Ying Cao1, Shujun Chen1, Yemei Liang1, Ting Wu1, Jianxin Pang1, Shuwen Liu1,2, Pingzheng Zhou1. 1. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. 2. State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Southern Medical University, Guangzhou, China.
Abstract
BACKGROUND AND PURPOSE: Carvedilol is a clinically effective β-blocker broadly used for treating congestive heart failure (CHF), and several clinical trials have demonstrated that it shows a favourable effect compared with other β-blockers in patients with CHF. The mechanism underlying this beneficial effect of carvedilol compared to other β-blockers is not clearly understood. In addition to β-blockers, inhibitors of hyperpolarization-activated cyclic nucleotide (HCN)-gated channels, which play a critical role in spontaneous rhythmic activity in the heart, have also been proposed to be suitable drugs for reducing heart rate and, therefore, beneficial for treating CHF. In the present study, we investigated the effect of carvedilol on HCN channels. EXPERIMENTAL APPROACH: Whole-cell patch-clamp recordings were used to assess the effect of carvedilol on currents from wild-type and mutant HCN1, HCN2 and HCN4 channels expressed in CHO cells. KEY RESULTS: Carvedilol was the only β-blocker tested that showed inhibitory effects on the major sinoatrial HCN channel isoform HCN4. Carvedilol inhibited HCN4 in a concentration-dependent manner with an EC50 of 4.4 μM. In addition, carvedilol also inhibited HCN1 and HCN2 channels. Carvedilol blocked HCN channels by decelerating the rate of channel activation and increasing that of deactivation, and shifted the voltage-dependence of activation leftwards. Our data also showed that carvedilol, unlike other inhibitors of this channel (ivabradine and ZD7288), is not an 'open-channel' inhibitor of HCN4. CONCLUSIONS AND IMPLICATIONS: Carvedilol is a negative gating modulator of HCN channels. It represents a novel structure for future drug design of HCN channel inhibitors.
BACKGROUND AND PURPOSE:Carvedilol is a clinically effective β-blocker broadly used for treating congestive heart failure (CHF), and several clinical trials have demonstrated that it shows a favourable effect compared with other β-blockers in patients with CHF. The mechanism underlying this beneficial effect of carvedilol compared to other β-blockers is not clearly understood. In addition to β-blockers, inhibitors of hyperpolarization-activated cyclic nucleotide (HCN)-gated channels, which play a critical role in spontaneous rhythmic activity in the heart, have also been proposed to be suitable drugs for reducing heart rate and, therefore, beneficial for treating CHF. In the present study, we investigated the effect of carvedilol on HCN channels. EXPERIMENTAL APPROACH: Whole-cell patch-clamp recordings were used to assess the effect of carvedilol on currents from wild-type and mutant HCN1, HCN2 and HCN4 channels expressed in CHO cells. KEY RESULTS:Carvedilol was the only β-blocker tested that showed inhibitory effects on the major sinoatrial HCN channel isoform HCN4. Carvedilol inhibited HCN4 in a concentration-dependent manner with an EC50 of 4.4 μM. In addition, carvedilol also inhibited HCN1 and HCN2 channels. Carvedilol blocked HCN channels by decelerating the rate of channel activation and increasing that of deactivation, and shifted the voltage-dependence of activation leftwards. Our data also showed that carvedilol, unlike other inhibitors of this channel (ivabradine and ZD7288), is not an 'open-channel' inhibitor of HCN4. CONCLUSIONS AND IMPLICATIONS: Carvedilol is a negative gating modulator of HCN channels. It represents a novel structure for future drug design of HCN channel inhibitors.
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