Celiprolol, a vasodilatory beta-blocker, inhibits pressure overload-induced cardiac hypertrophy and prevents the transition to heart failure via nitric oxide-dependent mechanisms in mice.
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BACKGROUND: The blockade of beta-adrenergic receptors reduces both mortality and morbidity in patients with chronic heart failure, but the cellular mechanism remains unclear. Celiprolol, a selective beta(1)-blocker, was reported to stimulate the expression of endothelial NO synthase (eNOS) in the heart, and NO levels have been demonstrated to be related to myocardial hypertrophy and heart failure. Thus, we aimed to clarify whether celiprolol attenuates both myocardial hypertrophy and heart failure via the NO-signal pathway. METHODS AND RESULTS: In rat neonatal cardiac myocytes, celiprolol inhibited protein synthesis stimulated by either isoproterenol or phenylephrine, which was partially suppressed by N(G)-nitro-L-arginine methyl ester (L-NAME). Four weeks after transverse aortic constriction (TAC) in C57BL/6 male mice, the ratio of heart weight to body weight (mg/g) (8.70+/-0.42 in TAC, 6.61+/-0.44 with celiprolol 100 mg x kg(-1) x d(-1) PO, P<0.01) and the ratio of lung weight to body weight (mg/g) (10.27+/-1.08 in TAC, 7.11+/-0.70 with celiprolol 100 mg x kg(-1) x d(-1) PO, P<0.05) were lower and LV fractional shortening was higher in the celiprolol-treated groups than in the TAC group. All of these improvements were blunted by L-NAME. Celiprolol treatment significantly increased myocardial eNOS and activated phosphorylation of eNOS. Myocardial mRNA levels of natriuretic peptide precursor type B and protein inhibitor of NO synthase, which were increased in the TAC mice, were decreased in the celiprolol-treated mice. CONCLUSIONS: These findings indicated that celiprolol attenuates cardiac myocyte hypertrophy both in vitro and in vivo and halts the process leading from hypertrophy to heart failure. These effects are mediated by a selective beta1-adrenergic receptor blockade and NO-dependent pathway. (+info)
Mechanisms of combined treatment with celiprolol and candesartan for ventricular remodeling in experimental heart failure.
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BACKGROUND: Both beta-adrenergic blockers and angiotensin-II receptor blockers were reported to improve the prognosis of patients with heart failure, but the efficacy of combination therapy with these agents has not been fully elucidated. Also the efficacy of celiprolol, a beta1-selective adrenoceptor antagonist with partial beta2-agonist properties, for heart failure treatment is still controversial. We examined the cardioprotective effects and mechanisms of the therapy with celiprolol or candesartan, an angiotensin-II receptor blockers and their combination in heart failure induced by isoproterenol (ISO). METHODS AND RESULTS: ISO 300 mg/kg was injected in rats to produce heart failure. Two months after the injection, the ISO-injected rats were divided into 4 groups (8 rats each) and treated for 4 weeks as follows: (a) vehicle; (b) celiprolol 10 mg/kg per day (BB); (c) candesartan 0.2 mg/kg per day (ARB); and (d) their combination BB+ARB. ISO significantly elevated left ventricular (LV) end-diastolic pressure, decreased peak-negative dP/dt and LV ejection fraction. BB and ARB similarly ameliorated cardiac dysfunction due to ISO, but BB+ARB were more potent than the individual therapies. Separately, ARB preserved the histological structure in LV myocardium. In contrast, BB ameliorated calcium handling, as shown by the increased ratio of SERCA2 to phospholamban protein, despite having little effect on the histology. CONCLUSION: Both celiprolol and candesartan showed cardioprotective effects in this heart failure model. The potential use of the combination treatment in heart failure might result in a synergistic effect through the different cardioprotective mechanisms of celiprolol and candesartan. (+info)
Impact of curcumin-induced changes in P-glycoprotein and CYP3A expression on the pharmacokinetics of peroral celiprolol and midazolam in rats.
