Inhibitors of nitric oxide synthesis and ischemia-reperfusion attenuate coronary vasodilator response to pinacidil in isolated rat heart

: Evidence indicates that ATP-sensitive potassium channels (KATP) participate in the metabolic regulation of coronary flow and that this regulation is attenuated when endothelial production of nitric oxide (NO) is blocked. A hypothesis tested in this study was that, in hearts with the impaired NO-pathway, either with an inhibitor or as a result of ischemia/reperfusion, a coronary vasodilator response to KATP stimulation is impaired as well. In Langendorff perfused rat hearts, a blocker of NO synthesis (N omega-nitro-L-arginine, L-NOARG, 10 microM) and KATP inhibitor (glibenclamide, 0.6 microM) reduced the basal coronary flow by 44% and 29%, respectively. Glibenclamide caused a further 25% drop in the flow in L-NOARG perfused hearts. To determine the responsiveness of coronary resistance vessels to KATP stimulation and NO, dose-response curves (DRC) for KATP opener, pinacidil-, and NO-donor, 3-morpholino-syndomine-hydrochloride (SIN-1)-induced increase in coronary flow were constructed, respectively. The pinacidil DRC was shifted to the right by glibenclamide and L-NOARG and to the left by SIN-1 and adenosine. The L-NOARG-induced effect was reversed by L-arginine. The SIN-1 DRC was shifted to the right by glibenclamide and not affected by L-NOARG. Another NO synthesis blocker, L-NG-monomethylarginine (L-NMMA, 50 microM), caused a 43% drop in coronary flow in the untreated hearts and only 24% drop in the hearts subjected to 20 min global ischemia and 40 min reperfusion. The pinacidil DRC obtained at reperfusion showed a 2.3-fold rightward shift as compared to the DRC obtained before ischemia/reperfusion. Similar displacement of the pinacidil DRC was observed also in L-NMMA perfused hearts and in L-NMMA-perfused hearts which were subjected to ischemia/reperfusion. These results indicate that in the isolated rat heart: (1) NO and KATP, acting simultaneously, participate in the setting of the vasodilator component of the basal coronary flow; (2) The responsiveness of coronary microcirculation to KATP stimulation is attenuated when endothelial NO-pathway is impaired either pharmacologically or by ischemia/reperfusion.