Anticholinergic action of quinidine sulfate in the rabbit atrioventricular node

Nishimura, Masao; Huan, Rong-Ming; Habuchi, Yoshizumi; Homma, Nobuo; Watanabe, Yoshio

doi:10.1007/bf00171731

Cited by 6 publications

(3 citation statements)

References 21 publications

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“…Similar conclusions had previously been reached in explaining the K + channel blocking action of class I drugs such as quinidine and aprindine on the atrioventricular node [22,27] and E-4031 on the sinoatrial node [9]. The former is characteristic of all class III antiarrhythmic agents, although both may well be dependent on the same mechanism of IK block.…”

Section: Discussionsupporting

confidence: 75%

Selective block of delayed rectifying potassium current in the rabbit sinoatrial node by a novel class III antiarrhythmic agent MS-551

et al. 1994

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Electrophysiological actions of MS-551, a novel class III antiarrhythmic agent, were studied using small preparations (0.2 × 0.2 x 0.1 mm) of the rabbit sinoatrial (SA) rode. MS-551 (0.1-3gM) exerted a negative chronotropic action by prolonging the action potential duration and diastolic interval. Automaticity was completely suppressed in 5 of 6 preparations at 1-31,tM. Voltage clamp experiments using double microelectrode techniques revealed that MS-551 (0.1-10 gM) blocked the delayed rectifying K + current (IK) in a concentration-dependent manner, and the block was almost saturated at >1 gM, attaining 60% _+ 10% at 10 gM (n = 5). The MS-551-sensitive IK tail (Kd = 0.4gM, Hill r = 1.4, n = 5) had fast and slow components of deactivation. MS-551 (1 gM) reduced the amplitudes of control IK fast and IK slow from 20 ___ 4 and 11 _+ 4 nA to 8 ___ 3 and 5 + 3 nA, respectively (P < 0.01, n = 4). Although the fast deactivation time constant at -6 0 mV remained unaltered (127 _+ 12 vs 113 ___ 13 ms), the slow deactivation time constant was prolonged from 1,117 _+ 130 to 1,555 + 407ms by l g M MS-551 (P < 0.05). This agent shifted the steady-state activation curve for IK from --21 _+ 2 to --26 + 4mV and increased the slope factor from 8 _+ 1 to 9 + 1 mV (P < 0.05, n = 4). The fully-activated IK exhibited prominent inward rectification and was reduced by MS-551. These results suggest that (1) MS-551 prolongs the action potential duration and diastolic interval, and exerts a negative chronotropic action by blocking IK, (2) MS-551 has a higher affinity for the activated than the resting state K + channel, and (3) this agent may either preferentially block one type of IK, or stabilize a single population of IK in a subconductance state in the rabbit SA node.

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Section: Discussionsupporting

confidence: 75%

Selective block of delayed rectifying potassium current in the rabbit sinoatrial node by a novel class III antiarrhythmic agent MS-551

et al. 1994

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“…Quinidine may likewise at tenuate the release of ACh by inhibition of the sodium channel in presynaptic nerve terminals. In addition, quini dine has an anti-muscarinic effect at the receptor binding site (25,26). The quinidine-induced suppression of the aconitine-induced tachyarrhythmia may involve the diverse effects of this compound on muscarinic signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Positive Chronotropic and Inotropic Effects of Higenamine and Its Enhancing Action on the Aconitine-Induced Tachyarrhythmia in Isolated Murine Atria

Kimura

Makino

Takamura

et al. 1994

Japanese Journal of Pharmacology

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Aconitine and higenamine are the components of aconite root. We investigated the cardiac effects of these compounds on murine right and left atria and the interaction of higenamine with aconitine on the rate of spontaneously beating right atria. Higenamine increased the rate (EC50=38 nM) and the force of contraction (EC50=97 nM), the maximal responses being comparable with those of isoproterenol. The positive chronotropic effect of higenamine was antagonized by propranolol (30-300 nM) and practolol (10 nM 3 tM), but not by butoxamine (1 ,uM), indicating that it was a j3,-adrenoceptor-mediated action. The positive chronotropic effect of higenamine was not changed by pretreatment with reserpine (4 mg/kg, i.p., 4 hr). Aconitine (0.16 0.25 pM) induced tachyarrhythmia in right atria was attenuated by quinidine (1 pM), atropine (8.6 pM) and AF-DX 116 (8.6 pM), suggesting that aconitine activates sodium channels and muscarinic receptors. Higenamine (2.5 nM) and dobutamine (1 nM) did not cause chronotropic effects by themselves, but enhanced the aconitine-induced tachyarrhythmia. These results indicate that higenamine is a ~1-adrenoceptor full agonist in murine atria and that the aconitine-induced tachyarrhythmia is augmented by the ,31-adrenergic action of higenamine.Keywords: Tachyarrhythmia (aconitine-induced), Higenamine, Chronotropic effect, Inotropic effect, Murine atria Aconite, a Sino-Japanese medicine, possesses a wide range of pharmacological actions (1). Aconitine, a main active component of aconite (1-4), induces cardiac ar rhythmia (5, 6) and has been used as an animal model of arrhythmia (7). The arrhythmogenic effect of aconitine results from direct activation of Na+ channels (8, 9). A cardiotonic compound, higenamine [(±)-demethylcoclau rine], was identified from a non-alkaloid fraction of aconite (10). Higenamine elicits a positive inotropic effect by activation of 13-adrenoceptors and subsequent increase in Ca" influx (11,12). We found in mice that aconitine (30 pg/kg, i.p.) produces a decrease in heart rate to 50010 of the basal level within 20 min after administration, and this effect of aconitine is mediated by activation of muscarinic receptors in the central nervous system (13). Interestingly, higenamine (10 pg/kg, i.p.) inhibited the bradycardia induced by aconitine in mice in vivo (13). The present experiments were carried out first to analyze the pharmacological characteristics of the cardiac effects of higenamine and aconitine and second, to further eluci date the mechanism of interaction between aconitine and higenamine in isolated murine atria. MATERIALS AND METHODS AnimalsMale ddY mice weighing 32-42 g (7 to 9-week-old) were used. Preparation of isolated murine atriaMice were sacrificed by decapitation and exsanguina tion. The thorax was opened, and the heart was rapidly re moved and placed in Krebs-Henseleit solution. The solu tion was composed of 118.4 mM NaCI, 4.69 mM KCI, 2.0 mM CaC12, 1.16 mM MgC12, 12.4 mM NaHCO3 and 5.0 mM glucose and gassed with 95076 02-507o C02 at 301C. R...

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“…38 Quinidine depresses atrioventricular nodal conduction, 39 and in the recipients of denervated cardiac transplants, the drug often causes prolongation of the A-H interval. 40 In patients with normally innervated hearts, however, vagolytic effects tend to predominate and may facilitate atrioventricular nodal conduction.…”

Section: Integrated Effectsmentioning

confidence: 99%