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1.
J Bone Joint Surg Am ; 103(21): 1986-1995, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34547011

RESUMO

BACKGROUND: In 2010, 2 authors of this current study reported the results of Ponseti treatment compared with primary posteromedial release (PMR) for congenital talipes equinovarus in a cohort of 51 prospective patients. This current study shows outcomes recorded at a median of 15 years after the original treatment. METHODS: Patient health records were available for all 51 patients at a median of 15 years (range, 13 to 17 years) following treatment of congenital talipes equinovarus with either the Ponseti method (25 patients [38 feet]) or PMR (26 patients [42 feet]). Thirty-eight of 51 patients could be contacted, and 33 patients (65%) participated in the clinical review, comprising patient-reported outcomes, clinical examination, 3-dimensional gait analysis, and plantar pressures. RESULTS: Sixteen (42%) of 38 Ponseti-treated feet and 20 (48%) of 42 PMR-treated feet had undergone a further surgical procedure. The PMR-treated feet were more likely to undergo osteotomies and intra-articular surgical procedures (15 feet) than the Ponseti-treated feet (5 feet) (p < 0.05). Of the 33 patients reviewed with multimodal assessment, the Ponseti group, compared with the PMR group, demonstrated better Dimeglio scores (5.8 compared with 7.0 points; p < 0.05), Disease Specific Instrument (80.7 compared with 65.6 points; p < 0.05), Functional Disability Inventory (1.1 compared with 5.1; p < 0.05), and American Academy of Orthopaedic Surgeons (AAOS) Foot and Ankle Outcomes Questionnaire scores (52.2 compared with 46.6 points; p < 0.05), as well as improved total sagittal ankle range of motion in gait and ankle plantar flexion range at toe-off. The PMR group with clinical hindfoot varus displayed higher pressures in the lateral midfoot and the forefoot. CONCLUSIONS: Although the numbers of repeat surgical interventions following Ponseti treatment and primary PMR were similar, the PMR-treated feet had greater numbers of osteotomies and intra-articular surgical procedures. Functional outcomes were improved at a median of 15 years for feet treated with the Ponseti method compared with feet treated with PMR, with advantages seen in the Ponseti group over several domains. This study provides the most comprehensive evaluation of outcomes close to skeletal maturity in prospective cohorts, reinforcing the Ponseti method as the initial treatment of choice for idiopathic clubfeet. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.


Assuntos
Articulação do Tornozelo/cirurgia , Moldes Cirúrgicos/estatística & dados numéricos , Pé Torto Equinovaro/terapia , Procedimentos Ortopédicos/estatística & dados numéricos , Articulação do Tornozelo/fisiopatologia , Criança , Pré-Escolar , Pé Torto Equinovaro/fisiopatologia , Feminino , Seguimentos , Marcha/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Procedimentos Ortopédicos/métodos , Estudos Prospectivos , Amplitude de Movimento Articular , Reoperação/estatística & dados numéricos , Resultado do Tratamento
2.
Health Sci Rep ; 1(5): e36, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-30623071

RESUMO

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is associated with significant morbidity and mortality. We aimed to describe AIT and its clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: We performed a retrospective chart review at a heart failure center in Winnipeg, Canada. We screened 1059 consecutive patients seen over a 12-month period (August 2011 to July 2012) for AIT in patients with HFrEF. Using descriptive and Cox proportional hazard analyses, we explored the association between AIT and mortality. RESULTS: A total of 110 patients with HFrEF who were exposed to amiodarone were included in the analysis. Of these, 13 (11.8%) were diagnosed with AIT. All AIT patients in our cohort were male. Amiodarone was discontinued in nearly half (46.2%) of patients with AIT. All patients were treated with antithyroid medications, and 5 patients (38.5%) also received prednisone. Euthyroidism was achieved in 2 patients (15.4%), hypothyroidism occurred in 6 patients (46.2%), and 5 patients remained thyrotoxic until death or time of chart review (38.5%). CONCLUSION: Thyrotoxicosis is common in patients with HFrEF on amiodarone and is challenging to treat. Due to the sample size, while no association was found in mortality for patients with HFrEF with AIT, a real association could have been missed.

