Activity Of Carvedilol Research Articles

Novel carvedilol-loaded pro-phytomicelles: formulation, characterization and enhanced protective efficacy against acetaminophen-induced liver injury in mice

The work describes a novel, small-molecule phytochemicals as nanomaterials based pro-micelles (pro-phytomicelles) drug delivery system, for oral delivery of carvedilol (CAR). This novel nanoformulation of CAR, named CAR pro-phytomicelles, was prepared with rebaudioside A (RA) and dipotassium glycyrrhizinate (DG) as mixed nanomaterials. The formulation was optimized, leading to a 502-fold increase in solubility of CAR in water as a result of encapsulation within mixed phytomicelles based on DG and RA. CAR pro-phytomicelles samples could be instantly dissolved into aqueous media to formulate clear phytomicelle solutions with CAR encapsulation efficiency of 99.67 ± 0.02 %, and small micelle size of 15.62 ± 0.27 nm. CAR pro-phytomicelles exhibited good storage stability, rapid in vitro release in simulated intestinal fluid, and improved in vitro antioxidant activity. CAR pro-phytomicelles had good biocompatibility. Protective efficacy evaluation revealed that acetaminophen overdose could induce high mortality and severe liver injury in mice, while CAR pro-phytomicelle treatment exhibited significant protective effect against acetaminophen overdose. This protective efficacy was due to a mechanism that involved the regulation of high-mobility group box 1 and its signaling-related proinflammatory cytokines. These results show that pro-phytomicelles could provide a new concept and promising therapeutics as nanomedicines for improving the activities of CAR against acetaminophen-induced liver injury.

β-Blockers bearing hydroxyethylamine and hydroxyethylene as potential SARS-CoV-2 Mpro inhibitors: rational based design, in silico, in vitro, and SAR studies for lead optimization.

The global COVID-19 pandemic became more threatening especially after the introduction of the second and third waves with the current large expectations for a fourth one as well. This urged scientists to rapidly develop a new effective therapy to combat SARS-CoV-2. Based on the structures of β-adrenergic blockers having the same hydroxyethylamine and hydroxyethylene moieties present in the HIV-1 protease inhibitors which were found previously to inhibit the replication of SARS-CoV, we suggested that they may decrease the SARS-CoV-2 entry into the host cell through their ability to decrease the activity of RAAS and ACE2 as well. Herein, molecular docking of twenty FDA-approved β-blockers was performed targeting SARS-CoV-2 Mpro. Results showed promising inhibitory activities especially for Carvedilol (CAR) and Nebivolol (NEB) members. Moreover, these two drugs together with Bisoprolol (BIS) as an example from the lower active ones were subjected to molecular dynamics simulations at 100 ns. Great stability across the whole 100 ns timeframe was observed for the top docked ligands, CAR and NEB, over BIS. Conformational analysis of the examined drugs and hydrogen bond investigation with the pocket's crucial residues confirm the great affinity and confinement of CAR and NEB within the Mpro binding site. Moreover, the binding-free energy analysis and residue-wise contribution analysis highlight the nature of ligand–protein interaction and provide guidance for lead development and optimization. Furthermore, the examined three drugs were tested for their in vitro inhibitory activities towards SARS-CoV-2. It is worth mentioning that NEB achieved the most potential anti-SARS-CoV-2 activity with an IC50 value of 0.030 μg ml−1. Besides, CAR was found to have a promising inhibitory activity with an IC50 of 0.350 μg ml−1. Also, the IC50 value of BIS was found to be as low as 15.917 μg ml−1. Finally, the SARS-CoV-2 Mpro assay was performed to evaluate and confirm the inhibitory effects of the tested compounds (BIS, CAR, and NEB) towards the SARS-CoV-2 Mpro enzyme. The obtained results showed very promising SARS-CoV-2 Mpro inhibitory activities of BIS, CAR, and NEB (IC50 = 118.50, 204.60, and 60.20 μg ml−1, respectively) compared to lopinavir (IC50 = 73.68 μg ml−1) as a reference standard.

