Oral Administration Of Carvedilol Research Articles

Acetovanillone augmented the cardioprotective effect of carvedilol against cadmium-induced heart injury via suppression of oxidative stress and inflammation signaling pathways

Cardiac toxicity is a public health issue that can be caused by both environmental and occupational exposures. The current study aimed to investigate the effectiveness of carvedilol (CV), Acetovanillone (ACET), and their combination for ameliorating cadmium (Cd)-induced oxidative stress, inflammation, and necroptosis. Rats were assigned to; the normal group, Cd group (2 mg/kg; i.p., single dose), and the other three groups received orally CV (10 mg/kg), ACET (25 mg/kg), and CV plus ACET, respectively and a single dose of Cd. Oral administration of CV, ACET, and their combination significantly dampens cardiac oxidative injury by increasing antioxidants GSH and SOD levels, while it decreases MDA and NADPH oxidase levels mediated by decreasing cardiac abundance of Nrf2, HO-1, and SIRT1 and downregulating KEAP-1 and FOXO-3 levels. Also, they significantly attenuated inflammatory response as indicated by reducing MPO and NOx as well as proinflammatory cytokines TNF-α and IL-6 mediated by downregulating TLR4, iNOS, and NF-κB proteins expression as well as IκB upregulation. Moreover, they potently counteracted cardiac necroptosis by downregulating RIPK1, RIPK3, MLKL, and caspase-8 proteins expression. Of note, the combination of CV and ACET have marked protection that exceeded each drug alone. Conclusively, CV ad ACET potently mitigated Cd-induced cardiac intoxication by regulating NADPH oxidase, KEAP-1/Nrf2/HO-1, SIRT1/FOXO-3, TLR4/NF-κB/iNOS, and RIPK1/RIPK3/MLKL signals.

Novel peripheral role of Nurr-1/GDNF/AKT trajectory in carvedilol and/or morin hydrate hepatoprotective effect in a model of hepatic ischemia/reperfusion

Although the central role of Nurr-1/GDNF has been reviewed amply, scarce data are available on their peripheral impact. Carvedilol and morin hydrate have previously conferred their hepatic anti-fibrotic action. AimThus, our aim was to unveil the potential hepatoprotective role of carvedilol (CR) and/or morin hydrate (MH) using a hepatic 70% partial warm ischemia/reperfusion (I/R) rat model. Main methodRats were allocated into sham-operated, hepatic I/R, and I/R preceded by oral administration of CR (10 and 30 mg/kg; CR10/CR30), MH (30 mg/kg), or CR10 + MH for one week. Key findingsOn the molecular level, pretreatment with CR and/or MH increased the hepatic contents of Nurr-1, GDNF, and the protein expression of active/p-AKT. On the other hand, they inactivated GSK3β and NF-κB to increase the antioxidant enzymes (GPx, SOD, CAT). All regimens also enhanced the autophagy/lysosomal function and boosted the protein expression of beclin-1, LC3II, and TFEB. Moreover, their antiapoptotic effect was signified by increasing the anti-apoptotic molecule Bcl2 and inhibiting Bax, Bax/Bcl2 ratio, and caspase-3, effects that were confirmed by the TUNEL assay. These improvements were reflected on liver function, as they decreased serum aminotransferases and liver structural alterations induced by I/R. Despite its mild impact, CR10 showed marked improvements when combined with MH; this synergistic interaction overrides the effect of either regimen alone. SignificanceIn conclusion, CR, MH, and especially the combination regimen, conferred hepatoprotection against I/R via activating the Nurr-1/GDNF/AKT trajectory to induce autophagy/lysosomal biogenesis, inhibit GSK3β/NF-кB hub and apoptosis, and amend redox balance.

In-situ Intestinal Absorption and Pharmacokinetic Investigations of Carvedilol Loaded Supersaturated Self-emulsifying Drug System.

