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 (approximately 150 microm) diameters was investigated by videomicroscopy. 3. OR-1896 elicited concentration-dependent (1 nM-10 microM) 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 microM) in coronary (maximal dilation: 83+/-6%; pD2: 7.06+/-0.14) and gracilis muscle arterioles (maximal dilation: 73+/-12%; pD2: 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 microM), 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. 6. Conversely, the selective inhibition of the large conductance Ca2+-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.
Erdei
Nóra
N
Division of Clinical Physiology, Institute of Cardiology, University of Debrecen, Debrecen H-4004, Hungary.
Papp
Zoltán
Z
Pollesello
Piero
P
Edes
István
I
Bagi
Zsolt
Z
D000081:Acetamides; D000818:Animals; D001160:Arterioles / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects; D006835:Hydrazones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism* / Q000502:physiology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism* / Q000502:physiology; D011724:Pyridazines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077464:Simendan; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000081:Acetamides; D006835:Hydrazones; D051036:Large-Conductance Calcium-Activated Potassium Channels; C414222:N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; D015221:Potassium Channels; D011724:Pyridazines; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D000077464:Simendan