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The aim of this study was to evaluate whether curcumin could modulate P-glycoprotein (P-gp) and CYP3A expression, and in turn modify the pharmacokinetic profiles of P-gp and CYP3A substrates in male Sprague-Dawley rats. Intragastric gavage of the rats with 60 mg/kg curcumin for 4 consecutive days led to a down-regulation of the intestinal P-gp level. There was a concomitant upregulation of hepatic P-gp level, but the renal P-gp level was unaffected. Curcumin also attenuated the CYP3A level in the small intestine but induced CYP3A expression in the liver and kidney. Regular curcumin consumption also caused the C(max) and area under the concentration-time curve (AUC(0-8) and total AUC) of peroral celiprolol (a P-gp substrate with negligible cytochrome P450 metabolism) at 30 mg/kg to increase, but the apparent oral clearance (CL(oral)) of the drug was reduced. Similarly, rats treated with curcumin for 4 consecutive days showed higher AUC (AUC(0-4) and total AUC) and lower CL(oral) for peroral midazolam (a CYP3A substrate that does not interact with the P-gp) at 20 mg/kg in comparison with vehicle-treated rats. In contrast, curcumin administered 30 min before the respective drug treatments did not significantly modify the pharmacokinetic parameters of the drugs. Analysis of the data suggests that the changes in the pharmacokinetic profiles of peroral celiprolol and midazolam in the rat model were contributed mainly by the curcumin-mediated down-regulation of intestinal P-gp and CYP3A protein levels, respectively. (+info)
Celiprolol, a selective beta1-blocker, reduces the infarct size through production of nitric oxide in a rabbit model of myocardial infarction.
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BACKGROUND: It is still unclear whether celiprolol, a beta(1)-selective blocker, reduces myocardial infarct size. This study will examine whether celiprolol reduces myocardial infarct size, as well as investigate the mechanisms for its infarct size-reducing effect in rabbits. METHODS AND RESULTS: Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Celiprolol (1 or 10 mg x kg (-1) x h(-1) for 60 min, iv) was administered 20 min before ischemia with or without pretreatment with N(omega)-nitro-L-arginine methylester (L-NAME, 10 mg/kg, iv, a nitric oxide synthase inhibitor) or 5-hydroxydecanoic acid sodium salt (5-HD, 5 mg/kg, iv, a mitochondrial K(ATP) channel blocker). The area at risk as a percentage of the left ventricle was determined by using Evans blue dye, and the infarct size was determined as a percentage of the area at risk by triphenyl tetrazolium chloride staining. Celiprolol 1 and 10 mg x kg(-1) x h(-1) significantly reduced the infarct size in a dose-dependent manner (36.4+/-1.7%, n=7 and 25.4+/-2.9%, n=7, respectively) compared with the control (46.2+/-3.1%, n=8). The infarct size-reducing effect of celiprolol was completely blocked by L-NAME (40.4 +/-2.8%, n=8) but not by 5-HD (27.3+/-1.0%, n=8). Celiprolol 1 mg x kg(-1) x h (-1) increased the myocardial interstitial levels of NOx, an indicator of nitric oxide, and reduced the intensity of dihydro-ethidium staining of myocardium, an indicator of superoxide, during reperfusion after 30 min of ischemia. CONCLUSION: Celiprolol reduces myocardial infarct size and also increases nitric oxide production and reduces superoxide levels but not mitochondrial K(ATP) channels in rabbits. (+info)
Celiprolol reduces the intimal thickening of autogenous vein grafts via an enhancement of nitric oxide function through an inhibition of superoxide production.
