RESUMO
Cardiotoxins (CaTxs) are a group of snake toxins that affect the cardiovascular system (CVS). Two types (S and P) of CaTxs are known, but the exact differences in the effects of these types on CVS have not been thoroughly studied. We investigated cellular mechanisms of action on CVS for Naja oxiana cobra CaTxs CTX-1 (S-type) and CTX-2 (P-type) focusing on the papillary muscle (PM) contractility and contraction of aortic rings (AR) supplemented by pharmacological analysis. It was found that CTX-1 and CTX-2 exerted dose-dependent effects manifested in PM contracture and AR contraction. CTX-2 impaired functions of PM and AR more strongly than CTX-1. Effects of CaTxs on PM were significantly reduced by nifedipine, an L-type Ca2+ channel blocker, and by KB-R7943, an inhibitor of reverse-mode Na+/Ca2+ exchange. Furthermore, 2-aminoethoxydiphenyl borate, an inhibitor of store-operated calcium entry, partially restored PM contractility damaged by CaTxs. The CaTx influence on AR contracture was significantly reduced by nifedipine and KB-R7943. The involvement of reverse-mode Na+/Ca2+ exchange in the effect of CaTxs on the rat aorta was shown for the first time. The results obtained indicate that CaTx effects on CVS are mainly associated with disturbance of transporting systems responsible for the Ca2+ influx.
Assuntos
Aorta/efeitos dos fármacos , Cardiotoxinas/farmacologia , Venenos Elapídicos , Naja naja , Músculos Papilares/efeitos dos fármacos , Animais , Aorta/fisiologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculos Papilares/fisiologia , Ratos Wistar , Vasoconstrição/efeitos dos fármacosRESUMO
The ICH S7B document, which provides guidance for the preclinical cardiovascular evaluation of pharmaceutical new chemical entities (NCE), is essentially focused on drug-induced QT lengthening, a biomarker for the proarrhythmic adverse drug reaction, torsades de pointes (TdP). In 2005, this guidance recommended the IKr assay and the in vivo QT telemetry study as mandatory assays for detecting potential torsades de pointes liability and relegated the cardiac action potential (AP) assay as a follow-up study. The IKr assay has become a mandatory screening tool in the early development and safety assessment process. Using only the IKr assay as a go/no go decision arbiter is regrettable since, due to the low specificity of the model (positives that are false for proarrhythmia liability, e.g. verapamil), promising, safe NCEs may be inadvertently discarded. Inclusion of additional medium throughput assays should be performed early to confirm or balance the putatively unfavourable IKr result with positive discovery model output (Pugsley et al., J Pharmacol Toxicol Methods 60:24-27, 2009). In the present chapter, the predictive value of in vitro guinea pig papillary muscle action potential assay will be discussed in terms of sensitivity and specificity and compared to currently available preclinical models such as IKr/hERG assay, dog Purkinje fibre action potential and in vivo QT measurements in dog and cynomolgus monkey.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Músculos Papilares/efeitos dos fármacos , Torsades de Pointes/induzido quimicamente , Animais , Cobaias , Técnicas In Vitro , Músculos Papilares/fisiologiaRESUMO
This work was aimed at evaluating the cardioprotective effects of Castanea sativa Mill. (CSM) bark extract characterized in its phenolic composition by HPLC-DAD-MS analysis. The study was performed using primary cultures of neonatal rat cardiomyocytes to investigate the antioxidant and cytoprotective effects of CSM bark extract and isolated guinea pig left and right atria, left papillary muscle, and aorta to evaluate its direct effect on cholinergic and adrenergic response. In cultured cardiomyocytes the CSM bark extract reduced intracellular reactive oxygen species formation and improved cell viability following oxidative stress in dose-dependent manner. Moreover, the extract decreased the contraction induced by noradrenaline (1 µ M) in guinea pig aortic strips and induced transient negative chronotropic and positive inotropic effects without involvement of cholinergic or adrenergic receptors in the guinea pig atria. Our results indicate that CSM bark extract exhibits antioxidant activity and might induce cardioprotective effect.