3.
Pharmacol Ther ; 154: 13-20, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26116810

RESUMO

Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery that occurs in up to 60% of patients. POAF is associated with increased risk of cardiovascular mortality, stroke and other arrhythmias that can impact on early and long term clinical outcomes and health economics. Many factors such as disease-induced cardiac remodelling, operative trauma, changes in atrial pressure and chemical stimulation and reflex sympathetic/parasympathetic activation have been implicated in the development of POAF. There is mounting evidence to support a major role for inflammation and oxidative stress in the pathogenesis of POAF. Both are consequences of using cardiopulmonary bypass and reperfusion following ischaemic cardioplegic arrest. Subsequently, several anti-inflammatory and antioxidant drugs have been tested in an attempt to reduce the incidence of POAF. However, prevention remains suboptimal and thus far none of the tested drugs has provided sufficient efficacy to be widely introduced in clinical practice. A better understanding of the cellular and molecular mechanisms responsible for the onset and persistence of POAF is needed to develop more effective prediction and interventions.


Assuntos
Fibrilação Atrial/fisiopatologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Inflamação/metabolismo , Estresse Oxidativo/fisiologia , Complicações Pós-Operatórias/fisiopatologia , Corticosteroides/administração & dosagem , Ácido Ascórbico/administração & dosagem , Fibrilação Atrial/prevenção & controle , Colchicina/administração & dosagem , Ácidos Graxos Ômega-3/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Mediadores da Inflamação/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Complicações Pós-Operatórias/prevenção & controle , Espécies Reativas de Oxigênio , Fatores de Risco , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Vitamina E/administração & dosagem
4.
J Shoulder Elbow Surg ; 24(6): 928-33, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25861852

RESUMO

BACKGROUND: The purpose of this study was to report the outcome of a large cohort of patients undergoing distal biceps tendon repair. We compared the endobutton and transosseous suture repair techniques, both performed through a 2-incision approach. METHOD: At an average of 2.1 years after a distal biceps repair, 46 male patients (19 endobutton and 27 transosseous suture) were reviewed. The mean age of our patients was 50 years. RESULTS: Forty-three patients (93%) were satisfied with the results of their distal biceps tendon repair. The average pain score was 1.3 of 10 at a mean 2.1 years after repair. More than 80% of patients had regained their premorbid function in both recreational and occupational activities. The mean Mayo Elbow Performance Score was 93 of 100. Biodex strength testing demonstrated restoration of 92% of low-velocity supination power, 102% of high-velocity supination power, and 104% endurance compared with the contralateral limb. There was no statistically significant difference in postoperative strength between the transosseous suture and endobutton groups. There were 3 complications in this series, 1 case of heterotopic ossification and 2 cases of injury to the lateral cutaneous nerve of the forearm. CONCLUSION: In this large cohort of 2-incision distal biceps repairs, we found a high degree of patient satisfaction and a low complication rate. We did not find any difference in clinical outcome with regard to subjective patient rating, pain, range of motion, or supination strength when comparing the 2-incision endobutton and transosseous suture fixation techniques.


Assuntos
Músculo Esquelético/lesões , Técnicas de Sutura , Traumatismos dos Tendões/cirurgia , Adulto , Idoso , Articulação do Cotovelo , Feminino , Antebraço , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Satisfação do Paciente , Amplitude de Movimento Articular , Ruptura/cirurgia , Supinação , Técnicas de Sutura/efeitos adversos
5.
J Physiol ; 591(17): 4141-7, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23652596

RESUMO

The transverse (t-) tubules of mammalian ventricular myocytes are invaginations of the surface membrane. The function of many of the key proteins involved in excitation-contraction coupling is located predominantly at the t-tubules, which thus form a Ca(2+)-handling micro-environment that is central to the normal rapid activation and relaxation of the ventricular myocyte. Although cellular arrhythmogenesis shares many ion flux pathways with normal excitation-contraction coupling, the role of the t-tubules in such arrhythmogenesis has not previously been considered. In this brief review we consider how the location and co-location of proteins at the t-tubules may contribute to the generation of arrhythmogenic delayed and early afterdepolarisations, and how the loss of t-tubules that occurs during heart failure may alter the generation of such arrhythmias, as well as contributing to other types of arrhythmia as a result of changes of electrical heterogeneity within the whole heart.


Assuntos
Arritmias Cardíacas/metabolismo , Sinalização do Cálcio , Acoplamento Excitação-Contração , Ventrículos do Coração/metabolismo , Miócitos Cardíacos/metabolismo , Sarcolema/metabolismo , Animais , Arritmias Cardíacas/etiologia , Ventrículos do Coração/citologia , Humanos , Miócitos Cardíacos/fisiologia
6.
J Theor Biol ; 310: 231-8, 2012 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-22789620

RESUMO

Understanding the persistence and growth of natural populations in environments subject to random localised change is relevant both to the conservation of threatened species and to the control of invasive species. By developing and analysing simple strategic growth models in environments subject to random fragmentation events, we show that simple approximations can be used to predict invasion speeds and extinction probabilities. The rate and size of fragmentation events interact in a nonlinear way, a finding with important consequences for the efficient control of invasive species. Infrequent, large-scale fragmentation events provide more effective means of control than more frequent, smaller scale efforts.


