Analysis of antiarrhythmic effect of ryanodine in guinea-pigs

Golovina, Vera A.; Zakharov, Sergey I.; Bogdanov, K. Yu.; Rosenshtraukh, Leonid V.

doi:10.1016/s0022-2828(88)80064-6

Cited by 9 publications

(8 citation statements)

References 23 publications

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“…In addition, ryanodine has demonstrated efficacy in reducing early afterdepolarizations and Torsades de Pointes in a canine model of chronic AV nodal block (Verduyn et al, 1995). Similar to the findings in canines, ryanodine has been shown to reduce ouabain-induced arrhythmias in guinea pigs (Golovina et al, 1988; Zakharov et al, 1991). There is also evidence suggesting that ryanodine may reduce reperfusion-induced arrhythmias (Thandroyen et al, 1988; Hayashi et al, 1996).…”

Section: Therapeutic Strategiessupporting

confidence: 78%

Dysregulated sarcoplasmic reticulum calcium release: Potential pharmacological target in cardiac disease

Györke

Carnes

2008

Pharmacology & Therapeutics

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In the heart, Ca 2+ released from the intracellular Ca 2+ storage site, the sarcoplasmic reticulum (SR), is the principal determinant of cardiac contractility. SR Ca 2+ release is controlled by dedicated molecular machinery, composed of the cardiac ryanodine receptor (RyR2) and a number of accessory proteins, including FKBP12.6, calsequestrin (CASQ2), triadin (TRD) and junctin (JN). Acquired and genetic defects in the components of the release channel complex result in a spectrum of abnormal Ca 2+ release phenotypes ranging from arrhythmogenic spontaneous Ca 2+ releases and Ca 2+ alternans to the uniformly diminished systolic Ca 2+ release characteristic of heart failure. In this article, we will present an overview of the structure and molecular components of the SR and Ca 2+ release machinery and its modulation by different intracellular factors, such as Ca 2+ levels inside the SR as well as phosphorylation and redox modification of RyR2s.We will also discuss the relationships between abnormal SR Ca 2+ release and various cardiac disease phenotypes, including, arrhythmias and heart failure, and consider SR Ca 2+ release as a potential therapeutic target.

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Section: Therapeutic Strategiessupporting

confidence: 78%

Dysregulated sarcoplasmic reticulum calcium release: Potential pharmacological target in cardiac disease

Györke

Carnes

2008

Pharmacology & Therapeutics

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“…Furthermore, KT-362 has been shown to reduce the extent of myocardial injury resulting from 90 min of coronary artery occlusion and 3 hr of reper fusion owing to a decrease in myocardial energy requirements during occlusion as a result of inhibition of intracellular calcium release (25). Recently it has also been re ported that other drugs that suppress the calcium mobilization from intracellular store sites should be effective on ventricular ar rhythmia (26)(27)(28) and cerebral vasospasm (29). Therefore, this type of compound with new mechanisms of action on calcium move ment in vascular smooth muscle and ven tricular muscle may introduce a novel thera peutic approach for cardiac vascular diseases.…”

Section: Discussionmentioning

confidence: 99%

Effects of KT-362, a New Calcium Release Blocker, on Vascular Selectivity and Hemodynamic Actions in Anesthetized Dogs

Wakabayashi

Mochizuki

Tomiyama

et al. 1990

Japanese Journal of Pharmacology

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Abstract-Pharmacologicalproperties of 5-(3-((2-(3,4-dimethoxyphenyl)ethyl)-amino) -1 -oxopropyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate (KT-362), a newly synthesized calcium release blocker, were studied by comparing its vascular selectivity and cardiovascular actions with those of verapamil, a calcium entry blocker. The relaxing effect of KT-362 in rabbit femoral and basilar artery strips contracted with norepinephrine was greater than that in aortic and coronary artery strips. In anesthetized mongrel dogs, KT-362 (0.1-3.0 mg/kg, i.v.) decreased the mean blood pressure, heart rate and total peripheral resistance in a dose-dependent manner, while cardiac output increased slightly despite a decrease in left ventricular pressure. This is consistent with the data on verapamil. Both La. and i.v. injections of KT-362 produced a marked dose-dependent increase in vertebral and femoral blood flow. Pretreatment of atropine, propranolol or diphenhydramine exerted no significant effect on the KT-362-induced vasodilation. Verapamil caused a marked increase in the vertebral and coronary blood flows after the injections, but only a slight increase in femoral blood flow. KT-362 at the dose of 10 mg/kg, i.v., had no significant effect on the PQ interval on the electrocardiogram in anesthetized dogs, but 0.1 mg/kg of verapamil increased this interval significantly. These results suggest that KT-362 has properties similar to calcium entry blockers such as verapamil on systemic hemodynamic actions except for the reactivity of vasculatures.

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“…Ryanodine can prevent the arrhythmias and reduce the positive inotropic effect produced by cardiotonic steroids without affecting their specific binding to sites on Na + –K + ‐ATPase in isolated guinea‐pig cardiac muscle, which suggest that the antagonism is mediated by ryanodine‐induced alterations in Ca 2+ release from the sarcoplasmic reticulum (Kafiluddi, Kennedy & Seifen, 1986). Ouabain significantly increased the delayed the afterpotentials, aftercontractions, and the amplitude of spontaneous oscillations of the membrane potential and of resting tension of guinea‐pig papillary muscle (Golovina, Zakharov, Bogdanov & Rosenshtraukh, 1988). Addition of ryanodine abolished the effects of ouabain.…”

Section: Calcium Channelsmentioning

confidence: 99%

Cardiotoxicity of digitalis glycosides: roles of autonomic pathways, autacoids and ion channels

Demiryürek

2005

Auton Autocoid Pharmacol

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1 Cardiac glycosides have been used for centuries as therapeutic agents for the treatment of heart diseases. In patients with heart failure, digoxin and the other glycosides exert their positive inotropic effect by inhibiting Na(+)-K(+)-ATPase, thereby increasing intracellular sodium, which, in turn, inhibits the Na(+)/Ca(2+) exchanger and increases intracellular calcium levels. As the therapeutic index of digitalis is narrow, arrhythmias are common problems in clinical practice. The mechanisms and mediators of these arrhythmias, however, are not completely understood. 2 The involvement of the sympathetic and parasympathetic nervous system in digitalis cardiac toxicity is reviewed. 3 Receptors, channels, exchange systems or other cellular components involved in digitalis-induced cardiotoxicity are also reviewed. 4 Possible mediators of digitalis-induced cardiac toxicity are discussed. 5 Management of digitalis toxicity in patients is summarized. 6 The determination of the possible mediators of digitalis-induced cardiac toxicity will enhance our knowledge and lead to the development of new therapeutic strategies to treat these lethal arrhythmias.

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Analysis of antiarrhythmic effect of ryanodine in guinea-pigs

Cited by 9 publications

References 23 publications

Dysregulated sarcoplasmic reticulum calcium release: Potential pharmacological target in cardiac disease

Dysregulated sarcoplasmic reticulum calcium release: Potential pharmacological target in cardiac disease

Effects of KT-362, a New Calcium Release Blocker, on Vascular Selectivity and Hemodynamic Actions in Anesthetized Dogs

Cardiotoxicity of digitalis glycosides: roles of autonomic pathways, autacoids and ion channels

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