Assuntos
Cardiotônicos/farmacologia , Fagaceae/química , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Animais Recém-Nascidos , Função Atrial/efeitos dos fármacos , Cardiotônicos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cobaias , Técnicas In Vitro , Miócitos Cardíacos/metabolismo , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Casca de Planta/química , Extratos Vegetais/química , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptores Adrenérgicos/metabolismo , Receptores Colinérgicos/metabolismoRESUMO
It is proved that polydatin has cardioprotection against ischemia-induced arrhythmia, but the electrophysiological mechanism is not clear. The aim of the present study was to investigate the effect of polydatin on action potential (AP) in ventricular papillary muscle and the underlying ionic mechanism in rat using intracellular recording and whole-cell patch clamp techniques. The results showed: (1) In normal papillary muscles, polydatin (50 and 100 µmol/L) shortened duration of 50% repolarization (APD(50)) and duration of 90% repolarization (APD(90)) in a concentration-dependent manner (P<0.01). But polydatin had no effects on resting potential (RP), overshoot (OS), amplitude of action potential (APA) and maximal rate of depolarization in phase 0 (V(max)) in normal papillary muscles (P>0.05). (2) In partially depolarized papillary muscles, polydatin (50 µmol/L) not only shortened APD(50) and APD(90) (P<0.05), but also decreased OS, APA and V(max) (P<0.05). (3) After pretreatment with glibenclamide (10 µmol/L), an ATP-sensitive K(+) channel blocker, the electrophysiological effect of polydatin (50 µmol/L) was partially inhibited. (4) Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 1 mmol/L), a nitric oxide (NO) synthase inhibitor, failed to abolish the effect of polydatin (50 µmol/L) on AP. (5) Polydatin (25, 50, 75 and 100 µmol/L) decreased L-type Ca(2+) current in ventricular myocytes in a concentration-dependent manner (P<0.05). (6) Polydatin (50 µmol/L) increased ATP-sensitive K(+) current in ventricular myocytes (P<0.05). The results suggest that polydatin can shorten the repolarization of AP in normal papillary muscle and inhibit AP in partially depolarized papillary muscle, which might be related to the blocking of L-type Ca(2+) channel and the opening of ATP-sensitive K(+) channel.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Glucosídeos/farmacologia , Ventrículos do Coração/citologia , Músculos Papilares/fisiologia , Estilbenos/farmacologia , Animais , Canais de Cálcio Tipo L/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Canais KATP/metabolismo , Masculino , Músculos Papilares/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To study the effect of Ginkgo biloba extract 50 (GBE50), a new multicomponent drug with a polyvalent action extracted from the leave of Ginkgo biloba, on the action potentials in normal and simulated ischemic guinea pig papillary muscles. METHOD: Standard intracellular microelectrode technique was used to examine the effects of GBE50 on the action potential parameters [action potential amplitude (APA), overshoot, rest potential, action potential amplitude at 20%, 50%, 90% of repolarization (APD20, APD50, APD90)]. RESULT: In normal guinea pig cardiac papillary muscles, GBE50 (20, 50, 100 mg x L(-1)) shortened APD50 and APD90, and did not affect the rest potential parameters. In simulated ischemic guinea pig cardiac papillary cells, action potential duration was significantly shortened, resting potential and action potential amplitude were reduced. 100 mg x L(-1) GBE50 partly attenuated the change induced by ischemia. CONCLUSION: GBE50 shortened APD of normal guinea pig cardiac papillary cells in a concentration-dependent manner. Under ischemia, all action potential parameters were reduced . GBES0 could alleviate the electrophysiological heterogeneity of ischemic myocardium, which may attenuate myocardial ischemia and block the onset of arrhythmia.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Ginkgo biloba/química , Isquemia Miocárdica/fisiopatologia , Músculos Papilares/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Animais , Modelos Animais de Doenças , Cobaias , Humanos , Masculino , Isquemia Miocárdica/tratamento farmacológico , Músculos Papilares/fisiologia , Músculos Papilares/fisiopatologia , Distribuição AleatóriaRESUMO
