ATP-sensitive potassium channel openers may mimic the effects of hypoxic preconditioning on the coronary artery

Background. This study was designed to investigate the effects of the potassium channel opener KRN4884 in mimicking hypoxic preconditioning on coronary arteries and to explore the possible mechanisms. Methods. In the organ chamber, porcine coronary artery rings (n = 96) were studied in 6 groups (n = 16 in each group): I. Control: normoxia (pO2 > 200 mmHg); II. Hypoxia-reoxygenation: 60-minute hypoxia (pO2 < 15 mmHg) followed by 30-minute reoxygenation; III. Preconditioning: 5-minute hypoxia followed by 10-minute reoxygenation prior to hypoxia-reoxygenation; IV. KRN4884-pretreatment: KRN4884 (30 μM) was added into the chamber 20 minutes before hypoxia-reoxygenation; V. 5-HD-pretreatment: sodium 5-hydroxydecanoate (5-HD, 10 μM) was given 20 minutes prior to KRN4884-pretreatment; and VI. GBC-pretreatment: glibenclamide (GBC, 3 μM) was added 20 minutes prior to KRN4884-pretreatment. Concentration-contraction curves for U46619 (n = 8 in each group) were constructed. Concentration-relaxation curves for bradykinin (n = 8 in each group) related to endothelium-derived hyperpolarizing factor (EDHF) were established in the rings precontracted with U46619 (30 μM) in the presence of Nω-nitro-image-arginine (image-NNA, 300 μM) and indomethacin (7 μM). Results. The maximal relaxation induced by bradykinin was reduced in hypoxia-reoxygenation (54.6 ± 4.3% versus 85.2 ± 5.7% in control, p = 0.001). This reduced relaxation was recovered in KRN4884-pretreatment (78.9 ± 3.7%, p = 0.014) or preconditioning (79.9 ± 3.7%, p = 0.009). 5-HD- but not GBC-pretreatment abolished the effect of KRN4884-pretreatment (78.9 ± 3.7% versus 53.5 ± 4.7%, p = 0.009). Conclusions. Hypoxia-reoxygenation reduces the relaxation mediated by EDHF in the coronary artery. This function can be restored by either hypoxic preconditioning or the potassium channel opener KRN4884. The mechanism of such effect is mainly related to the mitochondrial ATP-sensitive K+ channels.