Carvedilol (CD), a non-selective beta-blocker, is indicated for the management of mild to moderate congestive heart failure. After oral administration, CD is rapidly absorbed with an absolute bioavailability of 18-25% because of low solubility and extensive first-pass metabolism. The present investigation focused on enhanced oral delivery of CD using supersaturated self-emulsifying drug delivery (SEDDS) system. Optimized SEDDS consisted of a blend of Oleic acid and Labrafil-M2125 as an oil-phase, Cremophor-RH40, polyethylene glycol-400 and HPMC-E5 as a surfactant, co-surfactant and supersaturation promoter respectively. Formulations were characterized for physical characteristics, invitro release in simulated and biorelevant dissolution media, intestinal permeability and bioavailability studies in Wistar rats. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis, scanning electron microscopy (SEM) studies were used to confirm the crystalline nature and shape of the optimized formulation. DSC and XRD, SEM studies showed that the drug was in amorphous form, and droplets were spherical in shape. Dissolution studies clearly showed distinct CD release in compendial and biorelevant dissolution media. The results from permeability and in-vivo studies depicted 2.2-folds and 3.2-folds increase in permeability and bioavailability, respectively from supersaturated SEDDS in comparison with control. The results conclusively confirmed that the SEDDS formulation could be considered as a new alternative delivery vehicle for the oral supply of CD. Lay Summary: Carvedilol (CD) is a non-selective antihypertensive drug with poor oral bioavailability. Previously, various lipid delivery systems were reported with enhanced oral delivery. We developed suprsaturable SEDDS formulation with immediate onset of action. SEDDS formulation was developed and optimized as per the established protocols. The optimized SEDDS formulation was stable over three months and converted to solid and supersaturated SEDDS. The results from permeability and in-vivo studies demonstrated an enhancement in permeability and bioavailability from supersaturated SEDDS in comparison with control. The results conclusively confirmed that the SEDDS formulation could be considered as a new alternative delivery vehicle for the oral administration of CD.

Effects of Combination of Carvedilol and Melatonin on Induced Metabolic Syndrome in Rats

Background: The prevalence of metabolic syndrome is increasing and it is considered one of the main threats to human health worldwide. Fructose feeding induces hyper-insulinemia, insulin resistance and hyper-triglyceridemia. The main objective of the present study is to evaluate the pharmacological effects of the single and combined administration of carvedilol and melatonin in fructose-induced metabolic syndrome in rats. Methods: Male albino rats were fed a high fructose diet for ten weeks to induce metabolic syndrome. Oral administration of carvedilol (20 mg/kg/day), melatonin (10 mg/kg/day), carvedilol and melatonin (20 mg +10 mg/kg/ day) or vehicle was conducted for six weeks after stopping the high fructose feeding.Indices of systolic blood pressure (SBP), Fasting Blood Glucose (FBG), Fasting Serum Insulin (FSI), serum lipid profiles, serum Nitric Oxide (NO), serum lipid peroxides as well as levels of total antioxidants were determined. Insulin resistance index were calculated from FBG and FSI using HOMA-IR (Homeostasis Model Assessment). Results: A high-fructose diet was associated with hypertension, dyslipidemia, insulin resistance, decreased nitrite and increased of oxidative stress. Carvedilol, melatonin or combination of carvedilol and melatonin was able to reverse features of metabolic syndrome in the six weeks. The intensity of changes produced by melatonin was of greater extent in insulin resistance and lipid profiles than produced by carvedilol but the effect of carvedilol was higher in hypertension. The combination of carvedilol plus melatonin was superior of the others. Conclusion: A combination of both carvedilol (20 mg/kg/ day orally) and melatonin (10 mg/kg/ day orally) for 6 weeks revealed a statistical significant results in comparison to carvedilol (20 mg/kg/ day orally) or melatonin (10 mg/kg/ day orally) alone. A combination of carvedilol and melatonin may give an additive effect better than each of them alone.

Carvedilol ameliorates early diabetic nephropathy in streptozotocin-induced diabetic rats.

Diabetic nephropathy results in end-stage renal disease. On the other hand, carvedilol has been reported to have various pharmacological properties. The aim of this study therefore is to evaluate the possible protective effect of carvedilol on streptozotocin-induced early diabetic nephropathy and various mechanisms underlie this effect in rats. Single i.p. injection of streptozotocin (65 mg/kg) was administered to induce early diabetic nephropathy in Wistar rats. Oral administration of carvedilol at a dose level of 1 and 10 mg/kg daily for 4 weeks resulted in nephroprotective effect as evident by significant decrease in serum creatinine level, urinary albumin/creatinine ratio, and kidney index as well as renal levels of malondialdehyde, nitric oxide, tumor necrosis factor-α, and cyclooxygenase-2 with a concurrent increase in creatinine clearance and renal reduced glutathione level compared to diabetic untreated rats. The protective effect of carvedilol was confirmed by renal histopathological examination. The electron microscopic examination indicated that carvedilol could effectively ameliorate glomerular basement membrane thickening and podocyte injury. In conclusion, carvedilol protects rats against streptozotocin-induced early diabetic nephropathy possibly, in part, through its antioxidant as well as anti-inflammatory activities, and ameliorating podocyte injury.

