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Fulltext Multiple targets for flecainide action: implications for cardiac arrhythmogenesis

Salvage SC, Chandrasekharan KH, Jeevaratnam K, Dulhunty AF, Thompson AJ, Jackson AP, et al.

Br J Pharmacol, 2018 Apr;175(8):1260-1278.
PMID: 28369767 DOI: 10.1111/bph.13807

Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca2+ -mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro-arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Nav channel or intracellular ryanodine receptor (RyR2)-Ca2+ channel function. Flecainide accesses its transmembrane Nav 1.5 channel binding site during activated, open, states producing a use-dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak INa related to activation of Nav channels followed by rapid de-activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro-arrhythmic conditions reflecting loss of function of Nav 1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro-arrhythmic effects attributed to prolonged AP recovery by abnormal late INaL following gain-of-function modifications of Nav 1.5 channels in LQTS3 are reduced by flecainide. Anti-arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca2+ release could arise from its primary actions on Nav channels indirectly decreasing [Ca2+ ]i through a reduced [Na+ ]i and/or direct open-state RyR2-Ca2+ channel antagonism. The consequent [Ca2+ ]i alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Nav 1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na+ currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.
LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Matched MeSH terms: Potassium Channels/physiology
Vasorelaxant and chemical fingerprint studies of Citrus reticulatae pericarpium extracts

Tan CS, Loh YC, Ch'ng YS, Ng CH, Yeap ZQ, Ahmad M, et al.

J Ethnopharmacol, 2019 Mar 25;232:135-144.
PMID: 30543913 DOI: 10.1016/j.jep.2018.12.014

ETHNOPHARMACOLOGICAL RELEVANCE: Citrus reticulatae Pericarpium (Chen pi) was widely used as an important ingredient in the prescription of TCM to treat phlegm fluid retention type hypertension. Since Chen pi is involved in treatment as antihypertensive TCM formula, we have reasonable expectation in believing that it might possess vasorelaxant activity.
AIM OF THE STUDY: This study is designed to investigate the vasorelaxant effect of Chen pi and to study its pharmacology effects.
MATERIALS AND METHODS: The vasorelaxant effect of water extract of Chen pi (CRW) were evaluated on thoracic aortic rings isolated from Sprague Dawley rats. The fingerprint of Chen pi and the extracts were developed with quantification of hesperidin content by HPTLC.
RESULTS: CRW exhibited the strongest vasorelaxant activity. CRW caused the relaxation of the phenylephrine pre-contracted aortic rings in the presence and absence of endothelium as well as in potassium chloride pre-contracted endothelium-intact aortic ring. The incubation of propranolol (β-adrenergic receptor blocker), atropine (muscarinic receptor blocker), Nω-nitro-L-arginine methyl ester (NO synthase inhibitor), ODQ (sGC inhibitor), indomethacin (COX inhibitor), 4-aminopyridine (KV blocker), barium chloride (Kir blocker), and glibenclamide (KATP blocker) significantly reduced the vasorelaxant effects of CRW. CRW was also found to be active in reducing Ca2+ releases from the sarcoplasmic reticulum and suppressing the voltage-operated calcium channels.
CONCLUSION: The vasorelaxant effect of CRW on rat aorta involves NO/sGC, calcium and potassium channels, muscarinic and β-adrenergic receptors.

Matched MeSH terms: Potassium Channels/physiology
Underlying mechanism of vasorelaxant effect exerted by 3,5,7,2',4'-pentahydroxyflavone in rats aortic ring

Tew WY, Tan CS, Asmawi MZ, Yam MF

Eur J Pharmacol, 2020 Aug 05;880:173123.
PMID: 32335091 DOI: 10.1016/j.ejphar.2020.173123

Morin (3,5,7,2',4'-pentahydroxyflavone) is a yellow coloured natural flavonoid found in plants of the Moraceae family. This favonoid is easily sources from readily available fruits, vegetables and eve certain beverages. Among the sources that was identified, it is clear that morin is most abundantly found in almond, old fustic, Indian guava, and Osage orange. Multiple studies have suggested that morin has multiple therapeutic actions and possess potential to be a functional potent drug. Previous studies demonstrated that morin is capable of resolving deoxycorticosterone acetate-salt-induced hypertension and possess strong vasorelaxant properties. However, the exact mechanisms remains unknown. Therefore, this study is designed to investigate the in vitro mechanism of morin-induced vasorelaxant effects. The underlying mechanisms of morin's vasorelaxant activities were evaluated on thoracic aortic rings isolated from Sprague-Dawley rats. Results from the study demonstrated morin causing vasodilatory reaction in phenylephrine and potassium chloride pre-contracted endothelium-intact aortic rings with the effect being significantly affected in endothelium-denuded aortic rings. Pre-incubation of the aortic rings with ODQ (selective cGMP-independent sGC inhibitor), indomethacin (nonselective COX inhibitor), L-NAME (endothelial nitric oxide inhibitor), propranolol (β2-adrenegic receptors blocker), and atropine (muscarinic receptors blocker) significantly reduced the vasorelaxant effect of morin. It was also found to be able to reduce the intracellular calcium level by blocking VOCC and calcium intake from the extracellular environment and the intracellular release of calcium from the sarcoplasmic reticulum. The present study showed that the vasorelaxant effect of morin potentially involves the NO/sGC, muscarinic receptors, β2-adrenegic receptors, and calcium channels.

Matched MeSH terms: Potassium Channels/physiology
Fulltext Possible participation of nitric oxide/cyclic guanosine monophosphate/protein kinase C/ATP-sensitive K(+) channels pathway in the systemic antinociception of flavokawin B

Mohamad AS, Akhtar MN, Khalivulla SI, Perimal EK, Khalid MH, Ong HM, et al.

Basic Clin Pharmacol Toxicol, 2011 Jun;108(6):400-5.
PMID: 21214864 DOI: 10.1111/j.1742-7843.2010.00670.x

The possible mechanisms of action in the antinociceptive activity induced by systemic administration (intraperitoneal, i.p.) of flavokawin B (FKB) were analysed using chemical models of nociception in mice. It was demonstrated that i.p. administration of FKB to the mice at 0.3, 1.0, 3.0 and 10 mg/kg produced significant dose-related reduction in the number of abdominal constrictions. The antinociception induced by FKB in the acetic acid test was significantly attenuated by i.p. pre-treatment of mice with L-arginine, the substrate for nitric oxide synthase or glibenclamide, the ATP-sensitive K(+) channel inhibitor, but was enhanced by methylene blue, the non-specific guanylyl cyclase inhibitor. FKB also produced dose-dependent inhibition of licking response caused by intraplantar injection of phorbol 12-myristate 13-acetate, a protein kinase C activator (PKC). Together, these data indicate that the NO/cyclic guanosine monophosphate/PKC/ATP-sensitive K(+) channel pathway possibly participated in the antinociceptive action induced by FKB.

Matched MeSH terms: Potassium Channels/physiology*