Assuntos
Conservação dos Recursos Naturais , Ecossistema , Espécies Introduzidas , Modelos Biológicos , Animais , Simulação por Computador , Dinâmica Populacional , Processos Estocásticos , Fatores de Tempo
7.
J Physiol Pharmacol ; 61(5): 543-50, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21081797

RESUMO

(-)-Menthol and icilin are agonists of the thermoreceptor non-selective cation channel, TRPM8, and are commonly used to investigate TRPM8 function without a full appreciation of their non-specific effects. To investigate the hypothesis that (-)-menthol and icilin inhibit cardiovascular-type L-type Ca(2+) channel currents (I(Ca,L)), the actions of the TRPM8 agonists on rabbit ventricular myocyte I(Ca,L) were examined at near-physiological temperature (≈35°C) using whole-cell recording. Icilin (3-100 µM) did not significantly inhibit I(Ca,L). (3) in contrast, (-)-menthol concentration-dependently inhibited peak I(Ca,L) (IC(50)=74.6 µM; log(10)IC(50)(M)=-4.13±0.14). (-)-Menthol blocked the late I(Ca,L) remaining at the end of depolarising pulses with greater efficacy (96.1±2.4% block at 1 mM) than peak I(Ca,L) (68.9±5.7% block at 1 mM, P<0.01), although there was no difference in potency of block of peak and late currents. Block by (-)-menthol showed no voltage-dependence. The actions of (-)-menthol were compared with those of nimodipine. Nimodipine was a more efficacious (97.3±1.5 % block at 30 µM, P<0.01) and potent (IC(50)=0.74 µM; log(10)IC(50)(M)=-6.13±0.08, P<0.0001) blocker of peak I(Ca,L) than (-)-menthol. In contrast to (-)-menthol, nimodipine showed greater potency (IC(50)=0.056 µM; log(10)IC(50)(M)=-7.25±0.17, P<0.0001), but not greater efficacy, in block of late compared with peak I(Ca,L). In summary, these data demonstrate that, at near-physiological temperature, (-) -menthol blocks cardiac I(Ca,L) at concentrations similar to those reportedly effective in TRPM8-agonism. The data suggest that the mechanism of L-type Ca(2+) channel block by (-)-menthol differs from that of nimodipine.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/fisiologia , Mentol/farmacologia , Nimodipina/farmacologia , Pirimidinonas/farmacologia , Canais de Cátion TRPM/agonistas , Animais , Linhagem Celular , Temperatura Baixa , Ventrículos do Coração/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Técnicas de Patch-Clamp , Coelhos
8.
J Physiol Pharmacol ; 59(3): 395-407, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18953086

RESUMO

hERG (human ether-a-go-go-related gene) potassium (K+) channels are expressed in a range of tissue types including neuroblastoma cells and the heart, in which hERG K+ current is important for action potential repolarization. Whilst gender differences in cardiac repolarization and the QT interval of the cardiac electrocardiogram are well-established, comparatively little is known about regulation of hERG channels by sex hormones. In this study, whole-cell patch-clamp recordings were made at 37 degrees C from SH-SY5Y human neuroblastoma cells to investigate modulation of endogenous hERG K+ channel current (I(hERG)) by testosterone. Acutely applied testosterone at a physiologically relevant concentration (10 nM) produced a modest (approximately 13-15 %) increase in I(hERG) amplitude, whilst a high concentration (1 microM) slightly decreased I(hERG). The stimulatory effect of testosterone was inhibited by the androgen receptor antagonist flutamide (10 microM) and the PI-3 kinase inhibitor wortmannin (1 microM). Chronic (24 h) application of testosterone also augmented IhERG via flutamide-sensitive receptor activation, without modulation of the current's voltage-dependence. These results demonstrate for the first time that testosterone can stimulate (hERG) K+ channels via activation of classical androgen receptors and implicate PI-3 kinase in the acute response.