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BACKGROUND: Beta-adrenoceptor antagonist celiprolol has been widely used as an effective antihypertensive agent. Some studies reported that celiprolol enhances nitric oxide production. The purpose of the present study is to examine the effects of celiprolol on vein graft intimal hyperplasia and endothelium-dependent nitric oxide (NO)-mediated relaxation. METHODS: Japanese white rabbits were randomized to a control group that was fed regular rabbit chow or to a celiprolol group that was fed regular rabbit chow supplemented with 100 mg/body celiprolol sodium. The reversed jugular vein was implanted into the carotid artery. At 2 and 4 weeks after the operation, vein grafts in both groups were harvested, and intimal hyperplasia of the vein grafts was assessed. At 4 weeks after the operation, harvested vein grafts from both the groups were examined on the endothelium-dependent relaxation by application of Ach and were examined to detect for endothelial NO synthase (eNOS) expression and superoxide anion production. RESULTS: Celiprolol inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts 4 weeks after implantation (Intima/media index of celiprolol group, 0.48 +/- 0.01 vs control group, 1.07 +/- 0.08, P < .05) and suppressed cell proliferation in the neointima 2 weeks after implantation. In addition, celiprolol significantly enhanced endothelium-dependent NO-mediated relaxation in the vein graft with no change in eNOS expression and a reduction in superoxide production. CONCLUSIONS: These novel findings clearly demonstrate that beta-adrenoceptor antagonist celiprolol can suppress intimal hyperplasia of the vein graft, which may be due to the enhancement of nitric oxide function through an inhibition of superoxide production. These results strongly support the clinical usefulness of celiprolol administration for preventing intimal hyperplasia of the vein graft after bypass grafting. (+info)
Acute effects of beta-blocker with intrinsic sympathomimetic activity on stress-induced cardiac dysfunction in rats.
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Effects of itraconazole, dexamethasone and naringin on the pharmacokinetics of nadolol in rats.
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The aim of the present study was to clarify the involvement of P-glycoprotein (P-gp) or organic anion transporting polypeptide (Oatp) 1a5 in the pharmacokinetics of nadolol (NDL), a non-metabolized hydrophilic beta-adrenoceptor blocker, in rats. Pretreatment with itraconazole (ICZ, P-gp inhibitor, 50 mg/kg) for 30 min before oral administration of NDL (10 mg/kg) significantly increased the area under the plasma concentration-time curve (AUC(0)(-)infinity)of NDL by 1.7-fold compared with control. Intragastric administration of dexamethasone (DEX, 8 mg/kg) for 4 consecutive days increased P-gp level in the intestine and the liver. In line with this, DEX pre-treatment decreased maximum plasma concentration (C(max)) of NDL by 28% of control. To inhibit the intestinal Oatp1a5, naringin (NRG, 0.145 mg/kg) was preadministered orally for 30 min before the oral administrations of NDL or celiprolol (CEL, 10 mg/kg, Oatp1a5 substrate). Although NRG markedly reduced C(max) and AUC(0)(-)infinity of CEL by 60% and 65% of control, respectively, little difference was observed in the plasma concentration of NDL between NRG and control. These results suggest that P-gp is greatly involved in the pharmacokinetics of NDL, while the involvement of Oatp1a5 in the pharmacokinetics of NDL may be less than that of celiprolol in rats. (+info)
Comparison of inhibitory duration of grapefruit juice on organic anion-transporting polypeptide and cytochrome P450 3A4.
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Recently, a new type of interaction has been reported in which fruit juices diminish oral drug bioavailability through inhibition of organic anion-transporting polypeptide (OATP). In this study, we aimed to clarify the duration of OATP inhibition by grapefruit juice (GFJ), and to compare it with the duration of GFJ-induced inhibition of cytochrome P450 (CYP) 3A4 activity. Seven healthy volunteers were enrolled in this open-label, single-sequence study. They were orally administered celiprolol (100 mg) and midazolam (15 microg/kg) with water on the control day. Three days later, they ingested GFJ (200 mL) 3 times a day for 3 d. On day 1, the same drugs were administered with GFJ. On days 3 and 7, the same drugs were administered with water. Pharmacokinetics of both drugs were evaluated on each trial day. The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve from 0 to 8 h (AUC0-8) of celiprolol significantly decreased on day 1, and the mean ratios of these values and the corresponding control-day values were 0.18 and 0.25, respectively. The Cmax and AUC0-8 returned to the control levels on days 3 and 7. In contrast, AUC0-8 of midazolam were higher on days 1 and 3 than on the control day (mean ratio, 2.12 and 1.47, respectively). The AUC0-8 returned to the control level on day 7. In conclusion, results of this study indicated that the OATP inhibition caused by GFJ dissipated faster than GFJ-mediated alterations in CYP3A4 activity, which were sustained for at least 48 h. (+info)