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Mebudipine, Amlodipine, Endothelin-1, Heart failure, Doxorubicin, What&,rsquo s Known Among calcium-channel blockers, dihydropyridines are extensively used due to their potent vasodilatory and weak cardiodepressant properties. Mebudipine is a newly synthesized dihydropyridine calcium-channel blocker that has significant negative chronotropic effects but without considerable negative inotropic properties. What&,rsquo s New In an animal model, mebudipine reversed the increased plasma levels of biochemical markers, which act as the prognostic and diagnostic indicators of heart failure. Administration of mebudipine to animals with doxorubicin -induced heart failure palliated the clinical and biochemical signs of the disease. IntroductionHeart failure (HF) is a chronic condition that results from any structural or functional cardiac disorders, leading to reduced cardiac output. 1,, 2, The prevalence of HF is increasing and despite advances in pharmacotherapy, the disease is still associated with high morbidity and mortality. 3,, 4, A developing body of evidence suggests that mediators involved in the control of myocardial function and vascular tone may contribute to the pathophysiology of HF. A potential role for the endothelin (ET) system in the disease progression has been proposed by some recent studies. 5,, 6, The ET family consists of four closely related peptides, namely ET-1, ET-2, ET-3, and ET-4, which are produced from the biologically inactive &,ldquo big ET&,rdquo by ET-converting enzymes. ET-1 is the principal isoform of the ET family. 7, Many studies have found that the plasma level of ET-1 is increased in symptomatic patients with congestive HF&,nbsp and its concentration increases correlatively with the severity of HF. 8,- 10, The plasma levels of ET-1 and its precursor, big endothelin-1 (BET-1), have been shown to predict mortality in patients with moderate-to-severe HF. 11, Activated ET system has gained special interests in terms of its prognostic value along with various clinically applied tests to evaluate the impact of numerous therapeutic efforts and changes in extracardiac neurohormonal systems such as sympathetic and renin-angiotensin systems, which are upregulated in HF. Furthermore, the correlation between the increased plasma level of BET and the severity of the disease (left ventricular ejection fraction &,lt 20%) is well established. Therefore, the measurement of the plasma level of BET-1 is an appropriate method to determine the severity of doxorubicin (DOX)-induced HF and to evaluate the subsequent deterioration. 12,, 13, Calcium-channel blockers (CCBs) are drugs used in treatment of hypertension, angina pectoris, and other cardiovascular as well as non-cardiovascular diseases. 2, Among CCBs, dihydropyridines (DHPs) are extensively used due to their potent vasodilatory and weak cardiodepressant properties. 14,, 15, Since their introduction in the 1960s, the members of DHPs have been subjected to several changes to optimize their safety and efficacy.Among DHPs, amlodipine exhibits more stable pharmacokinetic and less cardioselectivity than the previously introduced congeners thus, it is well tolerated in patients with HF. 16, Many studies have reported that amlodipine prolongs survival and reduces myocardial damage in patients with myocardial infarction. 17,, 18, Since the beneficial effects of amlodipine have been clearly demonstrated in some patients with HF, especially in a subgroup of non-ischemic cardiomyopathy, 19, the synthesis of a new CCB with less cardioselective and more vasoselective properties has been on demand. Mebudipine ([&,plusmn ]-t-butyl, methyl-1, 4-dihydro-2, 6-dimethyl-4-[3-nitrophenyl]-3, 5-pyridine dicarboxylate) is a 1, 4-DHP derivative developed in our lab. 14, Compared with nifedipine, mebudipine has shown high potency in inhibiting calcium-evoked spikes in Helix aspersa. 20, Moreover, it has been demonstrated that the potency of mebudipine in inhibiting potassium chloride (KCl)-induced contractions of the isolated rat aorta and its time- and voltage-dependent actions are significantly greater than those of nifedipine. 14, It has also been shown that, compared with nifedipine, mebudipine possesses a negligible cardiodepressant activity, while its negative chronotropic property is markedly pronounced. 21, Furthermore, it appears that mebudipine offers some other advantages over nifedipine such as a longer biological half-life, a longer time to reach the maximum effect, 22, and higher vasoselectivity. 