Abstract 5087: Carvedilol prevents skin cancer independently of its antioxidant property

Abstract Carvedilol is an FDA approved β-blocker traditionally prescribed for cardiovascular diseases. Our previous work demonstrated that carvedilol has preventive activity against ultraviolet radiation (UVR)-induced skin damage, inflammation, and carcinogenesis. However, the photoprotective mechanism for carvedilol remains unknown. Interestingly, not all β-blockers have cancer preventive activity, suggesting that targeting the β-adrenergic receptors may not be responsible for carvedilol’s anticancer activity. Since carvedilol has been shown as a potent antioxidant and such property is not shared by majority of other β-blockers (e.g., metoprolol), we hypothesized that the antioxidant property may be, in part, responsible for carvedilol’s protective activity against photocarcinogenesis. The nontumorous mouse epidermal JB6 P+ cells were subjected to various doses of UVR exposure and H2O2 treatment to identify the optimal doses to examine protective activity. UVR and H2O2dose-dependently reduced cell viability. 25mJ/cm2 UVR and 100 μM H2O2 reduced cell viability detected by Trypan blue exclusion assay to 58.1% and 60.6%, respectively. 25mJ/cm2 UVR and 300 μM H2O2 increased the formation of intracellular fluorescent 2',7'-dichlorofluorescein (DCF) fluorescence, a marker of reactive oxidative species (ROS) detected by flow cytometry, to 5- and 4-fold compared to non-treated control, respectively. The cells were treated before or after UVR and H2O2 exposure with metoprolol, carvedilol or 4-hydroxycarbazole (4-OHC). 4-OHC is an intermediate compound for carvedilol synthesis that possesses an identical UV absorption profile as carvedilol. Additionally, the carbazole moiety is likely responsible for the antioxidant activity of carvedilol. Carvedilol, but not metoprolol and 4-OHC, was able to inhibit EGF-induced JB6 transformation in soft agar. Carvedilol, but not metoprolol and 4-OHC, also attenuated UVR and H2O2 induced cell death. Carvedilol, but not 4-OHC, inhibited UVR-induced NF-κB and AP-1 promoter activity. In addition, unlike carvedilol, 4-OHC failed to prevent chronic UVR induced skin carcinogenesis in SKH-1 mice. However, 4-OHC and carvedilol similarly attenuated UVR- and H2O2-induced ROS formation in JB6 P+ cells, while metoprolol had no effect. These results indicate that the photoprotective effects of carvedilol are primarily due to an unknown mechanism that is independent of β-adrenergic receptors and reactive oxygen species scavenging. Citation Format: Mengbing Chen, Sherry Liang, Bradley Andresen, Ying Huang. Carvedilol prevents skin cancer independently of its antioxidant property [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5087.

Investigation of Carvedilol as an Antidenaturing and Anticataract Agent

Cataract is an opacification of the lens of eye. Causes of cataract formation are aging, generation of free radicals, diabetes, protein denaturation by oxidative stress or any inducer etc. Antioxidants and antioxidant enzymes, antidenaturing agent protect the eyes by reducing free radical damage and eye lenses by inhibiting protein denaturation. The present study evaluated the in vitro anticataract and antidenaturing activities of carvedilol against glucose-induced cataractogenesis using goat lenses and heat induced egg albumin denaturation. Transparent isolated goat lenses are incubated in artificial aqueous humor and divided into five experimental groups. The carvedilol at a dose of 20μg/ml is incubated simultaneously with glucose (55 mM) and glucose (5.5 mM) for a period of 72 h. ascorbic acid (20 μg/ml) is used as the standard drug. At the end of the incubation lense opacity is measured by photographic evaluation. Antidenaturing activity is evaluated by taking different concentration of carvedilol (10 p.p.m – 500 p.p.m) with egg albumin and subjected for protein denaturation by using heat for 15 min. Standard drug is used as Diclofenac sodium, at the end protein denaturation is analyse by taking absorbance at 440 nm and 660 nmrsp. The carvedilol shows significant inhibition of cataractogenesis of eye lenses by carvedilol at conc. 20 p.p.m. and also thermally induced protein denaturation inhibited by carvedilol at conc. 500 p.p.m. The present supports carvedilol as an antidenaturing and anticataract agent.