We studied effects of hydrolysable tannins on rat papillary muscle contractions induced by propranolol. The developed force of papillary muscle was measured isometrically with an inductive force transducer. The IC(50) values for digallic acid, gallic acid, germin D, praecoxin A and 1-desgalloyl rugosin F were 4.2 x 10(-5) M, 1.3 x 10(-4) M, 1,4 x 10(-4) M, 1.5 x 10(-4) and 1.7 x 10(-4) M, respectively. Incubation with tannins significantly attenuated the propranolol-induced negative inotropic contractile response. These results show that hydrolysable tannins depress muscle contractions and potentiate the activities of ß-adrenergic blocker.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Betulaceae/química , Taninos Hidrolisáveis/farmacologia , Contração Miocárdica/efeitos dos fármacos , Músculos Papilares/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Concentração Inibidora 50 , Contração Isométrica/efeitos dos fármacos , Masculino , Músculos Papilares/fisiologia , Propranolol/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
AIM: Isolated papillary muscles and enzymatically dissociated myocytes of guinea-pig hearts are routinely used for experimental cardiac research. The aim of our study is to investigate adult mammalian ventricular slices as an alternative preparation. METHOD: Vibratome cut ventricular slices (350 microm thick) were examined histologically and with 2-photon microscopy for fibre orientation. Intracellular action potentials were recorded with conventional glass microelectrodes, extracellular potentials were measured with tungsten platinum electrodes and multi-electrode arrays (MEA). RESULTS: Dominant direction of fibre orientation was absent in vertical and horizontal transmural slices, but was longitudinal in tangential slices. Control action potential duration (APD(90), 169.9 +/- 4 ms) and drug effects on this parameter were similar to papillary muscles. The L-type Ca-channel blocker nifedipine shortened APD(90) with a half maximal effective concentration (EC(50)) of 4.5 microM. The I(Kr) blocker E4031 and neuroleptic drug risperidone prolonged APD(90) with EC(50) values of 31 nM and 0.67 microM, respectively. Mapping field potentials on multi-electrode arrays showed uniform spread of excitation with a mean conduction velocity of 0.47 m s(-1). CONCLUSION: Slices from adult mammalian hearts could become a useful routine model for electrophysiological and pharmacological research.
Assuntos
Coração/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Antipsicóticos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo L/metabolismo , Avaliação Pré-Clínica de Medicamentos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Cobaias , Coração/anatomia & histologia , Coração/fisiologia , Humanos , Técnicas In Vitro , Masculino , Microeletrodos , Nifedipino/farmacologia , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Ratos , Ratos Wistar , Risperidona/farmacologiaRESUMO
The inability of heart muscle to generate ventricular pressure to adequately propel blood through the cardiovascular system is a primary defect associated with congestive heart failure (CHF). Force-frequency relationship (FFR) is one of the main cardiac defects associated with congestive heart failure. Thus FFR is a convenient methodological tool for evaluating the severity of muscle contractile dysfunction and the effectiveness of therapeutic agents. Papillary muscle isolated from BIO TO-2 cardiomyopathic Syrian hamsters (CMSHs), show a depressed FFR and represents an animal model of human idiopathic dilated cardiomyopathy. In the present study we investigated the effect of CoQ10, omega-3 fatty acids, propionyl-L-carnitine (PLC) and a combination of these 3 agents (formulation HS12607) on FFR in 8 month old BIO TO-2 CMSHs. Papillary muscles isolated from the anesthetized animals were placed in an incubation bath and attached to an isometric force transducer. A digital computer with an analog/digital interface allowed control of both muscle developed force and electrical stimulus parameters. Force-frequency response was evaluated, at Lmax, with increasing frequencies: 0.06, 0.12, 0.25, 0.5, 1, 2 and 4 Hz. HS12607-treatment produced a positive inotropic effect resulting in a significant enhancement (p < 0.05) of the peak force at the highest frequencies (1-4 Hz). In the range of frequency of 1-4 Hz also CoQ10 and omega-3 significantly (p < 0.05) attenuated the fractional decline in developed force. The significant improvement (p < 0.05) of the timing parameter peak rate of tension rise (+ T') and peak rate of tension fall (-T') indicating a faster rate of muscle contraction and relaxation respectively, found in CoQ10, omega-3 and PLC-treated CMSHs, may be due to the positive effects of these substances on sarcoplasmic reticulum functions. These findings suggest that naturally occurring CoQ10, omega-3 and PLC, particularly when administered together in a coformulation, might be a valid adjuvant to conventional therapy in dilated cardiomyopathy especially when considering that they are natural substances, devoid of side effects.
