Electrophysiological Effects of Carvedilol on Rabbit Heart Pacemaker Cells

Abstract

SUMMARYThe electrophysiological effects of carvedilol, a β-blocking agent with vasodilating actions, have been studied on rabbit pacemaker cells using the whole-cell patch clamp technique. Nystatin-perforated patch recordings from the sinoatrial (SA) and atrioventricular (AV) nodes demonstrated that 1-3 µM of carvedilol caused a decrease in the spontaneous firing frequency, depolarization of the maximal diastolic potential, and prolongation of the action potential duration in both species. Voltage clamp experiments were performed using SA and AV node myocytes to identify and define the carvedilolinduced changes in the Ca 2+ current, I Ca , delayed rectifier K + current, I K , and hyperpolarization-activated inward current, I f . In the SA node cells, 1 µM of carvedilol blocked I K , I Ca , and I f by 72%, 47%, and 22%, respectively. In the AV node cells, the corresponding reductions were 64% (I K ) and 46% (I Ca ), respectively. In both the SA and AV nodes the decrease in I K appeared to be mainly due to the rapidly activating component of the delayed rectifier, I Kr , since the high dose of carvedilol blocked I K in the SA and AV nodes to a submaximal degree. In conclusion, effective doses of carvedilol have classical class III antiarrhythmic actions and a negative chronotropic effect resulting from the inhibition of I K and I Ca . Both actions may be efficacious for treating supraventricular tachyarrhythmias. (Int Heart J 2007; 48: 347-358)

Modulation of K2P2.1 and K2P10.1 K+ channel sensitivity to carvedilol by alternative mRNA translation initiation

“…Compared with K 2P 2.1 (IC 50 = 1.6 μM) and K 2P 10.1 channels (IC 50 = 7.6 μM), higher sensitivity implying greater clinical effect was demonstrated for the K 2P 3.1 channels (IC 50 = 0.8 μM; Staudacher et al ., ). The overall antiarrhythmic efficacy of the drug is likely to result primarily from its anti‐adrenergic properties, supported by multichannel blocking effects on potassium currents ( I Kr , I Ks , I to , I Kur , I TASK1 , I TREK1 , I TREK2 , I K,ATP ), pacemaker current ( I f ), L‐type calcium current and the cardiac ryanodine receptor with different affinities (Cheng et al ., ; Kawakami et al ., ; Kikuta et al ., ; Deng et al ., ; Yokoyama et al ., ; Staudacher et al ., ; Zhou et al ., ).…”

Cardiac potassium inward rectifier Kir2: Review of structure, regulation, pharmacology, and arrhythmogenesis

“…89 , 90 In addition to its effects on adrenoreceptors, it acts as a multichannel blocker that can inhibit I kr , I ks , I to , K atp , I ca-L , I ca-T , and I Na with variable potency. 91 – 94 Studies in HEK293 cells demonstrated that carvedilol inhibits K ATP and K ACh channels, with no direct effect on I K1 . 95 The high lipophilicity and alpha-hydroxyl secondary amine functional group of carvedilol may insert into the membrane and interfere with PIP 2 -channel interaction and thereby may inhibit Kir2 channels.…”

Inhibition of hyperpolarization‐activated cyclic nucleotide‐gated channels by β‐blocker carvedilol

“…In addition, carvedilol also inhibited HCN1 and HCN2 currents. The effect of carvedilol on I f in the rabbit sinoatrial node was investigated previously, and an inhibition of I f was noted at μM concentrations of carvedilol (Yokoyama et al ., ), but the characteristics and biophysical mechanism of action were not studied there. We analysed the biophysical mechanism of the HCN inhibition induced by carvedilol in detail in our study.…”