Abstract 1256: The chemopreventive effects of carvedilol on skin carcinogenesis

Abstract Skin cancer, the majority of which is non-melanoma skin cancer (NMSC), is the most common type of cancer in the US. The rate of NMSC is increasing mainly due to depletion of the ozone layer and increased exposure to ultraviolet radiation. To reduce the risk of skin cancer, it is recommended to all individuals to limit sun exposure and use sunscreens. Despite these efforts, the incidence of NMSC continues to rise. Novel chemopreventive targets and nontoxic agents are needed. Epidemiological studies identified an association of psychosocial factors such as chronic stress or depression with cancer onset and progression. These factors are partly mediated by activation of the sympathetic nervous system which results in release of norepinephrine and epinephrine, the effects of which are mediated through the alpha- and beta-adrenergic receptors (alpha- and beta-AR). Further, the use of beta-AR antagonists (beta-blockers) has been associated with reduced cancer incidence. However, whether beta-blockers have chemopreventive activity or whether beta-ARs contribute to carcinogenesis is unknown. To determine whether agonizing or antagonizing beta-ARs affect skin cell transformation, we tested the beta-AR agonist isoproterenol (Iso) and antagonist carvedilol on epidermal growth factor (EGF)-mediated transformation of JB6 P+ cells (a skin cell model to study tumor promotion). The cells were treated with EGF (10 ng/mL) plus 0.1 µM or 1.0 µM Iso, yet no effect was observed. However, treatment with carvedilol dose-dependently inhibited the formation of EGF-induced soft agar colonies. Such effect was not caused by growth inhibition, because cytotoxicity and inhibition of cell proliferation were not observed for tested concentrations. Next, the expression of beta1-, 2- and 3-AR was determined in JB6 cells using RT-PCR. The results showed that only beta2-AR was detectable. We also determined whether beta-ARs are expressed in other types of cancer. In tissues derived from a rat model of 7, 12-dimethylbenz[α]anthracene (DMBA)-induced mammary cancer, expression of beta1- and 2-AR was up-regulated in tumors in comparison with normal tissues. The human cancer cell lines A549 and MDA-MB-231 also express beta2-AR. To determine the in vivo chemopreventive activity of carvedilol, we used a skin hyperplasia model in SENCAR mice induced by topical treatment with 100 nM DMBA twice a week for four weeks. Carvedilol was tested topically (5 and 10 µM) or orally (5 and 20 mg/kg), beginning at two weeks before the first dose of DMBA, three times a week, for six weeks. DMBA alone increased the epidermal thickness from the average of 77.8 + 13.6 nm in normal skin to 294 + 49.7 nm in DMBA-treated skin. Both topical and oral carvedilol treatment inhibited DMBA-induced hyperplasia (P < 0.05). In conclusion, these results suggest that beta-blockers may have chemopreventive activity. This study also suggests that beta-ARs may serve as a novel target for cancer prevention. Citation Format: Andy Chang, Mandy Liu, Steven Yeung, Jijun Hao, Cyrus Parsa, Robert Orlando, Bradley Andresen, Ying Huang. The chemopreventive effects of carvedilol on skin carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1256. doi:10.1158/1538-7445.AM2014-1256

The effects of carvedilol on cardiac structural remodeling: The role of endogenous nitric oxide in the activity of carvedilol

