Mechanisms of hypoxic coronary vasodilatation in isolated perfused rat hearts

We pharmacologically investigated the potential involvement of nitric oxide (NO), prostacyclin, adenosine, adenosine triphosphate (ATP)-sensitive K (K-ATP) channel opening and Ca2+-activated K (K-Ca) channel opening in coronary vasodilatation during 15 min of hypoxia in isolated rat hearts perfused at a constant pressure of 70 mm Hg. The coronary flow suppressed by 10(-4) M N-omega-nitro-L-arginine methyl ester (L-NAME), which corresponds to the NO-dependent flow, decreased to almost zero during hypoxia. In contrast, the NO-dependent coronary flow amounted to similar to 40% of the total coronary flow during normoxia. The suppression of coronary flow by 10(-5) M 8-phenyltheophylline (8-PT), which corresponds to the adenosine-dependent flow, was remarkable in the middle and the late phases of a 15-min hypoxia. The coronary flow suppressed by 2 x 10(-6) M glibenclamide, which corresponds to the K-ATP channel opening-dependent flow, depended on the agents added to the perfusate. However, there was a marked increase in coronary flow in the early phase of hypoxia in the heart perfused with the combination of 8-PT, 10(-2) M tetraethylammonium (TEA) and L-NAME. During hypoxia, the coronary flow suppressed by TEA, which corresponds mainly to the K-Ca channel opening-dependent flow, also depended on the agents added to the perfusate. However, during reoxygenation, then was a transient significant increase in any combination of the agents. Our study suggests that hypoxia almost completely inhibits NO production, and that K-ATP channel opening immediately after hypoxia and subsequent enhanced adenosine production cause a marked hypoxic coronary vasodilatation. It also suggests that K-Ca channel opening causes vasodilatation during reoxygenation.