Assuntos
Carnitina/análogos & derivados , Ácidos Graxos Ômega-3/farmacologia , Contração Miocárdica/efeitos dos fármacos , Músculos Papilares/efeitos dos fármacos , Ubiquinona/análogos & derivados , Animais , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/fisiopatologia , Cardiomiopatia Dilatada/tratamento farmacológico , Cardiomiopatia Dilatada/fisiopatologia , Carnitina/farmacologia , Cricetinae , Masculino , Mesocricetus , Modelos Animais , Contração Miocárdica/fisiologia , Músculos Papilares/fisiologia , Estimulação Química , Ubiquinona/farmacologiaRESUMO
1. Brazilian forests show high diversity of medicinal plants and several are used in folk medicine for the treatment of hypertension and asthma. The aim of the present study was to investigate the effects of a methanol extract (ME) of Cecropia lyratiloba and its flavonoid fraction (FF) on the contractility of cardiac, vascular and tracheal smooth muscles. 2. Twitches of rat papillary muscles were obtained with electrical stimulation and were recorded before and after exposure to increasing concentrations of ME and FF. 3. Cardiac depression was induced by FF. At 500 microg/mL FF, the amplitude of twitches was reduced to 56.7 +/- 5.1% of control values (P < 0.05). 4. The contractile response to a single concentration of adrenaline (10 micromol/L) was measured before and after exposure to ME and FF in rat aorta rings with intact endothelium. Both ME and FF inhibited adrenaline-induced contractions of the aorta in a concentration-dependent manner. Adrenaline-induced contractions were reduced to 46.4 +/- 9.9 and 34.2 +/- 6.9% (P < 0.05) of control in the presence of 500 microg/mL ME and FF, respectively. 5. The flavonoids isolated from FF, namely isoorientin and a mixture of orientin and isovitexin, were also tested in the aorta. These flavonoid do not seem to be responsible for the vasorelaxant effects of ME and FF. 6. No changes were observed in acetylcholine-precontracted trachea when exposed to ME or FF. 7. Endothelium-dependent vasodilation induced by FF is likely to be mediated by the release of nitric oxide because vascular relaxation was abolished in the presence of N(omega)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. 8. In conclusion, vascular relaxation induced by ME and FF could explain the traditional use of the extract of C. lyratiloba for treatment of arterial hypertension.
Assuntos
Cecropia/química , Contração Muscular/efeitos dos fármacos , Músculos Papilares/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Inibidores Enzimáticos/farmacologia , Epinefrina/farmacologia , Flavonoides/farmacologia , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Masculino , Metanol/química , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Contração Miocárdica/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Músculos Papilares/fisiologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Ratos , Ratos Wistar , Traqueia/efeitos dos fármacos , Traqueia/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologiaRESUMO
Cardiac actions of the constituents of Sinomeni Caulis et Rhizome (SCR) and Mokuboi-to, a traditional herbal drug, were investigated. In voltage-clamp experiments, sinomenine (1 mM) and tetrandrine (100 microM) inhibited the ionic currents concentration-dependently. The constituents affected the action potential configurations. In multicellular preparations, SCR (1 mg/ml) decreased the maximum rate of depolarization. Tetrandrine (30 microM) and sinomenine (300 microM) also had similar effects, but magnoflorine (1 mM) had less or no effect. Dysrhythmias were abolished under Ca(2+) overload conditions by sinomenine. These results indicate that at even acute administrations, these drugs exert the active electropharmacological actions and cardioprotections.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Alcaloides/farmacologia , Aporfinas/farmacologia , Benzilisoquinolinas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Coração/efeitos dos fármacos , Morfinanos/farmacologia , Potenciais de Ação/fisiologia , Animais , Medicamentos de Ervas Chinesas/farmacologia , Cobaias , Canais Iônicos/efeitos dos fármacos , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologiaRESUMO
Inhibition of the potassium current I(Kr) and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of DW-286a, a new class of fluoroquinolone antibiotics reported to prolong the QT interval. To investigate the electrophysiological safety of DW-286a, we used conventional microelectrode recording techniques in isolated guinea pig papillary muscles, whole-cell patch clamp techniques in human ether-à-go-go related gene (hERG)-transient transfected Chinese hamster ovary cells, and in vivo electrocardiogram (ECG) measurements in Sprague-Dawley (SD) rats by the use of a telemetry system. DW-286a at 300 microM significantly (P<0.01) prolonged action potentials at 50% repolarization (APD50) and 90% repolarization (APD90). For IHERG, the IC50 value was 89.00+/-37.85 microM with a Hill coefficient (nH) of -0.97+/-0.49. However, when DW-286a was orally administered to conscious SD rats at a high dose (1000 mg/kg), no significant effect on ECG in vivo was detected. From a previous study, we know that concentration at 19.8 microM is the antimicrobial end-point of DW-286a. Therefore, our data suggest that in the electrophysiological aspect, it can be thought that the effective concentrations of DW-286a are between 19.8 and 100 microM (concentration in serum).