Effects of Silibinin on the Pharmacokinetics of Carvedilol after Oral Administration in Rats

ABSTRACT − This study was designed to investigate the effects of silibinin on the pharmacokinetics of carvedilol afteroral administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) with oral silibinin (0.3, 1.5 or 6 mg/kg) and intravenously (1 mg/kg) to rats. The effects of silibinin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9and CYP2D6 activity were also evaluated. Silibinin inhibited CYP2C9 and CYP2D6 enzyme activity with 50% inhibitionconcentration (IC 50 ) of 5.2 µ M and 85.4 µ M, respectively. In addition, silibinin significantly enhanced the cellular accu-mulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group, the area under theplasma concentration–time curve was significantly increased by 36.3–57.1%, and the peak concentration was significantlyincreased by 51.1–88.5% in the presence of silibinin after oral administration of carvedilol. Consequently, the relative bio-availability of carvedilol was increased by 1.13- to 1.57-fold and the absolute bioavailability was significantly increased by38.6–59.7%. The time to reach peak concentration and the terminal half-life were not significant. The enhanced oral bio-availability of carvedilol may result from inhibition of CYP2C9-mediated metabolism and P-gp-mediated efflux ofcarvedilol rather than inhibition of CYP2D6-mediated metabolism in the intestine and/or in the liver by silibinin. Key words

Effects of Glipizide on the Pharmacokinetics of Carvedilol after Oral and Intravenous Administration in Rats

This study was designed to investigate the effects of glipizide on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Clinically carvedilol and glipizide can be prescribed for treatment of cardiovascular diseases as the complications of diabetes, and then, Carvedilol and glipizide are all substrates of CYP2C9 enzymes. Carvedilol was administered orally or intravenously without or with oral administration of glipizide to rats. The effects of glipizide on cytochrome P450 (CYP) 2C9 activity and P-gp activity were also evaluated. Glipizide inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration (IC50) of 18 μM. Compared with the control group, the area under the plasma concentration-time curve (AUC) was significantly increased by 33.0%, and the peak concentration (Cmax) was significantly increased by 50.0% in the presence of glipizide after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.13- to 1.33-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of glipizide was increased by 36.8%. After intravenous administration, compared to the control, glipizide could not significantly change the pharmacokinetic parameters of carvedilol. Therefore, the enhanced oral bioavailability of carvedilol may mainly result from inhibition of CYP2C9- mediated metabolism rather than both P-gp-mediated efflux in the intestinal or in the liver and renal elimination of carvedilol by glipizide.

Pharmacokinetic Drug Interaction between Carvedilol and Ticlopidine in Rats

This study was designed to investigate the effects of ticlopidine on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) or intravenously (1 mg/kg) without or with oral administration of ticlopidine (4, 12 mg/kg) to rats. The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 activity were also evaluated. Ticlopidine inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration (<TEX>$IC_{50}$</TEX>) of <TEX>$25.2\;{\mu}M$</TEX>. In addition, ticlopidine could not significantly enhance the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group (given carvedilol alone), the area under the plasma concentration-time curve (AUC) was significantly (12 mg/kg, p<0.05) increased by 14-41%, and the peak concentration (<TEX>$C_{max}$</TEX>) was significantly (12 mg/kg, p<0.05) increased by 10.7-73.3% in the presence of ticlopidine after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.14- to 1.41-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of ticlopidine was increased by 36.2-38.5%. Compared to the i.v. control, ticlopidine could not significantly change the pharmacokinetic parameters of i.v. administered carvedilol. The enhanced oral bioavailability of carvedilol may result from inhibition of CYP2C9-mediated metabolism rather than P-gpmediated efflux of carvedilol in the intestinal and/or in liver and renal eliminatin of carvedilol by ticlopidine.