As a third-generation β-adrenergic blocker (β-blocker), carvedilol is able to reverse cardiac structural remodeling, however, its mechanism of action remains unclear. In order to investigate this mechanism, hypertension was induced in rats by unilateral renal artery narrowing. Additionally, carvedilol alone or carvedilol combined with L-NAME, a specific inhibitor of nitric oxide (NO) synthase, were administered to rats by gastric gavage for 8 weeks. Systolic blood pressure (SBP) was monitored once a week for each rat until sacrifice; the blood was kept to examine plasma NO level and the tissues were used for hematoxylin and eosin (H&E) and Masson's trichrome staining. Collagen volume fraction (CVF) and perivascular collagen area (PVCA) were calculated to quantitatively evaluate myocardial fibrosis. Our data showed that SBP was not different between the carvedilol-treated (Car) and carvedilol combined L-NAME groups (Car+L) at 8 weeks. Carvedilol significantly suppressed myocardial fibrosis and decreased both CVF and PVCA, although L-NAME blunted the effects caused by carvedilol. These results demonstrated that the effect caused by carvedilol on cardiac remodeling is largely dependent on endogenous NO.

Enantioselective pharmacokinetic and pharmacodynamic properties of carvedilol in spontaneously hypertensive rats: focus on blood pressure variability

The cardiovascular effects and pharmacokinetics of carvedilol were assessed in spontaneously hypertensive (SH) and Wistar Kyoto (WKY) animals with special focus on short-term blood pressure variability (BPV). Male SH and WKY rats were acutely treated with vehicle or carvedilol 1 or 5mgkg(-1) (i.v.), and effects on blood pressure (BP), heart rate (HR) and BPV were recorded. Plasma pharmacokinetics of R- and S-carvedilol was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by pharmacokinetic-pharmacodynamic (PK-PD) modelling. Short-term BPV was assessed by standard deviation of BP recording. Vascular sympatholytic activity of carvedilol was studied by estimation of drug effects on ratio between low frequency (LF) and high frequency (HF) BPV (LF/HF ratio). Although pharmacokinetic properties of carvedilol remained mainly unaffected in SH rats with regard to WKY rats, hypertensive animals showed a reduction in drug clearance of R- and S-carvedilol after administration of 1mgkg(-1) compared with WKY rats. PK-PD analysis of HR changes induced by S-carvedilol showed a greater maximal bradycardic response to carvedilol in SH rats (E (max), -27.6 ± 3.9%; p < 0.05) compared with WKY group (E (max), -13.4 ± 2.5%). SH rats showed a greater hypotensive effect of racemic carvedilol (E (max), -45.5 ± 5.0%; p < 0.05) with regard to WKY group (E (max), -17.9 ± 4.5%). Carvedilol induced a greater reduction of LF/HF ratio in SH rats compared with WKY rats. Short-term BPV was markedly reduced by carvedilol in WKY and SH rats. In conclusion, as a consequence of an enhanced bradycardic response and a greater vascular sympatholytic activity, carvedilol exerts a greater hypotensive response in SH rats compared with WKY animals and dramatically reduces short-term BPV.

Pharmacokinetic and pharmacodynamic properties of carvedilol in fructose hypertensive rats

Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokinetic–pharmacodynamic (PK–PD) modeling.Male Sprague–Dowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (1–3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK–PD modeling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis.A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Although PK–PD properties of S-carvedilol chronotropic effect were not altered in F rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in F rats.Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity.

Antioxidant properties of carvedilol: Inhibition of lipid peroxidation, protein oxidation and superoxide generation

Oxidative stress has been suggested to be an etiological factor in cerebro- and cardiovascular disorders. We examined antioxidant activities of carvedilol, a β- and α-adrenoreceptor blocker. Carvedilol suppressed lipid auto-oxidation and protein carbonyl formation in brain homogenate in a dose-dependent manner. Carvedilol also suppressed superoxide generation of human neutrophils. These properties of carvedilol should be suitable for treating hypertension resulting in cerebro- and cardiovascular diseases.

Effects of carvedilol alone and in the presence of cyclosporine A on the DNA synthesis of cultured vascular smooth muscle cells.

