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10.1111/bph.12805

http://scihub22266oqcxt.onion/10.1111/bph.12805
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C4209148!4209148!24909207
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suck abstract from ncbi


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pmid24909207      Br+J+Pharmacol 2014 ; 171 (19): 4413-24
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  • Vasorelaxant effects of novel Kv7 4 channel enhancers ML213 and NS15370 #MMPMID24909207
  • Jepps TA; Bentzen BH; Stott JB; Povstyan OV; Sivaloganathan K; Dalby-Brown W; Greenwood IA
  • Br J Pharmacol 2014[Oct]; 171 (19): 4413-24 PMID24909207show ga
  • Background and Purpose: The KCNQ-encoded voltage-gated potassium channel family (Kv7.1-Kv7.5) are established regulators of smooth muscle contractility, where Kv7.4 and Kv7.5 predominate. Various Kv7.2?7.5 channel enhancers have been developed that have been shown to cause a vasorelaxation in both rodent and human blood vessels. Recently, two novel Kv7 channel enhancers have been identified, ML213 and NS15370, that show increased potency, particularly on Kv7.4 channels. The aim of this study was to characterize the effects of these novel enhancers in different rat blood vessels and compare them with Kv7 enhancers (S-1, BMS204352, retigabine) described previously. We also sought to determine the binding sites of the new Kv7 enhancers. Key Results: Both ML213 and NS15370 relaxed segments of rat thoracic aorta, renal artery and mesenteric artery in a concentration-dependent manner. In the mesenteric artery ML213 and NS15370 displayed EC50s that were far lower than other Kv7 enhancers tested. Current-clamp experiments revealed that both novel enhancers, at low concentrations, caused significant hyperpolarization in mesenteric artery smooth muscle cells. In addition, we determined that the stimulatory effect of these enhancers relied on a tryptophan residue located in the S5 domain, which is the same binding site for the other Kv7 enhancers tested in this study. Conclusions and Implications: This study has identified and characterized ML213 and NS15370 as potent vasorelaxants in different blood vessels, thereby highlighting these new compounds as potential therapeutics for various smooth muscle disorders.
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