hmr-1098 and Reperfusion-Injury

Ischemic preconditioning (IP) may protect the lung from ischemia-reperfusion (I/R) injury following cardiopulmonary by-pass and lung or heart transplantation. The present study was undertaken to investigate the role of ATP-dependent potassium channels (K(ATP)) in IP in the isolated buffer-perfused rat lung (IBPR) under conditions of elevated pulmonary vasoconstrictor tone (PVT). Since pulmonary arterial perfusion flow and left atrial pressure were constant, changes in pulmonary arterial pressure (PAP) directly reflect changes in pulmonary vascular resistance (PVR). When compared to control value, the pulmonary vasodilator responses to histamine and acetylcholine (ACh) following 2 h of hypothermic ischemia were significantly attenuated, whereas the pulmonary vasodilator response to sodium nitroprusside (SNP) was not altered. IP in the form of two cycles of 5 min of ischemia and reperfusion applied prior to the two-hour interval of ischemia, prevented the decrease in the pulmonary vasodilator responses to histamine and ACh. Pretreatment with glybenclamide (GLB) or HMR-1098, but not 5-hydroxydecanoic acid (5-HD), prior to IP abolished the protective effect of IP. In contrast, GLB or 5-HD did not significantly alter the pulmonary vasodilator response to histamine without IP pretreatment. The present data demonstrate that IP prevents impairment of endothelium-dependent vasodilator responses in the rat pulmonary vascular bed. The present data further suggest that IP may alter the mediation of the pulmonary vasodilator response to histamine and thereby trigger a mechanism dependent on activation of sarcolemmal, and not mitochondrial, K(ATP) channels to preserve endothelial-dependent vasodilator responses and protect against I/R injury in the lung.

Topics: Acetylcholine; Animals; Anti-Arrhythmia Agents; Benzamides; Decanoic Acids; Endothelium, Vascular; Glyburide; Heart Transplantation; Histamine; Histamine Agents; Hydroxy Acids; Ischemic Preconditioning; Lung; Lung Diseases; Lung Transplantation; Male; Mitochondria; Nitroprusside; Perfusion; Potassium Channels; Rats; Rats, Wistar; Reperfusion Injury; Time Factors; Vascular Resistance; Vasoconstriction; Vasodilation; Vasodilator Agents

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