There is still no reliable method of preventing or treating chronic rejection or transplant vascular sclerosis. A recent in vitro cell culture study showed that carvedilol significantly inhibited the proliferation of vascular smooth muscle cells (VSMCs); however, the effect of carvedilol in the presence of cyclosporine (CsA) has not yet been reported. Using in vitro cultured VSMCs, we measured the antiproliferative activity of carvedilol alone and in combination with CsA. Growth-arrested cultured VSMCs from the thoracic aorta of Sprague-Dawley rats were exposed to platelet-derived growth factor (PDGF)-BB, endothelin (ET)-I, and angiotensin (ANG)-II. Carvedilol (1 and 10 microM) and/or CsA (100 nM) were added as test drugs. DNA synthesis was assessed by measuring the incorporated [3H]thymidine activity, and the percentage of inhibition in the presence of the test drugs was determined. Compared with the PDGF-stimulated control, DNA synthesis decreased significantly to 60.3% +/- 10.4% and 18.3% +/- 5.9% in the presence of 1 and 10 microM of carvedilol, respectively (P < 0.05, each). Carvedilol significantly inhibited the activity of VSMCs stimulated by ET-1 and ANG-II. The IC50 of carvedilol was 1-10 microM. CsA only inhibited VSMCs significantly in the PDGF-stimulated subgroup. The addition of CsA in the presence of carvedilol did not affect the inhibitory activity of carvedilol. The pattern of inhibition in the combined group was uniform and similar to that of the carvedilol alone group, regardless of the stimulator used. Carvedilol significantly inhibited the DNA synthesis of VSMCs regardless of the kind of stimulators examined, even in the presence of CsA. These results indicate that carvedilol has the unique potential to inhibit the development of transplant vascular sclerosis in hypertensive transplant recipients under CsA-based immunosuppression.

The antihypertensive drug carvedilol inhibits the activity of mitochondrial NADH-ubiquinone oxidoreductase.

A study is presented on the interaction of carvedilol with mitochondria isolated from several rat organs. It is shown that carvedilol causes a moderate uncoupling effect under non phosphorylating succinate supported respiration of intact mitochondria, as well as a marked inhibition of coupled respiration with NAD-dependent substrates. The inhibitory effect was also found in the bovine heart purified Complex I as well as in experiments with mitochondrial particles, where the individual redox segments of the respiratory chain were analysed. It is also shown that carvedilol, though exhibiting an intrinsic scavenger activity, caused reactive oxygen species to be produced as a consequence of its inhibitory effect on the steady-state respiration. Under these conditions the pro-oxidant activity of carvedilol appears to prevail over its scavenging activity, and a net generation of ROS is promoted.

Oxidative stress impairs the haemodynamic activity of cardiovascular agents with antioxidant properties

Reactive oxygen species (ROS) are known to be involved in the pathogenesis and progression of various cardiovascular diseases. For some therapeutics like carvedilol and captopril used in the treatment of such diseases antioxidant properties have been proposed to play a role in addition to their haemodynamic activities. It was the aim of the present study to assess whether ROS may affect the molecular integrity and the primary pharmacological actions of compounds with additional antioxidant properties. Accordingly, well-known drugs as mentioned were exposed to ROS, generated by electrolysis and analyzed by means of functional and chemical investigations. For this purpose rat thoracic aortic rings were incubated with either the beta1,2/alpha1-adrenoceptor antagonist carvedilol (100 nM), the alpha1-adrenoceptor antagonist prazosin (5 nM), the thiol-containing ACE-inhibitor captopril (3 microM) or lisinopril (300 nM), an ACE-inhibitor without a thiol moiety. Furthermore, isolated rat left atria were incubated with either carvedilol (14 nM) or with the beta1,2-adrenoceptor antagonist timolol (50 nM). After an incubation period of 15 min, electrolysis was applied to the buffer medium in order to generate ROS. After an additional 15 min, concentration-response curves were constructed for angiotensin I and phenylephrine in thoracic aortic rings incubated with the ACE-inhibitors and the alpha1-adrenoceptor antagonists, respectively. In addition, concentration-response curves were constructed for isoprenaline in presence of the beta1,2-adrenoceptor antagonists in isolated left atria. After exposure to oxidative stress the alpha1- and beta-adrenoceptor blocking activity of carvedilol was significantly impaired, when compared to control conditions. In contrast, the pharmacological effects of prazosin and timolol remained unaffected. The ACE-inhibition by captopril was completely abolished after electrolysis, while the pharmacological action of lisinopril was only slightly reduced. In addition, a complete oxidative degradation of captopril and carvedilol could be demonstrated by using UV/Vis spectroscopy and HPLC/fluorospectroscopy, respectively. From these results we conclude that the haemodynamic therapeutics with additional radical scavenging properties may undergo a chemical modification due to ROS-exposure which results in a loss of pharmacological activity.