Assuntos
Potenciais de Ação/efeitos dos fármacos , Antibacterianos/farmacologia , Eletrofisiologia , Naftiridinas/farmacologia , Canais de Potássio/efeitos dos fármacos , Animais , Antibacterianos/efeitos adversos , Células CHO , Cricetinae , Cricetulus , Cães , Canais de Potássio Éter-A-Go-Go , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Naftiridinas/efeitos adversos , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-DawleyRESUMO
In the present study, rats were treated with sodium selenite (5 micromol/kg body weight/day, ip) for 4 weeks and the parameters of contractile activity, action potential, L-type Ca2+-current (ICaL), as well as transient outward (Ito), inward rectifier (IK1), and steady state (Iss) K+-currents were investigated. Sodium selenite treatment increased rat blood glucose level and lowered plasma insulin level, significantly. This treatment also caused slightly prolongation in action potential with no significant effects on spontaneous contraction parameters and intracellular Ca2+ transients of the heart preparations. These effects were associated with marked alterations in the kinetics of both ICaL and Ito including a significant slowing in both inactivation time constants of ICaL and a significant shift to negative potential at half-inactivation of these channels without any change in the current density. Also, there was a significantly faster inactivation of Ito and no shift in half-inactivation of this channel without any change in its current density. Consequently, there was a approximately 50% increase in total charges carried by Ca2+ current and approximately 50% decrease in total charges carried by K+ currents of the treated rat cardiomyocytes. Additionally we observed a significant inhibition in IK1 density in treated rat cardiomyocytes. Oxidized glutathione level was significantly increased (70%) while the observed decrease in reduced glutathione was much less. Since a shift in redox state of regulatory proteins is related with cell dysfunction, selenium-induced increase in blood glucose and decrease in plasma insulin may correlate these alterations. These alterations, in the kinetics of the channels and in IK1 density, might lead to proarrhythmic effect of chronic selenium supplementation.
Assuntos
Cálcio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Potássio/metabolismo , Selênio/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Canais de Cálcio Tipo L/metabolismo , Células Cultivadas , Condutividade Elétrica , Feminino , Cinética , Masculino , Contração Muscular/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Selenito de Sódio/farmacologiaRESUMO
Drug concentrations that would prolong repolarization parameters by 10%, including action potential duration (APD90, APD30-90), in in vitro assays using guinea-pig papillary muscle and QTc intervals in in vivo assays using conscious dogs, conscious monkeys, and anesthetized dogs were compared. Although, both the in vitro and in vivo assays showed concentration-dependent responses for compounds that have been classified as torsadogenic in humans, only a weak correlation in EC10 values was observed between the in vitro and in vivo assays. Among the in vivo QT assays, the EC10 values obtained from conscious dogs, conscious monkeys, and anesthetized dogs correlated well with each other, but the EC10 values in monkeys were somewhat lower in comparison to those in dogs. When in vivo QT assay EC10 values were compared to the respective human effective therapeutic plasma concentration (ETPC), the ratios of EC10 values to ETPCs were less than 20 for most torsadogenic compounds. In conclusion, the relationships between the extent of QTc interval prolongation and the concentration of drugs was highly consistent among the three in vivo models, suggesting that the ratios of EC10 values in in vivo QT assays are useful for estimating the safety margin of drugs that prolong the QTc interval.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Síndrome do QT Longo/induzido quimicamente , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/induzido quimicamente , Bases de Dados Factuais , Cães , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Eletrocardiografia , Cobaias , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Modelos Animais , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Reprodutibilidade dos Testes , TelemetriaRESUMO
OBJECTIVE: Saline is not an ideal storage solution. It has a low pH, no buffering capacity, and lacks other ions and nutrients. The objective was to explore the effects of storing cardiac muscle in saline. DESIGN: Guinea pig papillary muscles and ventricular myocytes were exposed to saline. The effects on action potential, membrane current, contraction and cell shortening were recorded in vitro at 35-37 degrees C. RESULTS: Saline caused transient hyperpolarization of the resting potential (-140 mV), prolonged duration of the action potential, and increased contraction amplitude, which was later reversed. The membrane resting potential depolarized after a few minutes to about -15 mV and the preparations became unexcitable. The depolarized preparations remained slightly contracted. Upon reperfusion both papillary muscles and cells became unstable and spontaneously active. Storing myocytes in saline for only 2 h resulted in excessive cell death. CONCLUSION: Saline is disastrous for the function of the heart muscle and leads to depolarization, sustained contraction and unexcitable tissue. Saline should not be used as a storage medium, even for short periods of time.