Assuntos
Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Testosterona/farmacologia , Antagonistas de Androgênios/farmacologia , Androstadienos/farmacologia , Transporte Axonal , Linhagem Celular , Estimulação Elétrica , Eletrofisiologia , Inibidores Enzimáticos/farmacologia , Canais de Potássio Éter-A-Go-Go/agonistas , Flutamida/farmacologia , Humanos , Técnicas de Patch-Clamp , Inibidores de Fosfoinositídeo-3 Quinase , Receptores Androgênicos/efeitos dos fármacos , Temperatura , Wortmanina
9.
Br J Pharmacol ; 152(7): 981-3, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17828293

RESUMO

The common cardiac arrhythmia atrial fibrillation (AF) tends to show progression in its severity, which is associated with 'remodelling': structural and electrophysiological changes that facilitate arrhythmia induction and maintenance. In this issue of the BJP, Yeh and colleagues demonstrate for the first time, down-regulation of three types of muscarinic cholinergic receptor (mAChR) coupled K+ currents (IKM2, IKM3 and IKM4) and of M2, M3 and M4 mAChR subtype proteins, in a canine model of atrial tachycardia (AT) induced remodelling. The IKMs and their extent of AT-induced remodelling were similar in left-atrial and pulmonary vein (PV) myocytes, so remodelling of M2-M4 receptor-linked currents appears not to underlie the unique contribution of PVs to AF. Parasympathetic stimulation can increase susceptibility to AF; thus remodelling of M2-M4 receptors and K+ currents could be adaptive in AT. Further work is warranted to determine whether or not remodelling of multiple mAChRs and currents also contributes to human AF.


Assuntos
Fibrilação Atrial/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores Muscarínicos/metabolismo , Animais , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Taquicardia Atrial Ectópica/metabolismo , Taquicardia Atrial Ectópica/fisiopatologia
10.
Br J Pharmacol ; 152(4): 417-9, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17721550

RESUMO

Endothelin-1 (ET-1) is a peptide hormone produced within the myocardium which may modulate myocardial contractility in a paracrine-autocrine fashion. In the majority of species, ET-1 has a direct positive inotropic effect on the myocardium that involves both increased myofilament Ca(2+) sensitivity and increased Ca(2+) transients. Ca(2+) entry through reverse-mode Na(+)-Ca(2+) exchange, involving both indirect effects via elevation of intracellular [Na(+)] and direct activation of the Na(+)-Ca(2+) exchanger, have been suggested to contribute to the increase in Ca(2+) transients. Conversely, mouse cardiomyocytes show an exclusively negative inotropic response to ET-1. Here, Nishimaru and colleagues present novel evidence that the negative inotropic effect of ET-1 in mouse cardiomyocytes involves both a reduction in myofilament Ca(2+) sensitivity and increased Ca(2+) extrusion, via Na(+)-Ca(2+) exchange. Data obtained using the selective Na(+)-Ca(2+) exchange blocker, SEA0400, suggest that a re-assessment of the role of the exchanger in Ca(2+)-handling by mouse cardiomyocytes may be necessary.


Assuntos
Forma Celular/efeitos dos fármacos , Endotelina-1/farmacologia , Compostos de Anilina/farmacologia , Animais , Camundongos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Éteres Fenílicos/farmacologia , Trocador de Sódio e Cálcio/antagonistas & inibidores , Trocador de Sódio e Cálcio/fisiologia
11.
Biochem Pharmacol ; 74(3): 425-37, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17560554

RESUMO

HERG (human ether-à-go-go-related gene) encodes channels responsible for the cardiac rapid delayed rectifier potassium current, I(Kr). This study investigated the effects on HERG channels of doxepin, a tricyclic antidepressant linked to QT interval prolongation and cardiac arrhythmia. Whole-cell patch-clamp recordings were made at 37 degrees C of recombinant HERG channel current (I(HERG)), and of native I(Kr) 'tails' from rabbit ventricular myocytes. Doxepin inhibited I(HERG) with an IC(50) value of 6.5+/-1.4 microM and native I(Kr) with an IC(50) of 4.4+/-0.6 microM. The inhibitory effect on I(HERG) developed rapidly upon membrane depolarization, but with no significant dependence on voltage and with little alteration to the voltage-dependent kinetics of I(HERG). Neither the S631A nor N588K inactivation-attenuating mutations (of residues located in the channel pore and external S5-Pore linker, respectively) significantly reduced the potency of inhibition. The S6 point mutation Y652A increased the IC(50) for I(HERG) blockade by approximately 4.2-fold; the F656A mutant also attenuated doxepin's action at some concentrations. HERG channel blockade is likely to underpin reported cases of QT interval prolongation with doxepin. Notably, this study also establishes doxepin as an effective inhibitor of mutant (N588K) HERG channels responsible for variant 1 of the short QT syndrome.


