The levosimendan metabolite OR-1896 elicits vasodilation by activating the K _ATP and BK _Ca channels in rat isolated arterioles

1 We characterized the vasoactive effects of OR-1896, the long-lived metabolite of the inodilator levosimendan, in coronary and skeletal muscle microvessels. 2 The effect of OR-1896 on isolated, pressurized (80 mmHg) rat coronary and gracilis muscle arteriole (∼150 μm) diameters was investigated by videomicroscopy. 3 OR-1896 elicited concentration-dependent (1 nM-10 μM) dilations in coronary (maximal dilation: 66±6%, relative to that in Ca ²⁺-free solutions; pD ₂: 7.16±0.42) and gracilis muscle arterioles (maximal dilation: 73±4%; pD ₂: 6.71±0.42), these dilations proving comparable to those induced by levosimendan (1 nM-10 μM) in coronary (maximal dilation: 83±6%; pD ₂: 7.06±0.14) and gracilis muscle arterioles (maximal dilation: 73±12%; pD ₂: 7.05±0.1). 4 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%). 5 Glibenclamide (5 or 10 μM), a selective ATP-sensitive K ⁺ channel (K _ATP) blocker, elicited a greater reduction of OR-1896-induced dilations in skeletal muscle arterioles than in coronary microvessels. 6 Conversely, the selective inhibition of the large conductance Ca ²⁺-activated K ⁺ channels (BK _Ca) 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%). 7 Accordingly, OR-1896 elicits a substantial vasodilation in coronary and skeletal muscle arterioles, by activating primarily BK _Ca and K _ATP channels, respectively, and it is suggested that OR-1896 contributes to the long-term hemodynamic effects of levosimendan.