Assuntos
Membrana Celular/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Músculos Papilares/efeitos dos fármacos , Solução Salina Hipertônica/toxicidade , Cloreto de Sódio/toxicidade , Potenciais de Ação/efeitos dos fármacos , Animais , Técnicas Eletrofisiológicas Cardíacas , Cobaias , Contração Muscular/efeitos dos fármacos , Músculos Papilares/fisiologiaRESUMO
SSR149744C (SSR, 2-butyl-3-[4-[3-(dibutylamino)pro-pyl]benzoyl]-1-benzofuran-5-carboxylate isopropyl fumarate), is a new non-iodinated benzofuran derivative. The aim of this study was to evaluate in vivo its electrophysiological, hemodynamic, and anti-adrenergic properties and to determine its mechanism of action using in vitro studies. In chloralose-anesthetized dogs, SSR149744C (1-10 mg/kg i.v.) prolonged the sinus cycle length, A-H interval, Wenckebach cycle length, atrial effective refractory period (ERP), and atrio-ventricular node ERP in a dose-dependent manner without change of ventricular ERP and HV, QRS, or QTc intervals. Arterial blood pressure and ventricular inotropism were slightly decreased. SSR149744C, which has no or low affinity for alpha 1 and beta 1 adrenergic and angiotensin II AT1 receptors, reduced isoproterenol-induced tachycardia and phenylephrine- or angiotensin II-induced hypertension in anaesthetized dogs. In guinea pig papillary muscle, SSR149744C did not modify the resting potential, action potential amplitude and duration, but reduced the dV/dt max of the depolarization phase in a frequency-dependent manner. In isolated guinea pig cardiomyocytes and transfected CHO cells, SSR149744C (0.01-30 microM) inhibited several potassium currents: IKr (IC50 approximately 10 microM), IKs (IC50 approximately 30 microM), IK(ACh) (IC50 = 0.09 microM), and IKv1.5 (IC50 = 2.7 microM), the L-type calcium current: ICa(L) (IC50 approximately 5 microM) and also the amplitude of [Ca2+]i transient and cell shortening. Therefore, SSR149744C appears to have a multifactorial mechanism of action, which combines the blockade of several ion channels with the inhibition of responses of alpha 1 and beta 1 adrenergic as well as AT1 receptor stimulation. Like amiodarone, SSR149744C possesses the pharmacological effects of class I, II, III, and IV antiarrhythmic agents, which may confer upon this new drug a strong antiarrhythmic potential without ventricular proarrhythmia and iodine-related amiodarone-like side-effects.
