{"id":6069,"date":"2023-02-17T07:02:16","date_gmt":"2023-02-17T07:02:16","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2013-differential-effects-of-the-%ce%b2%e2%80%90adrenoceptor-blockers-carvedilol-and-metoprolol-on-sqt1%e2%80%90-and-sqt2%e2%80%90mutant-channels\/"},"modified":"2023-02-17T07:02:16","modified_gmt":"2023-02-17T07:02:16","slug":"2013-differential-effects-of-the-%ce%b2%e2%80%90adrenoceptor-blockers-carvedilol-and-metoprolol-on-sqt1%e2%80%90-and-sqt2%e2%80%90mutant-channels","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2013-differential-effects-of-the-%ce%b2%e2%80%90adrenoceptor-blockers-carvedilol-and-metoprolol-on-sqt1%e2%80%90-and-sqt2%e2%80%90mutant-channels\/","title":{"rendered":"2013 &#8211; Differential Effects of the \u03b2\u2010Adrenoceptor Blockers Carvedilol and Metoprolol on SQT1\u2010 and SQT2\u2010Mutant Channels"},"content":{"rendered":"<p>Background: N588K-KCNH2 and V307L-KCNQ1 mutations lead to a gain-of-function of I<sup>Kr<\/sup>\u00a0and IKs\u00a0thus causing short-QT syndromes (SQT1, SQT2). Combined pharmacotherapies using K<sup>+<\/sup>-channel-blockers and \u03b2-blockers are effective in SQTS. Since \u03b2-blockers can block I<sup>Kr<\/sup>\u00a0and IKs, we aimed at determining carvedilol&#8217;s and metoprolol&#8217;s electrophysiological effects on N588K-KCNH2 and V307L-KCNQ1 channels. Methods Wild-type (WT)-KCNH2, WT-KCNQ1 and mutant N588K-KCNH2 and V307L-KCNQ1 channels were expressed in CHO-K1 or HEK-293T cells and IKs\u00a0and I<sup>Kr<\/sup>\u00a0were recorded at baseline and during \u03b2-blocker exposure. Results Carvedilol (10 \u03bcM) reduced IKs\u00a0tail in WT- and V307L-KCNQ1 by 36.5 \u00b1 5% and 18.6 \u00b1 9% (P < 0.05). IC<sub>50<\/sub>\u00a0values were 16.3 \u03bcM (WT) and 46.1 \u03bcM (V307L), indicating a 2.8-fold decrease in carvedilol&#8217;s IKs-blocking potency in V307L-KCNQ1. Carvedilol&#8217;s (1 \u03bcM) inhibition of the I<sup>Kr<\/sup>\u00a0tail was attenuated in N588K-KCNH2 (4.5 \u00b1 3% vs 50.3 \u00b1 4%, WT, P < 0.001) with IC<sub>50<\/sub>\u00a0values of 2.8 \u03bcM (WT) and 25.4 \u03bcM (N588K). Carvedilol&#8217;s I<sup>Kr<\/sup>\u00a0end-pulse inhibition, however, was increased in N588K-KCNH2 (10 \u03bcM, 60.7 \u00b1 6% vs 36.5 \u00b1 5%, WT, P < 0.01).Metoprolol (100 \u03bcM) reduced\u00a0I<sup>Kr<\/sup>\u00a0end-pulse by 0.23 \u00b1 3% (WT) and 74.1 \u00b1 7% (N588K, P < 0.05), I<sup>Kr<\/sup>\u00a0tail by 32.9 \u00b1 10% (WT) and 68.8 \u00b1 7% (N588K, P < 0.05), and reduced IKs\u00a0end-pulse by 18.3 \u00b1 5% (WT) and 57.1 \u00b1 11% (V307L, P < 0.05) and IKs\u00a0tail by 3.3 \u00b1 1% (WT) and 45.1 \u00b1 13 % (V307L, P < 0.05), indicating an increased sensitivity to metoprolol in SQT mutated channels. Conclusions N588K-KCNH2 and V307L-KCNQ1 mutations decrease carvedilol's inhibition of the IKs\u00a0or I<sup>Kr<\/sup>\u00a0tail but increase carvedilol&#8217;s I<sup>Kr<\/sup> end-pulse inhibition and metoprolol&#8217;s inhibition of tail and end-pulse currents. These different effects on SQT1 and SQT2 mutated channels should be considered when using \u03b2-blocker therapy in SQTS patients.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[45],"resource_type":[75],"application_areas":[50],"therapeutic_areas":[54],"target_categories":[61],"target_families":[333],"targets":[92,95],"resource_keyword":[],"class_list":["post-6069","resource_library","type-resource_library","status-publish","hentry","products_tags-port-a-patch","resource_type-publication","application_areas-ion-channels","therapeutic_areas-cardiac-safety-cipa","target_categories-voltage-gated-ion-channels","target_families-kv-channels","targets-kv11-1-herg","targets-kv7-1"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/6069","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=6069"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=6069"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=6069"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=6069"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=6069"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=6069"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=6069"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=6069"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=6069"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}