hmr-1098 and 1-3-dipropyl-8-cyclopentylxanthine

The authors examined the role of adenosine triphosphate-sensitive potassium channels and adenosine A(1) receptors in sevoflurane-induced preconditioning on isolated human myocardium.. The authors recorded isometric contraction of human right atrial trabeculae suspended in oxygenated Tyrode's solution (34 degrees C; stimulation frequency, 1 Hz). In all groups, a 30-min hypoxic period was followed by 60 min of reoxygenation. Seven minutes before hypoxia reoxygenation, muscles were exposed to 4 min of hypoxia and 7 min of reoxygenation or 15 min of sevoflurane at concentrations of 1, 2, and 3%. In separate groups, sevoflurane 2% was administered in the presence of 10 microm HMR 1098, a sarcolemmal adenosine triphosphate-sensitive potassium channel antagonist; 800 microm 5-hydroxy-decanoate, a mitochondrial adenosine triphosphate-sensitive potassium channel antagonist; and 100 nm 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A(1) receptor antagonist. Recovery of force at the end of the 60-min reoxygenation period was compared between groups (mean +/- SD).. Hypoxic preconditioning (90 +/- 4% of baseline) and sevoflurane 1% (82 +/- 3% of baseline), 2% (92 +/- 5% of baseline), and 3% (85 +/- 7% of baseline) enhanced the recovery of force after 60 min of reoxygenation compared with the control groups (52 +/- 9% of baseline). This effect was abolished in the presence of 5-hydroxy-decanoate (55 +/- 14% of baseline) and 8-cyclopentyl-1,3-dipropylxanthine (58 +/- 16% of baseline) but was attenuated in the presence of HMR 1098 (73 +/- 10% of baseline).. In vitro, sevoflurane preconditions human myocardium against hypoxia through activation of adenosine triphosphate-sensitive potassium channels and stimulation of adenosine A(1) receptors.

Topics: Aged; Anesthetics, Inhalation; ATP-Binding Cassette Transporters; Benzamides; Decanoic Acids; Heart Atria; Humans; Hydroxy Acids; Hypoxia; In Vitro Techniques; Ischemic Preconditioning, Myocardial; Isometric Contraction; KATP Channels; Methyl Ethers; Middle Aged; Myocardial Contraction; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Inwardly Rectifying; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1; Reperfusion Injury; Sarcolemma; Sevoflurane; Xanthines

The protective roles of sarcolemmal (sarc) and mitochondrial (mito) KATP channels are unclear despite their apparent importance to ischemic preconditioning. We examined these roles by monitoring intracellular calcium ([Ca]int), using fura-2 and fluo-3, in enzymatically isolated rat right ventricular myocytes. Myocyte mortality, estimated using a trypan blue assay, changed approximately in parallel with changes in [Ca]int. Chemically induced hypoxia (CIH), induced by application of cyanide and 2-deoxy-glucose, caused a steady rise in [Ca]int. Calcium increased more rapidly on 'reoxygenation' by return to control solutions. The protein kinase C (PKC) activator PMA abolished both phases of calcium increase. The mitoKATP channel-selective blocker 5-hydroxydecanoate partially prevented the PMA-induced protection during CIH, but not during reoxygenation. In contrast, HMR 1098, a sarcKATP channel-selective blocker, abolished protection only during the reoxygenation. Adenosine (A1) receptor activation prevented or reduced increases in [Ca]int and improved cell viability via a PKC and mito/sarcKATP channel-dependent mechanism. PKC-dependent protection against cytoplasmic calcium increases was also observed in a human cell line (tsA201) transiently expressing sarcKATP channels. Protection was abolished only during the reoxygenation phase by the amino acid substitution (T180A) in the pore-forming Kir6.2 subunit, a mutation previously shown to prevent PKC-dependent modulation. Our data suggest that sarc and mitoKATP channel populations play distinct protective roles, triggered by PKC and/or adenosine, during chemically induced hypoxia/reoxygenation.

Topics: Adenosine; Adenosine Triphosphate; Animals; ATP-Binding Cassette Transporters; Benzamides; Calcium; Cell Hypoxia; Cell Line; Cell Survival; Cells, Cultured; Decanoic Acids; Dose-Response Relationship, Drug; Enzyme Activation; Heart Ventricles; Humans; Hydroxy Acids; Ischemic Preconditioning, Myocardial; KATP Channels; Luminescent Proteins; Membrane Potentials; Mitochondria; Myocardium; Oxygen; Potassium Channels; Potassium Channels, Inwardly Rectifying; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Recombinant Fusion Proteins; Sarcolemma; Time Factors; Ventricular Function; Xanthines