Hypoxic preconditioning in coronary microarteries: role of EDHF and K+ channel openers.
BACKGROUND
Hypoxic preconditioning may provide a useful method of myocardial protection in cardiac operations. The present study was designed to investigate the possible mechanisms of preconditioning regarding endothelium-derived hyperpolarizing factor (EDHF) and the effect of a potassium channel opener KRN4884 on the porcine coronary microartery in mimicking hypoxic preconditioning.


METHODS
Porcine coronary microartery rings (diameter 200 to 500 microm) studied in a myograph were divided into seven groups: (1) control group; (2) hypoxia-reoxygenation group (hypoxia for 60 minutes followed by reoxygenation for 30 minutes); (3) preconditioning group (hypoxia for 5 minutes followed by reoxygenation for 10 minutes before hypoxia reoxygenation); (4) KRN4884 pretreatment group (KRN4884 was added into the myograph chamber 20 minutes before hypoxia reoxygenation); (5) 5-hydroxydecanoate + KRN group (5-hydroxydecanoate was given 20 minutes before KRN4884 pretreatetment); (6) glibenclamide (GBC) + KRN group (GBC was added 20 minutes before KRN4884 pretreatment); and (7) endothelium denuded group (the endothelium was removed). The endothelium-derived hyperpolarizing factor-mediated relaxation to bradykinin was studied in the rings precontracted with U46619 in the presence of N(omega)-nitro-L-arginine and indomethacin.


RESULTS
The maximal relaxation induced by bradykinin was reduced in hypoxia reoxygenation (40.7% +/- 2.8% vs 66.9% +/- 2.5% in control, p = 0.000). This reduced relaxation was recovered in either preconditioning (64.6% +/- 4.6%, p = 0.002), or KRN4884 pretreatment (67.1% +/- 3.6%, p = 0.000). The 5-hydroxydecanoate, but not GBC pretreatment abolished the effect of KRN44884 pretreatment (67.1% +/- 3.6% vs 42.9% +/- 3%, p = 0.001).


CONCLUSIONS
Hypoxia reoxygenation reduces the relaxation mediated by endothelium-derived hyperpolarizing factor in the coronary microartery. This function can be restored by either hypoxic preconditioning or the K(ATP) channel opener KRN4884, and therefore K(ATP) channel openers may provide similar effect as preconditioning. The mechanism is mainly related to the mitochondrial ATP-sensitive K+ channels.
Providence Heart Institute, Albert Starr Academic Center, Department of Surgery, Oregon Health and Science University, Portland, USA.
Zhen
Z
Ren
Qin
Q
Yang
H Storm
HS
Floten
Guo-Wei
GW
He
D000818:Animals; D001685:Biological Factors / Q000502:physiology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008929:Mitochondria, Heart / Q000502:physiology; D015221:Potassium Channels / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*; D014666:Vasomotor System / Q000187:drug effects* / Q000502:physiology
D001685:Biological Factors; C096484:KRN 4884; D015221:Potassium Channels; D011725:Pyridines; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor