In Vitro Techniques; Isoenzymes; Male; Mice; Myocardial Contraction; Myocardial Infarction; NF-kappa B; Phenanthridines; Protein Kinase C; Purinergic P1 Receptor Antagonists; Receptor, Adenosine A3; Receptors, Purinergic P1

Normotensive rats fed a high-fructose diet (HFD) develop hypertriglyceridemia, hyperinsulinemia, and hypertension. The glomerular changes observed in the kidneys of these animals are similar to those observed in diabetic rats. The aim of this study was to evaluate whether lacidipine, a calcium antagonist, could have a protective effect with this animal model. Forty male Wistar-Kyoto (WKY) rats were divided into four groups treated with HFD + placebo; HFD + lacidipine, 0.3 mg/kg/day; HFD + lacidipine, 3 mg/kg/day; or standard diet + placebo for 4 weeks. Urinary excretion of the stable metabolic products of nitric oxide (NO) was determined, because this vasoactive agent has been found to cause hemodynamic changes in the diabetic kidney. Glomerular size was determined by means of morphometric analysis. The results of this study show that lacidipine prevents (a) the HFD-induced increase in blood pressure in a dose-dependent manner; (b) the HFD-induced increase in glomerular size and fibronectin synthesis; and (c) the increase of collagen III synthesis in the heart. The drug had no effect on the increased urinary excretion of the stable metabolic products of NO. These data suggest that lacidipine might be useful in preventing the renal and cardiac damage caused by hypertension and non-insulin-dependent diabetes mellitus.

Topics: Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; Collagen; Creatinine; Dietary Carbohydrates; Dihydropyridines; Dose-Response Relationship, Drug; Fibronectins; Fructose; Heart Diseases; Hypertension; Insulin; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Myocardium; Nitric Oxide; Organ Size; Rats; Rats, Inbred WKY; Triglycerides

(+/-)-S11568 (1, 3-ethyl-5-methyl-(+/-)-2-[(2-(2-aminoethoxy)ethoxy) methyl]-4-(2,3-dichlorophenyl)-6-methyl-1,4-dihydropyridine-3, 5-dicarboxylate), has an in vitro profile of high potency and of high selectivity for the low-voltage dependent. L-type calcium channel. In in vitro binding studies, it displaced specifically bound (-)-[3H]PN 200-110 (isradipine (2), the reference molecule for in vitro studies) from cardiac and vascular smooth muscle preparations with potencies of 5.6 and 51 nM, respectively. It also appears as a pure pharmacological antagonist acting at a single channel L-type and free of any interaction at the benzothiazepine binding site such as amlodipine (3). Both enantiomers of S11568 have in vitro activities, the dextro isomer S12967 ((+)-1) being 6 to 18-fold less potent than the levo one S12968 ((-)-1). Two couples of optically active labelling precursors of S11568, ((-)-10/(+)-10 and (-)-14/(+)-14) have been synthesized using a modified Hantzsch's dihydropyridine synthesis. In both cases, the enantiomers were separated by preparative chiral HPLC. They both have been independently labelled with carbon-11, using [11C]diazomethane or [11C]iodomethane to give multimilliCurie quantities of (-)-1 (S12968) and (+)-1 (S12967) with high specific activities (500-1000 mCi/mumol, 18.5-37.0 GBq/mumol). Both enantiomers appear suitable for PET experiments: their myocardial concentration increases after a bolus injection to reach a maximum in 2 min and then remains on a plateau with a slight downslope while the blood concentration falls rapidly. Myocardial uptake was threefold higher than lung uptake, leading to a good contrast on PET images. The present preliminary biological results obtained in Beagle dogs showed that both enantiomers have similar myocardial kinetics and in vivo affinity for the left ventricular myocardium.

Topics: Amlodipine; Animals; Binding, Competitive; Calcium Channel Blockers; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Dihydropyridines; Dogs; Heart; Heart Diseases; Isotope Labeling; Isradipine; Magnetic Resonance Spectroscopy; Muscle, Smooth, Vascular; Myocardium; Reproducibility of Results; Stereoisomerism; Tomography, Emission-Computed