Assuntos
Antidepressivos Tricíclicos/farmacologia , Doxepina/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Animais , Células Cultivadas , Canal de Potássio ERG1 , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Técnicas de Patch-Clamp , Coelhos
12.
Arterioscler Thromb Vasc Biol ; 26(8): 1768-76, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16763162

RESUMO

OBJECTIVE: Vascular endothelial growth factor (VEGF) exerts many of its effects by stimulating endothelial calcium influx, but little is known about channels mediating VEGF-induced cation entry. The aim of this study was to measure and characterize for the first time the VEGF-activated cation current in human microvascular endothelial cells (HMVECs). METHODS AND RESULTS: Whole-cell patch-clamp recordings were made from HMVECs. During applied voltage ramps, VEGF activated a current that reversed at 0 mV, was sensitive to gadolinium, and required extracellular cations. Noise analysis yielded a single-channel conductance of 27 pS. The current was not dependent on intracellular calcium stores, and was not blocked by inositol triphosphate (IP3) receptor or serine/threonine kinase inhibition but was partially inhibited by flufenamic acid. A similar current was activated by 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeant analog of diacylglycerol (DAG). To determine whether VEGF could activate recombinant ion channels with similar properties, we investigated the effect of VEGF on Chinese hamster ovary cells cotransfected with VEGFR2 and the canonical transient receptor potential (TRPC) channels, TRPC3 or TRPC6. VEGF induced a similar current to that described above in VEGFR2-TRPC3 and VEGFR2-TRPC6 cells but not in cells transfected with either cDNA alone. CONCLUSIONS: VEGF activates a receptor-operated cation current in HMVECs and OAG can activate directly a similar current in these cells. VEGF is also able to activate heterologously expressed TRPC3/6 channels through VEGFR2.


Assuntos
Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/fisiologia , Células Endoteliais/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Células CHO , Cátions/metabolismo , Cricetinae , Cricetulus , Diglicerídeos/farmacologia , Condutividade Elétrica , Humanos , Microcirculação , Técnicas de Patch-Clamp , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Canais de Cátion TRPC/metabolismo , Canal de Cátion TRPC6 , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
13.
Cell Calcium ; 30(5): 351-60, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11733942

RESUMO

The cardiac Na+-Ca2+ exchanger participates in Ca homeostasis, and Na+-Ca2+ exchanger-mediated ionic current (I(NaCa)) also contributes to the regulation of cardiac action potential duration. Moreover, I(NaCa) can contribute to arrhythmogenesis under conditions of cellular Ca overload. Although it has been shown that the peptide hormone endothelin-1 (ET-1) can phosphorylate the cardiac Na+-Ca2+ exchanger via protein kinase C (PKC), little is known about the effect of ET-1 on I(NaCa). In order to examine the effects of ET-1 on I(NaCa), whole-cell patch clamp measurements were made at 378C from guinea-pig isolated ventricular myocytes. With major interfering currents inhibited, I(NaCa) was measured as the current sensitive to nickel (Ni; 10mM) during a descending voltage ramp. ET-1 (10 nM) significantly increased I(NaCa) ( approximately 2-fold at -100 mV). Application of a PKC activator (PMA; 1mM: phorbol 12-myristate 13-acetate), mimicked the effect of ET-1. In contrast, the PKC inhibitor chelerythrine (CLT, 1mM) abolished the stimulatory effect of ET-1. An inactive phorbol ester, 4-alpha-phorbol-12,13-didecanoate (4a-PDD, 1mM) had no effect on I(NaCa). Collectively, these data indicate that ET-1 activated I(NaCa) through a PKC-dependent pathway. In additional experiments, isoprenaline (ISO; which has also been reported to activate I(NaCa) ) was applied. The increase in I(NaCa) density with ISO (1mM) was similar to that induced by ET-1 (10nM). When I(NaCa) was pre-stimulated by ET-1, application of ISO elicited no further increase in current and vice versa. ISO also had no additional effect on I(NaCa) when the cells were pretreated with PMA. Application of CLT did not alter the response of I(NaCa) to ISO. We conclude that ET-1 stimulated ventricular I(NaCa) via a PKC-dependent mechanism under our recording conditions. Concentrations of ET-1 and ISO that stimulated I(NaCa) to similar extents when applied separately were not additive when co-applied. The lack of synergy between the stimulatory effects of ET-1 and ISO may be important in protecting the heart from the potentially deleterious consequences of excessive stimulation of I(NaCa).


