The levosimendan metabolite OR‐1896 elicits vasodilation by activating the KATP and BKCa channels in rat isolated arterioles

Abstract

We characterized the vasoactive effects of OR‐1896, the long‐lived metabolite of the inodilator levosimendan, in coronary and skeletal muscle microvessels. The effect of OR‐1896 on isolated, pressurized (80 mmHg) rat coronary and gracilis muscle arteriole (∼150 μm) diameters was investigated by videomicroscopy. OR‐1896 elicited concentration‐dependent (1 nM–10 μM) dilations in coronary (maximal dilation: 66±6%, relative to that in Ca2+‐free solutions; pD2: 7.16±0.42) and gracilis muscle arterioles (maximal dilation: 73±4%; pD2: 6.71±0.42), these dilations proving comparable to those induced by levosimendan (1 nM–10 μM) in coronary (maximal dilation: 83±6%; pD2: 7.06±0.14) and gracilis muscle arterioles (maximal dilation: 73±12%; pD2: 7.05±0.1). The maximal dilations in response to OR‐1896 were significantly (P<0.05) attenuated by the nonselective K+ channel inhibitor tetraethylammonium (1 mM) in coronary (to 34±9%) and gracilis muscle arterioles (to 28±6%). Glibenclamide (5 or 10 μM), a selective ATP‐sensitive K+ channel (KATP) blocker, elicited a greater reduction of OR‐1896‐induced dilations in skeletal muscle arterioles than in coronary microvessels. Conversely, the selective inhibition of the large conductance Ca2+‐activated K+ channels (BKCa) with iberiotoxin (100 nM) significantly reduced the OR‐1896‐induced maximal dilation in coronary arterioles (to 21±6%), but was ineffective in skeletal muscle arterioles (72±8%). Accordingly, OR‐1896 elicits a substantial vasodilation in coronary and skeletal muscle arterioles, by activating primarily BKCa and KATP channels, respectively, and it is suggested that OR‐1896 contributes to the long‐term hemodynamic effects of levosimendan. British Journal of Pharmacology (2006) 148, 696–702. doi:10.1038/sj.bjp.0706781