Population Pharmacokinetics of R- and S-Carvedilol in Japanese Patients with Chronic Heart Failure

Carvedilol is a beta-adrenoceptor antagonist used for treating chronic heart failure (CHF). Two clinical studies were conducted to evaluate the population pharmacokinetics and pharmacodynamics of R- and S-carvedilol, and associated covariates, in patients with CHF. Fifty-eight patients (male=45, female=13) with New York Heart Association class I-IV CHF were enrolled in two clinical studies. R- and S-carvedilol concentrations were measured using HPLC at steady-state after oral administration of carvedilol at 1.25-20 mg o.d. or b.i.d. The data from both studies were used to estimate the population pharmacokinetic parameters and covariates using the nonlinear mixed effects model program. For 40 patients evaluated in one clinical study, the cytochrome P450 (CYP)2D6 *1, *10, and *5 genotypes were determined using allele-specific primer PCR, and individual patients' oral clearance (CL/F) of both enantiomers were estimated by the empirical Bayes method. A one-compartment model with a first-order absorption rate was established, in which body weight and alpha(1)-acid glycoprotein were significant covariates. Individual CL/F values for carvedilol were significantly lower in Japanese CHF patients with the CYP2D6 *1/*5, *5/*10 and *10/*10 genotypes. Estimation of the population pharmacokinetic parameters and their covariates for each enantiomer in Japanese patients with CHF showed that the CL/F values for R- and S-carvedilol were dependent on body weight, alpha(1)-acid glycoprotein, and CYP2D6 genotype. Prediction of exposure to free plasma carvedilol is important for dosage adjustment of beta-blocker therapy in patients with CHF.

EFFECTS OF CARVEDILOL ON MORTALITY AND INFLAMMATORY RESPONSES TO SEVERE HEMORRHAGIC SHOCK IN RATS

The nonselective beta-adrenoceptor and the selective alpha1-adrenoceptor blocker carvedilol are widely used in hypertensive and/or cardiac failure patients because of its efficacy. However, there have been few studies regarding the effects of carvedilol on severe hemorrhagic shock. The present study was performed to evaluate the effects of carvedilol on severe hemorrhagic shock in rats. Twenty-four male Sprague-Dawley rats were randomly assigned to 1 of the following 2 groups (n = 12 per group): control group, no medication; and treatment group, oral administration of carvedilol (10 mg/kg per day) for 5 days. All animals were anesthetized with i.p. pentobarbital. Severe hemorrhagic shock was induced by partial exsanguination. Eight minutes after shock, all removed blood was returned to the animal. No other treatments were administered before, during, or after shock. Hemodynamics and arterial blood gases were recorded, mortality was calculated for the 5-h observation period, and plasma cytokine concentrations were measured at 5 h after shock. The mortality rates at 5 h after cardiac arrest were 8% and 50% for control and treatment groups, respectively. The increases in base deficit and lactate concentrations were less in the control group than that in the treatment group. Moreover, the increases in TNF-alpha concentrations were less in the control group than in the treatment group. The present study indicated that oral administration of carvedilol had adverse effects on mortality and inflammatory responses to severe hemorrhagic shock in rats. These findings suggest that carvedilol may adversely affect recovery from severe hemorrhagic shock.

Transdermal delivery of car vedilol in rats: probing the percutaneous permeation enhancement mechanism of soybean extract–chitosan mixture

Background: This study was designed for investigating the effect of soybean (SS) extract and chitosan (CTN) in facilitating the permeation of carvedilol (CDL) across rat epidermis. Method: Transdermal flux of carvedilol through heat-separated rat epidermis was investigated in vitro using vertical Keshary–Chien diffusion cells. Biophysical and microscopic manifestations of epidermis treated with SS-extract, CTN, and SS extract–CTN mixture were investigated by using DSC, TEWL, SEM, and TEM. Biochemical estimations of cholesterol, sphingosine, and triglycerides were carried out for treated excised as well as viable rat epidermis. The antihypertensive activity of the patches in comparison to that after oral administration of carvedilol was studied in deoxycorticosterone acetate-induced hypertensive rats. Results: The solubility of CDL was found to be maximum in the presence of 1% (w/v) SS extract. The KIPM/PB of CDL decreased with increase in concentration of SS extract. The in vitro permeation of CDL across rat epidermis increased and was maximum with combination of SS extract and chitosan (CTN). Biochemical and microscopic studies revealed the initiation of reversal of barrier integrity after 12 hours. Furthermore, the application of patches containing SS extract–CTN mixture resulted in sustained release of carvedilol, which was able to control the hypertension in deoxycorticosterone acetate (DOCA) induced hypertensive rats through 24 hours. CTN was found to potentiate the permeation enhancing activity of SS extract. Conclusion: The developed transdermal patches of CDL containing SS extract–CTN mixture exhibited better performance as compared to oral administration in controlling hypertension in rats.