Pharmacology of carvedilol: rationale for use in hypertension, coronary artery disease, and congestive heart failure.

Carvedilol is a novel, multiple-action cardiovascular drug that is currently approved in many countries for the treatment of hypertension. The reduction in blood pressure produced by carvedilol results primarily from beta-adrenoceptor blockade and vasodilation, the latter resulting from alpha 1-adrenoceptor blockade. These actions, as well as several of the other activities of carvedilol, are associated with cardioprotection in animal models that occurs to a degree that is greater than that observed with other drugs. The multiple actions of carvedilol may also provide the underlying rationale for the use of the drug in the treatment of coronary artery disease and congestive heart failure. By virtue of being both a beta-blocker and a vasodilator, carvedilol significantly decreases myocardial work by reducing all three components of myocardial oxygen demand, namely, heart rate, contractility, and wall tension. The vasodilatory effects of carvedilol reduce afterload, and the resulting decrease in impedance to left ventricular ejection offsets the negative inotropic effect that would normally result from beta-blockade. As a consequence, stroke volume and cardiac output are maintained or even increased in animals and in patients with congestive heart failure who are treated with carvedilol. Carvedilol and several of its metabolites are potent antioxidants, and this activity may account, in part, for the cardioprotective effects of the drug observed in animal models of acute myocardial ischemia and, in theory, could also serve to protect the myocardium of patients with hypertension, coronary artery disease, and congestive heart failure, in which oxidative stress is now recognized to occur. The antioxidant effects of carvedilol may both inhibit the direct cytotoxic actions of reactive oxygen radicals and prevent oxygen-radical induced activation of transcription factors and genes associated with inflammatory and remodeling processes. Accordingly, carvedilol inhibits the gene expression of the intracellular adhesion molecule-1 (ICAM-1), an adhesion molecule for polymorphonuclear leukocytes, which typically infiltrate the myocardium under conditions of ischemia and may exacerbate ischemic injury. The antioxidant activity of carvedilol has been shown to inhibit the oxidation of low density lipoprotein (LDL) in vitro, thereby preventing the formation of this cytotoxic and atherogenic form of LDL. It follows, therefore, that in animal models of hyperlipidemia, carvedilol attenuates aortic lipid accumulation and decreases the aortic content of monocytes and foam cells, and at the same time it has been shown to preserve endothelial integrity and function. These actions of carvedilol are not shared by other beta-blockers or by other drugs currently used in the management of hypertension, coronary artery disease, or congestive heart failure. The multiple actions of carvedilol may provide the underlying pharmacologic rationale for the use of this drug in the treatment of patients with coronary artery disease or congestive heart failure, and these actions may account, at least in part, for the reduction in mortality produced by carvedilol in clinical trials involving patients with congestive heart failure. Likewise, these actions of carvedilol may also provide protection, beyond that afforded from reduction in blood pressure, against secondary organ damage in hypertensive patients treated with the drug.

Vasodilatory action of carvedilol.

