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

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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.

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