Comparison of the pharmacokinetic properties of bisoprolol and carvedilol in healthy dogs

To compare the pharmacokinetic properties and bioavailability following oral and IV administration of bisoprolol, a second-generation beta1-adrenoceptor-selective blocking agent, with those of carvedilol, a third-generation beta1/beta2 and alpha1-adrenoceptor blocking agent, in dogs. 12 healthy adult Beagles. A prospective, parallel group study was performed. The dogs were allocated to 1 of 2 groups (6 dogs/group) and were administered orally a 1 mg/kg dose of either bisoprolol or carvedilol. Following a 1-week washout period, each cohort received a 1 mg/kg dose of the same drug IV. Blood samples were collected before and after drug administration, and serum concentrations, pharmacokinetic variables, and bioavailability for each agent were assessed. After oral administration of bisoprolol, the geometric mean value of the area under the concentration-time curve extrapolated to infinity (AUCinf) was 2,195 microg/L (coefficient of variation [CV], 15%). After IV administration of bisoprolol, the dose-normalized geometric mean AUCinf was 2,402 microg/L (CV, 19%). Oral bioavailability of bisoprolol was 91.4%. After oral administration of carvedilol, the geometric mean AUCinf was 70 microg/L (CV, 81%). After IV administration of carvedilol, the geometric mean AUCinf was 491 microg/L (CV, 23%). Oral bioavailability of carvedilol was 14.3%. Total body clearance was low (0.42 L/h/kg) for bisoprolol and high (2.0 L/h/kg) for carvedilol. After oral administration, carvedilol underwent extensive first-pass metabolism and had limited bioavailability; bisoprolol had less first-pass effect and higher bioavailability. Collectively, these differences suggested that, in dogs, bisoprolol has less interindividual pharmacokinetic variability, compared with carvedilol.

Abstract P126: Effects of Carvedilol on Mortality and Inflammatory Responses to Hemorrhagic Cardiac Arrest in Rats

Recent studies showed that beta-blocker is often used in hypertensive and/or cardiac failure patients because of its drug efficacy. Moreover, several papers reported that beta-blocker has the beneficial effects in patients with cardiogenic shock. However, there are few studies about the effects of beta-blocker during hemorrhagic shock and hemorrhagic cardiac arrest. To evaluate the effects of beta-blocker in an animal model of hemorrhagic cardiac arrest. Carvedilol was used as the beta-blocker agents. Twenty-four male Sprague Dawley rats were used. Animals were randomly assigned to one of two groups (n = 12 per group): control group, no medication; treatment group, oral administration of carvedilol (10 mg/kg/day) for 5 days. After then, all animals were anesthetized with pentobarbital ip. Hemorrhagic cardiac arrest was induced with removing of blood. After 8 minutes of cardiac arrest, the all removing blood was administered. There were no other therapies before, during or after cardiac arrest. Hemodynamics and arterial blood gases were recorded, and mortality were calculated for the 5-hr observation period and plasma cytokine (TNF-alpha and Interleukin-6) concentrations were measured at 5-hr after cardiac arrest. The mortality rates at 5hrs after cardiac arrest were 8% and 50% for control and treatment groups, respectively. The increases of base deficit and lactate concentrations were less for the control group than the treatment group. Moreover, the increases of TNF-alpha and IL-6 concentrations were less for the control group than the treatment group. The present study showed that oral administration of carvedilol had the disadvantage effects on mortality and inflammatory effects to hemorrhagic cardiac arrest in rats. These finding suggest that beta-blocker may worsen the recovery of hemorrhagic shock.