21, In contrast to the beneficial effects seen with amlodipine, some other DHPs have demonstrated deleterious effects in HF. 23, Therefore, any information regarding the safety and efficacy profile of any other CCBs in cardiac failure would be helpful. Since the effect of mebudipine in HF has not yet been investigated, the present study aimed to assess the potential therapeutic effects of mebudipine in an animal model of HF. In this study, the plasma levels of big BET-1, as a prognostic marker, as well as cardiac marker enzymes including creatine kinase-myocardial band (CK-MB) and lactate dehydrogenase (LDH), were determined. Additionally, the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. These parameters were assessed in a rat model of DOX-induced HF treated with mebudipine, compared with amlodipine. Materials and MethodsDrugs Amlodipine was purchased from Razak Pharmaceutical Company (Tehran, Iran). Mebudipine was provided by Pars Biopharmacy Research Co (Tehran, Iran). DOX was also commercially purchased (Adriblastina&,reg , Pfizer Inc, NY, USA). Polyethylene glycol 400 was used as a solvent.Animals In this study, 35 adult male Wistar albino rats (weight=200&,ndash 250 g) were purchased from the Razi Vaccine and Serum Research Institute (Karaj, Iran). The rats were randomly divided into five groups (seven animals per group). The sample size was calculated using the following formula, 24, n=z2p (1-p) (d2)-1 where n represents the sample size, z the level of confidence, p the estimated proportion of the population that presents the characteristic, and d the tolerated margin of error. All the rats were housed in a controlled environment with an approximate room temperature of 25&,plusmn 2 &,deg C in a 12 hour/12 hour day-night cycle and were given ad libitum access to food and water. Experimental ProtocolThe present study carried out in the Department of Pharmacology at the Iran University of Medical Sciences during the years of 2009-2011. All the applied protocols were approved by the Research Ethics Committee of Iran University of Medical Sciences (Code of Ethics, IR.IUMS.FMD.REC.1387.87005). The rats were randomly divided into five groups with seven animals in each group, Group I consisted of distilled water-treated animals serving as normal controls Group II and Group III were comprised of DOX-induced HF animals serving as HF control groups I and II, respectively Group IV comprised DOX-induced HF animals treated with mebudipine and Group V contained DOX-induced HF animals treated with amlodipine. The induction of HF was in keeping with a previously described procedure. 25, Briefly, DOX was intraperitoneally (ip) administered at a total dose of 15 mg/kg, at six-time points, every three days for a duration of 15 days followed by four weeks of rest. At the end of week four, the animals of the normal control group (Group I) and HF control1 (Group II) were euthanized following ketamine (100 mg/kg Alfasan, Worden, Netherlands)/xylazine (10 mg/kg Alfasan, Worden, Netherlands) anesthesia to evaluate the baseline values in the DOX-induced HF animals. Blood samples were collected in ethylenediaminetetraacetic acid (EDTA) tubes (Sigma, St. Louis, USA). Subsequently, all the remaining animals (Groups III, IV, and V) were assigned to a following treatment for the next 14 days, Group III equivolume of distilled water, Group IV mebudipine (0.5 mg/kg ip), and Group V amlodipine (0.35 mg/kg ip), once daily. Finally, 24 hours after the last treatment, blood samples were taken from the euthanized animals, via cardiac puncture, and collected in EDTA tubes. Biochemical Analysis The plasma level of BET-1 was measured using the ELISA kit (IBL, Gunma, Japan). The plasma levels of marker enzymes, namely AST, ALT, CK-MB, and LDH, were also assessed using a commercially available kit (Pars Azmoon Kits, Tehran, Iran). The clinical signs of HF, namely the systolic blood pressure and the heart rate, were assessed by monitoring the animals before and after treatment using a non-invasive tail-cuff method (Power Lab, Australia). Statistical Analysis The data were presented as mean&,plusmn SEM. The statistical analyses were carried out using the one-way analysis of variance (ANOVA), followed by the Tukey post hoc test, via SPSS software, version 18, (SPSS Inc, Chicago, IL, USA). A P value of less than 0.05 was considered statistically significant.ResultsFour weeks following the DOX regimen, all the rats in Group II presented elevated plasma BET-1 (P&,lt 0.001) (table 1,) and marker enzymes, comprised of LDH (P=0.001), AST (P=0.005), ALT (P&,lt 0.001), and CK-MB (P&,lt 0.001) (table 2,), compared with the normal control rats (Group I), which was indicative of pronounced HF signs, comprising a decreased blood pressure (P=0.077) and an increased heart rate (P&,lt 0.001) (table 3,), as well as edema, dyspnea, and acrocyanosis.Animal Groups (each group [n=7])Plasma Big Endothelin-1 Values (pg/mL)mean&,plusmn SEMP valueFour weeks after DOX regimen |