| Objective Carvedilol, a ? -adrenoceptor-blocking agent, has been reported to possess clinical antiarrhymia properties. We studied ion channel and action potential modulation by carvedilol in guinea pig ventricular preparations to fully elucidate its electrophysiological effects.Methods (1) L-type calcium current (Ica-L), delayed rectifier potassium current (IK), inward rectifying current (7K1) and inward fast sodium current (INa) were recorded using whole-cell patch clamp techniques in isolated guinea pig myocytes. The effects of carvedilol on these ionic currents were studied. Dofetilide was used as a specific 1Kr inhibitor to explore the effects of carvedilol on Iks (2) Standard microelectrode techniques were used to record transmembrane action potentials in papillary muscles. The resting potential (RP), action potential amplitude (APA), maximal depolarization rate (Vmax) and action potential duration (APD) were compared before and after adminstration of carvedilol.Results (1)Carvedilol 0.5?mol/L had no significant effect on Ica-L (-6.68?.15pA/pF vs. -6.61 ?.55pA/pF)( n=7, P>0.05). But 2?mol/Lcarvedilol decreased ICa-L to -4.06 ? 0.99pA/pF(P<0.01). And ICa-L was decreased from -7.28 ? 2.21pA/pF to -4.09 ? 1.76pA/pF, -2.09 ?2.09pA/pF and -1.62?.91pA/pF (n=6, P al<0.01) by 3.5?mol/L, 5?mol/L and 10?mol/L carvedilol, repectively. The concentration corresponding to a 50% current inhibition (IC50) was 3.18?mol/L. (2) Carvedilol 0.01 and 1.5?mol/L inhibited INa from -102.3 ? 11.2pA/pF to -94.8?12.6 pA/pF and -22.1?9.1 pA/pF (n=5, P alK<0.01). Similarity, 0.05 , 0.3,mol/L carvedilol decreased INafrom -102.3 ? 17.0pA/pF to -71.2 ?1.0 pA/pF and -35.2?15.4 PA/pF(n=6, P all<0.01). Carvedilol inhibited INa most potently with an IC50 of 0.16?mol/L. (3)As to IK1, the maximal amplitude of inward currents amplitude was decreased not significantly from -73.15? 8.25pA/pF in control to -62.21? 18.28pA/pF at 25?mol/L carvedilol (n=5, P>0.05). But its rectifying range was enlarged from (-20-+40) mV to (-20-+80) mV. (4)Accumulative perfusion of carvedilol decreased the amplitude of IK.tail from 4.08?.85pA/pF in control to 3.27?.64pA/pF (0.3?mol/L), 2.37?.41 pA/pF (5?mol/L) and 1.58?.59 pA/pF (n=6, P all <0.01). After IKr was completely blocked by 1?mol/L dofetilide, the amplitude of IKs.tail at +50mV was decreased significantly from 3.15 ? 0.73pA/pF in control to 1.79 ? 0.35 pA/pF at 10?mol/L and 0.82 ? 0.13pA/pF at 50?mol/L of carvedilol (n=5, P all <0.01). In the same manner, the tail of IKs was decreased from 3.53 ? 0.76pA/pF to 2.51?0.54 pA/pF, 1.41?0.31pA/pFand 0.13?.08pA/pF following accumulative administration of 5, 20 and 100?mol/L of carvedilol (n=5, P<0.05 or 0.01). Carvedilol blocked IKs with an IC50 of 12.43?mol/L.(5)APD90 was prolonged from 153 ?4ms to 163 ?22ms and 180 ?26ms with 1?mol/L and 5?mol/L of carvedilol at 1Hz stimulation frequency (n=7, P<0.01), respectively. The prolongation of APD90 was reverse frequency-dependent. Carvedilol 5?mol/L also decreased APA from 119 ? 7mV to 108?10mV ( P<0.01) and Vmax from 300 ? 23V/S to 238 ? 38V/S (P<0.01). RP and APD30 were not significantly influenced by carvedilol.Conclusions We conclude that carvedilol possesses a property of blocking INa and IKr at a relatively low concentration. Ica-L and IKs were also inhibited by carvedilol at high concentrations. It prolongs APD90 in a reverse frequency-dependent manner and decreases Vmax and APA in standard action potential investigation. These properties would be beneficial in the treatment of cardiac tachyarrhythmias.
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