Assuntos
Antiarrítmicos/química , Antiarrítmicos/farmacocinética , Benzofuranos/química , Benzofuranos/farmacocinética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Antagonistas Adrenérgicos/administração & dosagem , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/farmacocinética , Angiotensina II/administração & dosagem , Angiotensina II/antagonistas & inibidores , Angiotensina II/farmacocinética , Animais , Antiarrítmicos/administração & dosagem , Benzofuranos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/fisiologia , Fenômenos Fisiológicos Celulares/efeitos dos fármacos , Cricetinae , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Cobaias , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Injeções Intravenosas , Isoproterenol/administração & dosagem , Isoproterenol/antagonistas & inibidores , Isoproterenol/farmacocinética , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Músculos Papilares/citologia , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Técnicas de Patch-Clamp/métodos , Veículos Farmacêuticos/administração & dosagem , Veículos Farmacêuticos/farmacocinética , Fenilefrina/administração & dosagem , Fenilefrina/antagonistas & inibidores , Fenilefrina/farmacocinética , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/genética , Canais de Potássio/metabolismo , Transdução de Sinais/efeitos dos fármacos , TransfecçãoRESUMO
We investigated effects of sasanquasaponin (SQS), a traditional Chinese herb's effective component, on ischemia and reperfusion injury in mouse hearts and the possible role of intracellular Cl- homeostasis on SQS's protective effects during ischemia and reperfusion. An in vivo experimental ischemia model was made in mice (weight 27-45 g) using ligation of left anterior descending coronary artery, and in vitro models were made in perfused hearts by stopping flow or in isolated ventricular myocytes by hypoxia. The in vivo results showed that SQS inhibited cardiac arrhythmias during ischemia and reperfusion. Incidence of arrhythmias during ischemia and reperfusion, including ventricular premature beats and ventricular fibrillation, was significantly decreased in the SQS-pretreated group (P<0.05). Results in perfused hearts showed that SQS suppressed the arrhythmias, prevented against ischemia-induced decrease in contract force and promoted the force recovery from reperfusion. Furthermore, intracellular Cl- concentrations ([Cl-]i) were measured using a MQAE fluorescence method in isolated ventricular myocytes in vitro. SQS slightly decreased [Cl-]i in non-hypoxic myocytes and delayed the hypoxia/reoxygenation-induced increase in [Cl-]i during ischemia and reperfusion (P<0.05). Our results showed that SQS protected against ischemia/reperfusion-induced cardiac injury in mouse hearts and that modulation of intracellular Cl- homeostasis by SQS would play a role in its anti-arrhythmia effects during ischemia and reperfusion.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Isquemia/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Saponinas/uso terapêutico , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/complicações , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/prevenção & controle , Pressão Sanguínea/efeitos dos fármacos , Cloretos/metabolismo , Vasos Coronários/lesões , Vasos Coronários/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Frequência Cardíaca/efeitos dos fármacos , Injeções Intravenosas , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Isquemia/complicações , Isquemia/fisiopatologia , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos ICR , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Músculos Papilares/citologia , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Perfusão/métodos , Plantas Medicinais/química , Saponinas/química , Saponinas/isolamento & purificação , Saponinas/farmacologia , Fatores de TempoRESUMO
The aim of this study is to define the possible effects of vegetable oils used as vitamin E vehicle on the electrical activity of the rat heart. To test the possible effects of vitamin E vehicles we studied the effect of i.p. injected corn oil, hazelnut oil or peanut oil on the action potential parameters recorded in both papillary and left atrial muscle strips. Four experimental groups were used. The control group was injected (i.p.) with distilled water, while the three remaining groups received injections of corn oil, hazelnut oil, or peanut oil for five weeks (in a dose of 0.4 ml/kg/day--minimum amount of oil in which vitamin E could be dissolved). We used borosilicated (15-20 megaohms) capillary electrodes and intracellular action potentials (AP) were recorded in isolated papillary and left atrium muscle strips. While administration of three different types of vegetable oil had no significant effect on AP parameters of papillary muscle, they significantly prolonged the repolarization phase of AP in atrial strips. These results show that vegetable oils used as vitamin E vehicles may alter the electrical activity of the heart in a tissue-dependent manner. The present data indicate that the possible effect of vegetable oil vehicles should be kept in mind while evaluating the possible effects of in vivo vitamin E administration.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Coração/fisiologia , Óleos de Plantas/farmacologia , Vitamina E/farmacologia , Potenciais de Ação/fisiologia , Animais , Função Atrial/efeitos dos fármacos , Função Atrial/fisiologia , Óleo de Milho/administração & dosagem , Óleo de Milho/farmacologia , Corylus/química , Eletrofisiologia , Feminino , Coração/efeitos dos fármacos , Injeções Intraperitoneais , Masculino , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Óleo de Amendoim , Veículos Farmacêuticos , Óleos de Plantas/administração & dosagem , Ratos , Ratos Wistar , Vitamina E/administração & dosagemRESUMO
The aim of this study was to assess the cardiovascular effects of a selective phosphodiesterase 5 inhibitor ER-118585, 4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-6-phthalazinecarbonitrile monohydrochloride. The present results indicated that 1) ER-118585 significantly inhibited the human ether-a-go-go related gene (HERG) tail current at 10 nM and above with an IC(50) value of 40.7 nM in human embryonic kidney 293 cells transfected with HERG cDNA; 2) ER-118585 at 100 and 1000 nM significantly increased the action potential duration (APD) at 50% and 90% repolarization in isolated papillary muscles of guinea pig; and 3) intravenous infusion of ER-118585 at 10 microg/kg/min significantly prolonged the QT interval by 10.5+/-1.6% from 281+/-2 ms to 311+/-6 ms in six anesthetized dogs subjected to atrial pacing. In consideration of both the plasma concentration of ER-118585 (984+/-78 nM, n=3) and its protein binding fraction (99.0+/-0.1%, n=5), the free plasma concentration was estimated at 9.8+/-0.8 nM, which is consistent with the minimum concentration of HERG current inhibition. In conclusion, these evaluation methods demonstrated that ER-118585 could prolong the QT interval via APD prolongation, attributable to the inhibition of the HERG potassium current.
