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

Nóra Erdei, Zoltán Papp, Piero Pollesello, István Édes, Zsolt Bagi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)696-702
Number of pages7
JournalBritish Journal of Pharmacology
Volume148
Issue number5
DOIs
StatePublished - Jul 5 2006
Externally publishedYes

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Large-Conductance Calcium-Activated Potassium Channels
Arterioles
Vasodilation
Dilatation
Adenosine Triphosphate
Skeletal Muscle
Microvessels
simendan
N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide
Video Microscopy
Tetraethylammonium
Glyburide
Hemodynamics

Keywords

  • Coronary
  • K channels
  • Levosimendan
  • Microvessel
  • OR-1896
  • Skeletal muscle
  • Vasodilation

ASJC Scopus subject areas

  • Pharmacology

Cite this

The levosimendan metabolite OR-1896 elicits vasodilation by activating the K ATP and BK Ca channels in rat isolated arterioles. / Erdei, Nóra; Papp, Zoltán; Pollesello, Piero; Édes, István; Bagi, Zsolt.

In: British Journal of Pharmacology, Vol. 148, No. 5, 05.07.2006, p. 696-702.

Research output: Contribution to journalArticle

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T1 - The levosimendan metabolite OR-1896 elicits vasodilation by activating the K ATP and BK Ca channels in rat isolated arterioles

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AU - Papp, Zoltán

AU - Pollesello, Piero

AU - Édes, István

AU - Bagi, Zsolt

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N2 - 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.

AB - 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.

KW - Coronary

KW - K channels

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KW - Microvessel

KW - OR-1896

KW - Skeletal muscle

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