Assuntos
Endotelina-1/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Miocárdio/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Alcaloides , Animais , Benzofenantridinas , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Cobaias , Ventrículos do Coração/metabolismo , Técnicas In Vitro , Isoproterenol/farmacologia , Cinética , Masculino , Técnicas de Patch-Clamp , Fenantridinas/farmacologia , Ésteres de Forbol/farmacologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo
14.
Biochem Biophys Res Commun ; 284(4): 1048-55, 2001 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-11409900

RESUMO

It has been suggested that the positive inotropic effect of the vasoactive peptide hormone, endothelin-1 (ET-1), involves inhibition of cardiac K(+) currents. In order to identify the K(+) currents modulated by ET-1, the outward K(+) currents of isolated rat ventricular myocytes were investigated using whole-cell patch-clamp recording techniques. Outward currents were elicited by depolarisation to +40 mV for 200 ms from the holding potential of -60 mV. Currents activated rapidly, reaching a peak (I(pk)) of 1310 +/- 115 pA and subsequently inactivating to an outward current level of 1063 +/- 122 pA at the end of the voltage-pulse (I(late)) (n = 11). ET-1 (20 nM) reduced I(pk) by 247.6 +/- 60.7 pA (n = 11, P < 0.01) and reduced I(late) by 323.2 +/- 43.9 pA (P < 0.001). The effects of ET-1 were abolished in the presence of the nonselective ET receptor antagonist, PD 142893 (10 microM, n = 5). Outward currents were considerably reduced and the effects of ET-1 were not observed when K(+) was replaced with Cs(+) in the experimental solutions; this indicates that ET-1 modulated K(+)-selective currents. A double-pulse protocol was used to investigate the inactivation of the currents. The voltage-dependent inactivation of the currents from potentials positive to -80 mV was fitted by a Boltzmann equation revealing the existence of an inactivating transient outward component (I(to)) and a noninactivating steady-state component (I(ss)). ET-1 markedly inhibited I(ss) by 43.0 +/- 3.8% (P < 0.001, n = 7) and shifted the voltage-dependent inactivation of I(to) by +3.3 +/- 1.2 mV (P < 0.05). Although ET-1 had little effect on the onset of inactivation of the currents elicited from a conditioning potential of -70 mV, the time-independent noninactivating component of the currents was markedly inhibited. In conclusion, the predominant effect of ET-1 was to inhibit a noninactivating steady-state background K(+) current (I(ss)). These results are consistent with the hypothesis that I(ss) inhibition contributes to the inotropic effects of ET-1.


Assuntos
Endotelina-1/farmacologia , Coração/fisiologia , Canais de Potássio/fisiologia , Animais , Células Cultivadas , Coração/efeitos dos fármacos , Ventrículos do Coração , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Miocárdio/citologia , Oligopeptídeos/farmacologia , Técnicas de Patch-Clamp , Potássio/farmacologia , Potássio/fisiologia , Bloqueadores dos Canais de Potássio , Ratos , Ratos Wistar
15.
Clin Chim Acta ; 303(1-2): 133-8, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11163033

RESUMO

There is increasing evidence that extracellular ATP acting on purinoceptors may play an important signalling role in renal epithelial cells, often through alterations in cellular Ca(2+). In this paper effects of extracellular ATP and related purinoceptor agonists and antagonists on [Ca(2+)](i) have been studied in single cells from primary cultures of rat proximal tubule cells. Responses to 1--100 micromol/l ATP were heterogeneous; 55% of cells showed a transient rise in [Ca(2+)](i), 20% of cells showed a transient fall; in 25% there was no response. ATP actions on [Ca(2+)](i) were abolished by pre-treatment with thapsigargin. The P(2) receptor antagonist suramin unexpectedly increased the [Ca(2+)](i) response to ATP; the related antagonist XAMR 0721 did not significantly alter ATP responses. This difference is likely to arise from the inhibition of ATP hydrolysis by suramin. UTP, ADP and the non-hydrolyzable ATP analogue adenosine-5'-O-(3-thio)-triphosphate (ATP gamma S)produced similar increases in [Ca(2+)](i). The magnitude of the [Ca(2+)](i) responses to 100 micromol/l agonist gave an agonist potency order of ATP> or =ADP> or =UTP approximately ATP gamma S. Desensitisation experiments demonstrated the presence of more than one P2Y ATP receptor subtype on a single cell. These results are consistent with the expression of purinoceptors of both P2Y(1) and P2Y(2) subclasses on individual rat proximal tubule cells coupled to inositol trisphosphate-mediated release of intracellular calcium stores.


