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The mechanism underlying this beneficial effect of carvedilol compared to other \u03b2\u2010blockers is not clearly understood. In addition to \u03b2\u2010blockers, inhibitors of hyperpolarization\u2010activated cyclic nucleotide (HCN)\u2010gated 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Whole\u2010cell patch\u2010clamp recordings were used to assess the effect of carvedilol on currents from wild\u2010type and mutant HCN1, HCN2 and HCN4 channels expressed in CHO cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Carvedilol was the only \u03b2\u2010blocker tested that showed inhibitory effects on the major sinoatrial HCN channel isoform HCN4. Carvedilol inhibited HCN4 in a concentration\u2010dependent manner with an EC<jats:sub>50<\/jats:sub> of 4.4\u00a0\u03bcM. 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\u2010dependence of activation leftwards. Our data also showed that carvedilol, unlike other inhibitors of this channel (ivabradine and ZD7288), is not an \u2018open\u2010channel\u2019 inhibitor of HCN4.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Carvedilol is a negative gating modulator of HCN channels. It represents a novel structure for future drug design of HCN channel inhibitors.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14469","type":"journal-article","created":{"date-parts":[[2018,8,11]],"date-time":"2018-08-11T06:49:37Z","timestamp":1533970177000},"page":"3963-3975","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Inhibition of hyperpolarization\u2010activated cyclic nucleotide\u2010gated channels by \u03b2\u2010blocker carvedilol"],"prefix":"10.1111","volume":"175","author":[{"given":"Ying","family":"Cao","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences Southern Medical University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shujun","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical 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