Carvedilol increases ciclosporin bioavailability by inhibiting P-glycoprotein-mediated transport

Carvedilol is often used to treat hypertension and for prophylaxis in vascular sclerosis in renal transplant recipients, who require concomitant treatment with ciclosporin. However, there are few reports regarding the pharmacokinetic interactions between carvedilol and ciclosporin. We have investigated the potential effects of carvedilol on the pharmacokinetics of ciclosporin, and examined the inhibitory effects of carvedilol on P-glycoprotein-mediated transcellular transport using Caco2 cells. Ciclosporin alone or with carvedilol was orally or intravenously administered to rats. The oral administration of carvedilol (10 mg kg(-1)) with ciclosporin (10 mg kg(-1)) increased the whole blood concentration of ciclosporin. When ciclosporin (3 mg kg(-1)) was intravenously administered with carvedilol (3 mg kg(-1)), there was no difference in the whole blood ciclosporin concentration between administration with and without carvedilol. Co-administration with carvedilol increased ciclosporin bioavailability from 33% to 70%. In Caco2 cells, carvedilol caused a concentration-dependent increase in the intracellular accumulation of ciclosporin, and its effect was comparable with that of verapamil. Carvedilol considerably raised the concentration of ciclosporin in the blood and this interaction was associated with the absorption phase of ciclosporin. This interaction was caused by the inhibition of P-glycoprotein-mediated transport by carvedilol in the intestine.

Carvedilol, a pharmacological antioxidant, inhibits neointimal matrix metalloproteinase-2 and -9 in experimental atherosclerosis

Matrix metalloproteinase (MMP) is critical to the progression of atherosclerosis and neointima hyperplasia after vascular injury. We investigated the effects of carvedilol, a pharmacological antioxidant with α- and β-adrenergic blocking activity, on MMP-2 and MMP-9 expression. Vascular injury was induced with the balloon catheters on abdominal aortas of high-cholesterol-fed rabbits. On Day 21, there was significant aortic neointima formation with increased oxidative DNA damage by immunostaining with 8-hydroxy-2′-deoxyguanosine and enhanced MMP-2 and MMP-9 expressions by Western blotting, which were significantly reduced by oral administration of carvedilol (20 mg/kg/day) or probucol (100 mg/kg/day). Vascular expression (by Western blot), activity (by gelatin zymography), and mRNA levels of MMP-2 and MMP-9 were also reduced by carvedilol or probucol. Besides, pretreatment with carvedilol or probucol but not propranolol, a β-blocker, or prazocin, an α-blocker, inhibited tumor necrosis factor-α-stimulated expressions and activities of MMP-2 and MMP-9 in human aortic smooth muscle cells. On electrophoretic mobility-shift assay, carvedilol inhibited the binding activities of activator protein-1 and specific protein-1, two major transcription factors for MMP promoter regions. Accordingly, carvedilol, a pharmacological antioxidant, inhibited in vivo and in vitro expression of MMP-2 and MMP-9 properly by modulating the redox-related pathways, suggesting its potential clinical implications.

Carvedilol enhances atrial and brain natriuretic peptide mRNA expression and release in rat heart.

To clarify the role of the natriuretic peptide (NP) system in the myocardial protective effects of carvedilol, a beta-blocking agent, we investigated the effects of carvedilol on the NP system in the rat heart. After oral administration of carvedilol (low-dose group: 2 mg/kg/day, group C2; high-dose group: 20 mg/kg/day, group C20) for 1 week, plasma rat atrial NP (r-ANP), atrial mRNA levels of ANP, left ventricular mRNA of brain NP (BNP), NP receptor-A and NP receptor-C (NPR-C) (as a clearance receptor) were measured. Values were compared with those in vehicle-treatment rats (group V). The concentration of r-ANP was significantly higher in group C2 (135 +/- 9 pg/ml) and group C20 (161 +/- 11 pg/ml) than group V (75 +/- 6 pg/ml; both p < 0.01). ANP and BNP mRNA levels were significantly increased and NPR-C was significantly down regulated in group C2 (151 +/- 7, 120 +/- 8 and 78 +/- 7%, respectively, vs. group V) and group C20 (164 +/- 8. 133 +/- 7 and 72 +/- 8%, respectively, vs. group V) compared with group V (all p < 0.01). These results suggest that not only a high dose, but a low dose of carvedilol has the effect of increasing plasma ANP and BNP levels. This effect was closely related to the upregulation of ANP and BNP mRNA expression, and the down regulation of NPR-C mRNA expression in the heart. These mechanisms seem to account for a sizable portion of the protective effect of carvedilol for heart diseases.

