Electrophysiological effects of Ro 22–9194, a new antiarrhythmic agent, on guinea‐pig ventricular cells

Maruyama, Kazuyasu; Kodama, Itsuo; Anno, Takafumi; Suzuki, Ryouko; Toyama, Junji

doi:10.1111/j.1476-5381.1995.tb14900.x

Cited by 13 publications

(7 citation statements)

References 23 publications

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“…In these experiments, Ro 22-9194 prolonged HV intervals more than AH intervals. This result supports previous work with guinea pig ventricular myocytes showing that the relative potency of Ro 22-9194 for inhibition of calcium channels is considerably less than that for inhibition of sodium channels (12).…”

supporting

confidence: 91%

“…1) (16). Ro 22-9194, but not mexiletine and disopyramide (-1 X 10K3 M), inhibited TXA, synthase activity and arachidonic acid-induced aggregation of human platelets at concentrations comparable to those that inhibited sodium channels in guinea pig ventricular myocytes (12). The IC,, values of Ro In anesthetized dogs, coronary reperfusion following a 30-min coronary ligation induced VF in 8 of 11 animals, and venous thromboxane B, (TXB,, a major breakdown product of TXA,) concentrations in the local coronary vein were markedly increased during coronary ligation.…”

Section: Inhibitory Effects Of Ro 22-9194 On Thromboxane a Synthasementioning

confidence: 90%

“…Maruyama et af. (12,13) investigated the electrophysiological effects of Ro 22-9194 in papillary muscles and single ventricular myocytes isolated from guinea pig hearts. In papillary muscles stimulated at 1.0 Hz, Ro 22-9194 (3 X 10-6-1 X M) decreased the maximum upstroke velocity (Vma) and the action potential duration (APD) in a concentration-dependent manner.…”

Section: Electrophysiological Effects Of Ro 22-9194 On Guinea Pig Venmentioning

confidence: 99%

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Ro 22‐9194: A New Class I Antiarrhythmic Agent

Murakami¹,

Furukawa²,

Nakashima³

et al. 1996

Cardiovascular Drug Reviews

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Key Words: Arrhythmia models--Cardiac responses-Fast sodium channels-Ro 22-919" Thromboxane A, synthase.Many antiarrhythmic agents are currently available, but more potent and safer drugs are needed. Most antiarrhythmic agents, especially Class I drugs, are far from ideal for treating ventricular fibrillation (VF) or preventing sudden cardiac death. These drugs also depress the activity of the cardiovascular system and may exhibit proarrhythmic actions.Class I drugs exhibit onset and offset kinetics, block sodium channels in a state-dependent manner (9,11), are potent in various models of ventricular arrhythmias (8), and affect conduction velocity, sinoatrial nodal automaticity, and myocardial contractility (2,3,20). Ro22-9194, (2R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propionamide D-tartrate, is a newly synthesized Class I antiarrhythmic agent with a thromboxane A, (TXA,) synthase inhibitory activity. Several experimental studies with Ro 22-9 194 have recently been published, and the cardiovascular, electrophysiological, and antiarrhythmic properties of this drug have been revealed (12-17). This article summarizes the preclinical and phase I clinical pharmacology of Ro 22-9194, a new Class I antiarrhythmic agent that inhibits TXA, synthesis. CHEMISTRYRo 22-9194 is structurally related to lidocaine and has a pyridine ring in the side chain (Fig. 1). It has a molecular weight of 461.52. It exists as a white crystalline powder that is soluble in water or methanol and insoluble in ether, and is stable at room temperature.

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supporting

confidence: 91%

Section: Inhibitory Effects Of Ro 22-9194 On Thromboxane a Synthasementioning

confidence: 90%

Section: Electrophysiological Effects Of Ro 22-9194 On Guinea Pig Venmentioning

confidence: 99%

See 1 more Smart Citation

Ro 22‐9194: A New Class I Antiarrhythmic Agent

Murakami¹,

Furukawa²,

Nakashima³

et al. 1996

Cardiovascular Drug Reviews

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“…Ro 22-9194 decreases the Vmax in a rate-and voltage-dependent manner due to the inhibition of the sodium (Na) channel, and is an intermediate kinetic class 1 drug (Maruyama et al, 1995), as the recovery time constant of Ro 22-9194 from the rate-dependent block was reported to be less than 10 s (Campbell, 1983;Kodama et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Tonic block of the Na⁺ current in single atrial and ventricular guineapig myocytes, by a new antiarrhythmic drug, Ro 22‐9194

Hiroe¹,

Hisatome²,

Tanaka³

et al. 1997

Fundamemntal Clinical Pharma

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Ro 22-9194 reduced the Na+ current in the atrial myocytes as well as ventricular myocytes in a tonic block fashion. Ro 22-9194 had a higher affinity to the inactivated state Na+ channels (KdI = 3.3 microM in atrial myocytes, KdI = 10.3 microM in ventricular myocytes) than to those in the rested state (KdR = 91 microM in atrial myocytes, KdR = 180 microM in ventricular myocytes), which indicated that Ro 22-9194 had a higher affinity to the Na+ channels in atrial myocytes than in ventricular myocytes. Ro 22-9194 shifted the inactivation curve in the hyperpolarized direction in both atrial and ventricular myocytes. These findings suggest that Ro 22-9194 more strongly inhibited the Na+ channel of the atrial myocytes of the diseased hearts with the depolarized membranes potentials than the Na+ channels in ventricular myocytes.

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“…We evaluated the approximate extent of sodium channel block by various antiarrhythmic drugs during the activated and the inactivated states. A percentage decrease in V, , , by a 10 ms clamp pulse from the reference level (tonic block subtracted value) was defined as an activated channel block (ACB), whereas an additional percentage decrease in V, , , when the clamp pulse duration was prolonged from 10 to 500 ms was defined as an inactivated channel block (ICB) (14,15,19,20). Block of sodium channel during the slow inactivation can be neglected by this definition, since V, , , of control myocytes was decreased significantly only when the conditioning 0 mV clamp was longer than 500 ms. ACB and ICB by 10 pM SD-3212 were estimated to be 4.9% and 60.1%, respectively, giving rise to their ratio (ICB/ACB) of 12.3.…”

mentioning

confidence: 99%