Carvedilol is a dual-acting drug designed to produce two complementary effects: beta-blockade and vasodilation. These effects are induced in the same dose range, a prerequisite for utilizing both properties in an appropriate manner. The vasodilation is mediated predominantly by specific alpha 1-adrenoceptor blockade. At markedly higher concentrations, additional vasodilating actions besides alpha 1-blockade can be observed. These effects resemble those of Ca(2+)-antagonistic properties. However, they do not contribute to the acute blood pressure-lowering activity of carvedilol but may be responsible for the increased blood flow to specific organs. At beta-blocking doses, carvedilol reduces the regional and systemic vascular resistance in various experimental models, healthy volunteers, and in patients with cardiovascular diseases such as hypertension, coronary artery disease, and heart failure. The profile of carvedilol thus insures beneficial treatment of hemodynamic disorders characterized by increased sympathetic tone and increased vascular resistance.

Effects of carvedilol on adrenergic receptor pharmacology in human ventricular myocardium and lymphocytes.

Carvedilol, a new beta-blocker with vasodilating properties due to alpha 1-blockade, was investigated in preparations of human ventricular myocardium. Carvedilol demonstrated a high affinity and is a slightly beta 1-selective competitive beta-blocking agent, with a KD for beta 1-receptors of approximately 4-5 nM and a mild selectivity for beta 1 vs. beta 2 receptors of 6- to 39-fold, depending on the method employed to assess subtype potency. In addition, carvedilol was also a potent alpha 1-blocking agent, with a beta 1:alpha 1 blocking relative potency of 1.7-fold. In human lymphocytes containing beta 2-receptors and in human myocardial membranes containing both beta 1- and beta 2-receptors carvedilol exhibited the unique property of guanine nucleotide modulatable binding. Despite this, no intrinsic sympathomimetic activity of carvedilol was detected in preparations of isolated human heart or in myocardial membranes. Vasodilation related to alpha 1-blockade and the lack of intrinsic activity should translate into improved tolerability and good efficacy in the treatment of heart failure.

Carvedilol (Kredex&amp;reg;) Reduces Infarct Size in a Canine Model of Acute Myocardial Infarction

Carvedilol (Kredex) is a multiple action, antihypertensive agent that may also prove to be useful in the treatment of angina and congestive heart failure. Carvedilol combines in one molecule both beta-adrenoceptor blocking and vasodilating activities. Inasmuch as beta-adrenoceptor blocking agents are known to be cardioprotective and thereby reduce infarct size, it is logical to assume that carvedilol, likewise, would possess this desirable activity. Furthermore, the additional vasodilating activity of carvedilol could contribute to further reductions in infarct size by reducing myocardial work (and therefore myocardial oxygen demand) through reductions in both afterload and myocardial wall tension. As such, we have investigated the ability of carvedilol to reduce infarct size in a canine model of acute myocardial infarction. Carvedilol (1 mg/kg i.v.) or its vehicle, dimethylformamide, were administered 15 min before left circumflex coronary artery (LCX) occlusion. Following 1 h of LCX occlusion, dogs were reperfused through a critical stenosis and then allowed to recover for 24 h. Carvedilol-treated animals exhibited a 78% reduction in infarct size compared to vehicle controls, such that the percentage of the left ventricle infarcted was reduced significantly from 16.2 +/- 4.1% in control animals to 3.6 +/- 1.3% in animals treated with carvedilol (p = 0.017, n = 6). Stained tissue sections of the left ventricle were photographed, digitized and color-enhanced using an Image Analysis Computer System, and three-dimensional reconstruction of the left ventricle, including the infarcted areas, was performed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenoceptor-Blocking Activity and Cardiohemodynamic Effects of Carvedilol in Animals