Assuntos
Trifosfato de Adenosina/metabolismo , Cálcio/metabolismo , Túbulos Renais/metabolismo , Suramina/análogos & derivados , Animais , Células Cultivadas , Espaço Extracelular/metabolismo , Túbulos Renais/citologia , Túbulos Renais/efeitos dos fármacos , Ratos , Suramina/farmacologia
16.
Nephrol Dial Transplant ; 15(6): 791-8, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10831630

RESUMO

BACKGROUND: End-stage renal failure is associated with a low-output cardiomyopathy, left ventricular hypertrophy and increased QTc dispersion. Cardiac dysfunction is prevalent in patients at the beginning of dialysis and is an important predictor of mortality. Ca(2+) influx through voltage-gated L-type Ca(2+) channels plays a key role in the excitation-contraction coupling of cardiac myocytes. The purpose of this study was to examine the effect of subtotal nephrectomy (SNx) in the rat on both cardiac L-type Ca(2+) currents and action potential duration. METHODS: Wistar rats underwent two-stage SNx; control rats (C) underwent bilateral renal decapsulation. Animals were sacrificed after 8 weeks, and ventricular myocytes were isolated. SNx rats showed a 2-fold increase in plasma urea and creatinine compared with C rats. Whole-cell patch clamp techniques were used to examine L-type Ca(2+) channel currents in isolated cardiac myocytes at 37 degrees C. In separate experiments, the epicardial monophasic action potentials of isolated perfused whole hearts from C and SNx rats were recorded. RESULTS: The amplitude and current-voltage relationships of the L-type Ca(2+) current were not significantly different in myocytes from C (n=11) and SNx (n=8) rats. However, the rate of inactivation of the Ca(2+) current was increased by approximately 15-25% (P<0. 05) in myocytes from SNx rats. The action potential duration (APD(33)) at the apex of the left ventricle was approximately 20% shorter (P<0.01) in hearts from SNx rats as compared with controls. CONCLUSIONS: Renal failure is associated with rapid inactivation of cardiac ventricular myocyte L-type Ca(2+) currents, which may reduce Ca(2+) influx and contribute to shortening of the action potential duration.


Assuntos
Canais de Cálcio Tipo L/fisiologia , Coração/fisiopatologia , Falência Renal Crônica/fisiopatologia , Uremia/fisiopatologia , Animais , Células Cultivadas , Coração/fisiologia , Ventrículos do Coração , Masculino , Potenciais da Membrana , Nefrectomia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar
17.
Biochem Biophys Res Commun ; 273(1): 10-6, 2000 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-10873555

RESUMO

External divalent cations are known to play an important role in the function of voltage-gated ion channels. The purpose of this study was to examine the sensitivity of the voltage-gated K(+) currents of human atrial myocytes to external Ca(2+) ions. Myocytes were isolated by collagenase digestion of atrial appendages taken from patients undergoing coronary artery-bypass surgery. Currents were recorded from single isolated myocytes at 37 degrees C using the whole-cell patch-clamp technique. With 0.5 mM external Ca(2+), voltage pulses positive to -20 mV (holding potential = -60 mV) activated outward currents which very rapidly reached a peak (I(peak)) and subsequently inactivated (tau = 7.5 +/- 0.7 msec at +60 mV) to a sustained level, demonstrating the contribution of both rapidly inactivating transient (I(to1)) and non-inactivating sustained (I(so)) outward currents. The I(to1) component of I(peak), but not I(so), showed voltage-dependent inactivation using 100 msec prepulses (V(1/2) = -35.2 +/- 0.5 mV). The K(+) channel blocker, 4-aminopyridine (4-AP, 2 mM), inhibited I(to1) by approximately 76% and reduced I(so) by approximately 33%. Removal of external Ca(2+) had several effects: (i) I(peak) was reduced in a manner consistent with an approximately 13 mV shift to negative voltages in the voltage-dependent inactivation of I(to1). (ii) I(so) was increased over the entire voltage range and this was associated with an increase in a non-inactivating 4-AP-sensitive current. (iii) In 79% cells (11/14), a slowly inactivating component was revealed such that the time-dependent inactivation was described by a double exponential time course (tau(1) = 7.0 +/- 0.7, tau(2) = 90 +/- 21 msec at +60 mV) with no effect on the fast time constant. Removal of external Ca(2+) was associated with an additional component to the voltage-dependent inactivation of I(peak) and I(so) (V(1/2) = -20.5 +/- 1.5 mV). The slowly inactivating component was seen only in the absence of external Ca(2+) ions and was insensitive to 4-AP (2 mM). Experiments with Cs(+)-rich pipette solutions suggested that the Ca(2+)-sensitive currents were carried predominantly by K(+) ions. External Ca(2+) ions are important to voltage-gated K(+) channel function in human atrial myocytes and removal of external Ca(2+) ions affects I(to1) and 4-AP-sensitive I(so) in distinct ways.