Assuntos
Avaliação Pré-Clínica de Medicamentos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/efeitos dos fármacos , Ftalazinas/farmacologia , Compostos de Espiro/farmacologia , 3',5'-GMP Cíclico Fosfodiesterases , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Estimulação Cardíaca Artificial , Doenças Cardiovasculares/tratamento farmacológico , Linhagem Celular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Cães , Relação Dose-Resposta a Droga , Eletrocardiografia , Eletrofisiologia , Cobaias , Humanos , Infusões Intravenosas , Rim/citologia , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/genética , Síndrome do QT Longo/prevenção & controle , Masculino , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Técnicas de Patch-Clamp , Inibidores de Fosfodiesterase/efeitos adversos , Inibidores de Fosfodiesterase/sangue , Diester Fosfórico Hidrolases/metabolismo , Piperidinas/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Ligação Proteica , Piridinas/farmacologia , Transfecção/métodos , Função Ventricular/efeitos dos fármacos , Função Ventricular/genética , Função Ventricular/fisiologia , Complexos Ventriculares Prematuros/tratamento farmacológico , Complexos Ventriculares Prematuros/genética , Complexos Ventriculares Prematuros/prevenção & controleRESUMO
Retinoic acid (RA) plays a role in regulating cardiac geometry and function throughout life. The aim of this study was to analyze the cardiac effects of RA in adult rats. Wistar rats were randomly allocated to a control group (n = 18) receiving standard rat chow and a group treated with RA (n = 14) receiving standard rat chow supplemented with RA for 90 days. All animals were evaluated by echocardiography, isolated papillary muscle function, and morphological studies. Whereas the RA-treated group developed an increase in both left ventricular (LV) mass and LV end-diastolic diameter, the ratio of LV wall thickness to LV end-diastolic diameter remained unchanged when compared with the control group. In the isolated papillary muscle preparation, RA treatment decreased the time to peak developed tension and increased the maximum velocity of isometric relengthening, indicating that systolic and diastolic function was improved. Although RA treatment produced an increase in myocyte cross-sectional area, the myocardial collagen volume fraction was similar to controls. Thus our study demonstrates that small physiological doses of RA induce ventricular remodeling resembling compensated volume-overload hypertrophy in rats.
Assuntos
Ceratolíticos/farmacologia , Tretinoína/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Ecocardiografia , Técnicas In Vitro , Masculino , Células Musculares/fisiologia , Contração Miocárdica/efeitos dos fármacos , Tamanho do Órgão/fisiologia , Músculos Papilares/diagnóstico por imagem , Músculos Papilares/fisiologia , Ratos , Ratos Wistar , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologiaRESUMO
OBJECTIVE: To evaluate the effects of Rbl on action potentials and force of contraction in guinea pig ventricular papillary muscles. METHOD: The ventricular papillary muscles of guinea pig were isolated regularly and immersed with Tyrode, s solution. The effects of Rbl (purified saponins of panaxnotoginseng) on the action potentials (AP), the slow action potentials and the force of contraction (FC) of the muscles were studied. The AP and FC were measured synchronously. RESULT: Rbl shortened the duration of AP, including APD2O and APD90, and reduced the FC(n = 5, P < 0.01), but didn't affect the rest potential (RP), the amplitude of action potential (APA), overshot (OS) and maximal upstrok velocity (Vmax). Rbl also decreased the APA of slow action potential, but quinidine had no such effects. CONCLUSION: Rbl may be a channel blocker.