The beta-blocking activities of a new beta-adrenoceptor blocking drug, carvedilol, evaluated in isolated atria and trachea of the guinea pig were 2.0 (beta 1) and 3.2 times (beta 2), respectively, as potent as those of propranolol. Carvedilol exhibited the alpha-blocking activities in the aorta of guinea pigs and rats. Carvedilol was 2 and 50 times less potent in guinea pigs and rats, respectively, than prazosin as an alpha-blocker. Thus, the alpha-blocking activities were twice as potent as the beta-blocking activity in the rat and one-fifth that of the beta-blocking activity in the guinea pig. In anesthetized open-chest dogs, the beta-blocking activity of carvedilol was 1.5 times more potent than that of propranolol and had 3.8 times the alpha-blocking activity. Thus, carvedilol is a nonselective beta-blocking drug with a potent alpha-blocking activity. Carvedilol and propranolol showed dose-dependent and significant decreases in the blood pressure, total cardiac output, left ventricular pressure, dp/dt, heart rate, coronary flow, and oxygen consumption in anesthetized open-chest dogs. Carvedilol decreased the total peripheral resistance significantly (the decrease was not proportional to the decreases in the blood pressure at high doses), while propranolol increased it significantly and dose-dependently. These results indicate the importance of alpha-adrenoceptor blocking activity in the decrease in blood pressure produced by carvedilol.

Mode of Vasodilating Activity of Carvedilol in Isolated Perfused Hind Limbs of Rabbits

Mode of Vasodilating Activity of Carvedilol in Isolated Perfused Hind Limbs of Rabbits

Dose-effect relationship of carvedilol in essential hypertension. An open study.

This study was performed to find the optimal dose of carvedilol, in terms of efficacy and safety, in Japanese patients with mild to moderate essential hypertension. 134 patients with blood pressure greater than 160/95 mm Hg after a 4-week placebo run-in period were initially given carvedilol 5mg once daily. The dose was increased to 10 and 20mg at 4-weekly intervals if the target blood pressure was not achieved. The duration of treatment was 12 weeks. After 12 weeks' administration, the average blood pressure was significantly (p less than 0.001) reduced from 170/101 to 150/91 mm Hg. The hypotensive activity of carvedilol 5mg was mild, but sufficient hypotensive effect was observed in 65% of patients receiving up to 20 mg/day. No significant postural changes in blood pressure were observed. Although heart rate was significantly decreased (77 to 66 beats/min, p less than 0.001), no patient was judged to have bradycardia. Side effects occurred in 5.2% of patients. Carvedilol 10 to 20mg once daily is considered to be an effective and safe treatment for essential hypertension.

Studies on the Mode of Vasodilating Action of Carvedilol

Investigations were performed on isolated rat aortic strips and in pithed rats in order to elucidate the mechanism of vasorelaxation or the acute blood pressure lowering effect induced by carvedilol. In particular, the possible role of the beta-receptor-stimulating activities or alpha-blocking properties has been investigated. beta 2-stimulation can be ruled out, since preincubation of isolated vessels with the beta 2-receptor blocker ICI 118.551 does not influence the vasorelaxing activity of carvedilol. Additionally, its optical enantiomers also induce the same vasorelaxing effect in vitro. In contrast to the standard alpha-blocking agents phentolamine or prazosin, carvedilol does not inhibit effects of alpha-receptor agonists at hypotensive doses, but inhibition of the effects of alpha-receptor agonists has been found in vitro and in vivo at high concentrations or doses and indicates a potential alpha-blocking activity of carvedilol. For example, the dose required for a specific inhibitory effect on norepinephrine responses observed in pithed rats is at least 20 times higher than that required for a decrease in blood pressure in spontaneously hypertensive rats. Furthermore, the alpha-blocking activity is at least 20 times lower than the beta-blocking activity, whereas hypotension and beta-blockade can be observed in intact animals after acute administration in the same dose range of carvedilol. It can therefore be assumed that the alpha-blocking activity does not contribute substantially to the decrease in blood pressure at doses normally used. It is suggested that a not yet defined postreceptor mechanism is involved in the vasorelaxing and acute blood pressure lowering activity of carvedilol.