Assuntos
Cálcio/farmacologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Canais de Potássio/metabolismo , Potássio/metabolismo , 4-Aminopiridina/farmacologia , Cálcio/antagonistas & inibidores , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Cátions Bivalentes/antagonistas & inibidores , Cátions Bivalentes/metabolismo , Cátions Bivalentes/farmacologia , Células Cultivadas , Césio/farmacologia , Condutividade Elétrica , Átrios do Coração/citologia , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Cinética , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio , Temperatura , Verapamil/farmacologia
19.
Jpn Heart J ; 37(5): 661-71, 1996 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8973379

RESUMO

The chloride conductance that arises from the stimulation of beta-adrenoceptors has been shown to be carried by a cardiac isoform of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels. This brief review will focus first upon the cellular signal transduction system for the activation of this type of Cl- channels and then its regulation by catecholamines, muscarinic agonists, endothelin-1 and angiotensin-II. Both in physiological and pathological conditions, the complex interaction of these agonists modulates the Cl- conductance, which is potentially arrhythmogenic by shortening the action potential duration and inducing the depolarization.


Assuntos
Angiotensina II/fisiologia , Catecolaminas/fisiologia , Canais de Cloreto/fisiologia , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Endotelina-1/fisiologia , Miocárdio/metabolismo , Potenciais de Ação/fisiologia , Adenilil Ciclases/metabolismo , Animais , Sistema Nervoso Autônomo/fisiologia , AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Coração/inervação , Fosforilação , Transdução de Sinais
20.
Nephrol Dial Transplant ; 11(8): 1532-7, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8856206

RESUMO

BACKGROUND: In both ischaemic and nephrotoxic models, renal failure is associated with increased endothelin-1 (ET-1) and cell calcium overload, and ET receptor antagonists are protective. Vascular and tubular actions of endothelins appear to be involved. This study examines the actions of ET-1 on intracellular Ca ([Ca2+]i) in the tubule model cell line MDCK (Madin-Darby canine kidney). METHODS: Single-cell [Ca2+]i was measured using fura-2 and actions of ET-1 were compared with thapsigargin, which empties IP3-sensitive intracellular Ca stores. RESULTS: Mean resting [Ca2+]i was 84 nM (s.e.m. 6, n = 87). 1 microM thapsigargin and 100 nM ET-1 each caused a transient increase in [Ca2+]i by 696 nM (s.e.m. 160, n = 9) and 727 nM (s.e.m. 121, n = 5) respectively. After 1 microM thapsigargin, 100 nM ET-1 had no effect on [Ca2+]i. Oscillations in [Ca2+]i were frequently observed following 100 nM ET-1. In Ca(2+)-free extracellular solution, mean resting [Ca2+]i was reduced by 37 nM (s.e.m. 5, n = 11) and the mean transient increase in [Ca2+]i in response to ET-1 was 419 nM (s.e.m. 97, n = 5). Inhibition of the plasma membrane Ca-ATPase with La3+ halved the rate of [Ca2+]i removal from the cytoplasm following ET-1. The PKC inhibitor, chelerythrine (1 microM), reduced the ET-1 induced increase in [Ca2+]i to 349 nM (s.e.m. 97, n = 5) and also reduced the rate of removal of [Ca2+]i. Ligand binding studies demonstrated ETA receptor expression in MDCK cells sensitive to ET-1. CONCLUSIONS: ET-1 releases Ca2+ from IP3-sensitive stores in MDCK cells as well as stimulating extracellular Ca2+ entry leading to oscillations of [Ca2+]i. Ca2+ responses to ET-1 are potentiated by PKC; the plasma membrane Ca-ATPase contributes to removal of Ca2+ from the cytoplasm.


Assuntos
Cálcio/metabolismo , Endotelina-1/farmacologia , Homeostase/efeitos dos fármacos , Túbulos Renais/metabolismo , Animais , Ligação Competitiva , Linhagem Celular , Citoplasma/metabolismo , Cães , Ativação Enzimática , Corantes Fluorescentes , Fura-2 , Líquido Intracelular/metabolismo , Túbulos Renais/citologia , Concentração Osmolar , Proteína Quinase C/metabolismo , Cloreto de Sódio/farmacologia , Tapsigargina/farmacologia
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