Functional role of potassium channels in the vasodilating mechanism of levosimendan in porcine isolated coronary artery.
Levosimendan, a new type of inodilator drugs, is known to activate membrane adenosine 3',5'-triphosphate-sensitive potassium (KATP) channels in some vascular smooth muscles and causes vasorelaxation. The involvement of potassium channels in the mechanism of the coronary artery relaxing effect of the drug has not been established. In the present study performed in the porcine epicardial coronary artery, the effect of levosimendan (0.009-3.2 microM) was compared to cromakalim (0.0125-5 microM), the known activator of ATP-sensitive potassium (KATP) channels, in the presence of glibenclamide (GLI), an inhibitor of KATP channels and tetraethylammonium (TEA), the non-selective inhibitor of potassium channels. The interaction of levosimendan with the specific calcium-activated potassium channel (KCa) blocker, iberiotoxin (IBTX), and the voltage-sensitive potassium channel (KV) blocker, 4-aminopyridine (4-AP), was also studied. All the experiments were performed in the isometric tension of endothelium denuded porcine isolated epicardial coronary arteries precontracted with 20 mM potassium chloride. 1 microM GLI decreased the maximum of cromakalim-induced relaxation by 60% but did not affect the action of levosimendan. In contrast, 2 mM TEA decreased only the coronary artery relaxing effect of levosimendan. 100 nM IBTX suppressed the maximum effect of levosimendan by only 15% while 0.5 mM 4-AP significantly shifted the concentration-response curve of the inodilator to the right. 5 mM 4-AP caused a maximum of 33% decrease of levosimendan-induced relaxation. These results indicate that, in porcine isolated epicardial coronary artery, the vasorelaxing mechanism of levosimendan involves the activation of voltage-sensitive and, at large concentrations, calcium-activated potassium channels.
Pataricza
János
J
Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6701, Szeged, Dóm tér 12., Hungary.
Krassói
Irén
I
Höhn
József
J
Kun
Attila
A
Papp
Julius Gyula
JG
D015761:4-Aminopyridine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D019806:Cromakalim / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006835:Hydrazones / Q000494:pharmacology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007537:Isometric Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology*; D000077464:Simendan; D013552:Swine; D019789:Tetraethylammonium / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D006835:Hydrazones; D010455:Peptides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011724:Pyridazines; D014665:Vasodilator Agents; D019806:Cromakalim; D000077464:Simendan; D019789:Tetraethylammonium; C064719:iberiotoxin; D000255:Adenosine Triphosphate; D015761:4-Aminopyridine; D005905:Glyburide; D002118:Calcium