Effects of Pinacidil on Electrophysiological Properties of Epicardial Border Zone of Healing Canine Infarcts

Coromilas, James; Costeas, Constantinos; Deruyter, Bernard; Dillon, Stephen M.; Peters, Nicholas S.; Wit, Andrew L.

doi:10.1161/01.cir.0000016292.14390.16

Cited by 16 publications

(10 citation statements)

References 37 publications

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“…The beneficial effects of nicorandil were abolished after adding glibenclamide, indicating that these effects were achieved via the activation of K ATP channel. Our results were consistent with the findings of Coromilas et al [22], showing that K ATP channels remain functional after infarction and can be activated by K ATP channel agonists.…”

Section: Discussionsupporting

confidence: 93%

“…Our results were consistent with the findings of Coromilas et al . , showing that K ATP channels remain functional after infarction and can be activated by K ATP channel agonists. Nicorandil can modify macrophages from an M1 to an M2 phenotype through a ROCK‐dependent pathway. The result was consistent with recent studies, showing that ROCK signalling can modulate polarization of macrophages .…”

Section: Discussionmentioning

confidence: 99%

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Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats

Lee

Lin

Chang

2017

J Cellular Molecular Medi

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We have demonstrated that ATP‐sensitive potassium (KATP) channel agonists attenuated fibrosis; however, the mechanism remained unclear. Since RhoA has been identified as a mediator of cardiac fibrosis, we sought to determine whether the anti‐fibrotic effects of KATP channel agonists were mediated via regulating macrophage phenotype and fibroblast differentiation by a RhoA/RhoA‐kinase‐dependent pathway. Wistar male rats after induction of myocardial infarction were randomized to either vehicle, nicorandil, an antagonist of KATP channel glibenclamide, an antagonist of ROCK fasudil, or a combination of nicorandil and glibenclamide or fasudil and glibenclamide starting 24 hrs after infarction. There were similar infarct sizes among the infarcted groups. At day 3 after infarction, post‐infarction was associated with increased RhoA/ROCK activation, which can be inhibited by administering nicorandil. Nicorandil significantly increased myocardial IL‐10 levels and the percentage of regulatory M2 macrophages assessed by immunohistochemical staining, Western blot, and RT‐PCR compared with vehicle. An IL‐10 receptor antibody increased myofibroblast infiltration compared with nicorandil alone. At day 28 after infarction, nicorandil was associated with attenuated cardiac fibrosis. These effects of nicorandil were functionally translated in improved echocardiographically derived cardiac performance. Fasudil showed similarly increased expression of M2 macrophages as nicorandil. The beneficial effects of nicorandil on fibroblast differentiation were blocked by adding glibenclamide. However, glibenclamide cannot abolish the attenuated fibrosis of fasudil, implying that RhoA/RhoA‐kinase is a downstream effector of KATP channel activation. Nicorandil polarized macrophages into M2 phenotype by inhibiting RhoA/RhoA‐kinase pathway, which leads to attenuated myofibroblast‐induced cardiac fibrosis after myocardial infarction.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats

Lee

Lin

Chang

2017

J Cellular Molecular Medi

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“…Cardiomyocyte sizes, cardiac fibrosis, and echocardiographically derived LVESD and LVEDD were significantly smaller in either the pinacidil-or nicorandil-treated group than those in the vehicle. Our results were consistent with the findings of Coromilas et al (22), showing that K ATP channels at the border zone remain functional and can be activated by K ATP channel agonists. The involvement of K ATP channels is further supported by the antagonizing action of glibenclamide.…”

Section: Discussionsupporting

confidence: 93%

Effect of ATP-Sensitive Potassium Channel Agonists on Ventricular Remodeling in Healed Rat Infarcts

Lee¹,

Lin²,

Chang³

2008

Journal of the American College of Cardiology

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“…11 After at least 2 sequential beats of the VT had been mapped and the location of the reentrant pathway determined (Figure 1), the location of the line of block that formed during the tachycardia was carefully marked on a transparent electrode grid. The size and location of the central and outer pathways were noted, and the heart was removed.…”

Section: Methodsmentioning

confidence: 99%

Remodeling in Cells From Different Regions of the Reentrant Circuit During Ventricular Tachycardia

et al. 2005

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Background-Anisotropic reentrant excitation occurs in the remodeled substrate of the epicardial border zone (EBZ) of the 5-day infarcted canine heart. Reentry is stabilized because of the formation of functional lines of block. We hypothesized that regional differences of ionic currents in cells of the EBZ form these lines of block. Therefore, we first mapped reentrant circuits of sustained tachycardias, then dispersed cells (infarct zone cells, IZs) from the central common pathway of the circuit (IZc) as well as from the other side of the line of block (outer pathway, IZo) for study. Methods and Results-We mapped reentrant circuits in the EBZ of infarcted hearts during sustained ventricular tachycardias (Ͼ30 seconds, nϭ17 episodes, cycle lengthsϭ218Ϯ7.9 ms). I Na density was reduced in both IZc and IZo, and the kinetic properties of IZc I Na were markedly altered versus IZo. Structural remodeling of the sodium channel protein Na v 1.5 occurred in IZs, with cell surface localization differing from normal cells. Both IZc and IZo have similar but reduced I CaL , whereas IZc showed changes in Ca 2ϩ current kinetics with an acceleration of current decay. Computer simulations of the 2D EBZ showed that incorporating only differences between I Na in IZc and IZo prevented stability of the reentrant circuit. Incorporating only differences between I CaL in the IZc and IZo cells also prevented stability of the circuit. However, incorporating both I Na and I CaL current differences stabilized the simulated reentrant circuit, and lines of block formed between the 2 distinct regions. Conclusions-Despite differences in I Na and I CaL properties in cells of the center and outer pathways of a reentrant circuit, the resulting changes in effective refractory periods tend to stabilize reentry in this remodeled substrate.

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Effects of Pinacidil on Electrophysiological Properties of Epicardial Border Zone of Healing Canine Infarcts

Cited by 16 publications

References 37 publications

Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats

Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats

Effect of ATP-Sensitive Potassium Channel Agonists on Ventricular Remodeling in Healed Rat Infarcts

Remodeling in Cells From Different Regions of the Reentrant Circuit During Ventricular Tachycardia

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