Carvedilol and Lacidipine Prevent Cardiac Hypertrophy and Endothelin-1 Gene Overexpression After Aortic Banding

Carvedilol and lacidipine have been shown to exert cardioprotective effects in rat models of chronic hypertension. We investigated their effects in an acute model of pressure overload produced by suprarenal aortic constriction, in which enhanced myocardial production of endothelin-1 could play a crucial role. In the absence of drug treatment, after 1 week, aortic banding provoked an increase in carotid pressure associated with left ventricular hypertrophy (29%; P<0.01). These changes were accompanied by increased myocardial expression of preproendothelin-1 (2.5 times; P<0.05) and skeletal alpha-actin (3.6 times; P<0.05), but the expression of cardiac alpha-actin was not modified. Oral administration of carvedilol at a dose of 30 mg. kg(-1). d(-1) to rats with aortic banding normalized carotid pressure and left ventricular weight as well as preproendothelin-1 and skeletal alpha-actin gene expression. Carvedilol at a lower dose (7.5 mg x kg(-1) x d(-1)) and lacidipine 1 mg x kg(-1) x d(-1) had only moderate and nonsignificant effects on carotid pressure but largely prevented left ventricular hypertrophy (P<0.01) and preproendothelin-1 overexpression (P<0.05). Labetalol (60 mg x kg(-1) x d(-1)) tended to exert similar effects but insignificantly. These results show that the antihypertrophic properties of carvedilol and lacidipine are partly independent of their antihypertensive effects and may be related to their ability to blunt myocardial preproendothelin-1 overexpression. Moreover, carvedilol at a dose of 7.5 mg x kg(-1) x d(-1) did not prevent myocardial overexpression of skeletal alpha-actin, which suggests that, in this model, reexpression of a fetal gene can be activated by pressure overload independently of cardiac hypertrophy.

ラットにおけるカルベジロールとアムロジピンの用量依存的相互作用

The pharmacokinetic interaction between carvedilol, a nonselective β-blocking agent and amlodipine besilate, a dihydropyridine calcium-channel blocker were investigated in rats. To determine the concentration-time profile of plasma carvedilol, blood samples were obtained from the tail vein after the oral administration of carvedilol either with or without amlodipine besilate. The plasma carvedilol concentrations and pharmacokinetic parameters, comprising the area under the concentration-time curve from 0 to 24 hours (AUC0-24) showed no changes after the simultaneous oral administration of 20 mg/kg carvedilol and 5 mg/kg amlodipine besilate. In contrast, the plasma carvedilol concentrations at 6 hr-12 hr and AUC0-24 after the oral administration of carvedilol with 40 mg/kg amlodipine besilate were significantly higher than those without amlodipine besilate.These results suggested the pharmacokinetic interaction between carvedilol and amlodipine to be dependent on the dose of amlodipine.

ラット血しょう中カルベジロール濃度に及ぼすメトクロプラミドと臭化プロパンテリンの影響

We investigated the effects of metoclopramide and propantheline bromide on the bioavailability of carvedilol in rats. To determine the concentration-time profile of plasma carvedilol, the blood samples were obtained from the tail vein after the simultaneous administration of 20mg/ kg carvedilol either with or without 5 mg/kg metoclopramide and 15 mg/kg propantheline bromide. The plasma carvedilol concentrations were significantly higher than the controls at 15 min.-1 hr and 3, 4 hr, and the drug pharmacokinetic parameters time to Cmax (Tmax) was 0.45 time shorter, while the absorption rate constant (Ka) and area under the concentration-time curve(AUC0-24) were 2.5 and 1.5 times higher after the oral administration of carvedilol with metoclopramide. The rate of bioavailability for carvedilol was accelerated by metoclopramide which stimulates gastric emptying. In contrast, the plasma carvedilol concentrations and Tmax., A UC0-24 did not change after the single intraperitoneal administration of carvedilol with the oral administration of metoclopramide. Conversely, propantheline bromide, which delays gastric emptying, slowed absorption, but not according the AUC0-24 of carvedilol.Other similar pharmacokinetic interaction probably occur since carvedilol are poorly absorbed from the stomach and numerous therapeutic agents influence gastrointestinal motility.