Ishibashi Y, Duncker D J, Zhang J, Bache R J
Department of Medicine, University of Minnesota Medical School, Minneapolis 55455, USA.
Circ Res. 1998 Feb 23;82(3):346-59. doi: 10.1161/01.res.82.3.346.
We previously reported that combined blockade of adenosine receptors and ATP-sensitive K+ channels (K+(ATP) channels) blunted but did not abolish the response of coronary blood flow to exercise. This study tested the hypothesis that the residual increase in coronary flow in response to exercise after adenosine receptor and K+(ATP) channel blockade is dependent on endogenous NO. Dogs were studied at rest and during a four-stage treadmill exercise protocol under control conditions, during K+(ATP) channel blockade with glibenclamide (50 microg x kg(-1) x min(-1) i.c.) in the presence of adenosine receptor blockade with 8-phenyltheophylline (8-PT, 5 mg/kg i.v.), and after the addition of the NO synthase inhibitor N(G)-nitro-L-arginine (LNNA, 1.5 mg/kg i.c.). During control conditions, coronary blood flow was 49 +/- 3 mL/min at rest and increased to 92 +/- 8 mL/min at peak exercise. LNNA alone or in combination with 8-PT did not alter resting coronary flow and did not impair the normal increase in flow during exercise, indicating that when K+(ATP) channels are intact, neither NO nor adenosine-dependent mechanisms are obligatory for maintaining coronary blood flow. Combined K+(ATP) channel and adenosine blockade decreased resting coronary flow to 27 +/- 3 mL/min (P<.05), but exercise still increased flow to 45 +/- 5 mL/min (P<.05). The subsequent addition of LNNA further decreased resting coronary flow to 20 +/- 2 mL/min and markedly blunted exercise-induced coronary vasodilation (coronary vascular conductance, 0.20 +/- 0.03 mL x min(-1) x mm Hg(-1) at rest versus 0.24 +/- 0.04 mL x min(-1) x mm Hg(-1) during the heaviest level of exercise; P=.22), so that coronary flow both at rest and during exercise was below the control resting level. The findings suggest that K+(ATP) channels are critical for maintaining coronary vasodilation at rest and during exercise but that when K+(ATP) channels are blocked, both adenosine and NO act to increase coronary blood flow during exercise. In the presence of combined K+(ATP) channel blockade and adenosine receptor blockade, NO was able to produce approximately one quarter of the coronary vasodilation that occurred in response to exercise when all vasodilator systems were intact.
我们之前报道过，联合阻断腺苷受体和ATP敏感性钾通道（K⁺(ATP)通道）可减弱但并未消除冠状动脉血流对运动的反应。本研究检验了以下假设：在腺苷受体和K⁺(ATP)通道被阻断后，运动引起的冠状动脉血流残余增加依赖于内源性一氧化氮（NO）。研究了犬在静息状态下以及在四个阶段的跑步机运动方案过程中的情况，分别处于对照条件下、在用格列本脲（50μg·kg⁻¹·min⁻¹，腹腔注射）阻断K⁺(ATP)通道且同时用8-苯基茶碱（8-PT，5mg/kg，静脉注射）阻断腺苷受体的情况下，以及在添加一氧化氮合酶抑制剂N(G)-硝基-L-精氨酸（LNNA，1.5mg/kg，腹腔注射）之后。在对照条件下，静息时冠状动脉血流为49±3mL/min，运动峰值时增加至92±8mL/min。单独使用LNNA或与8-PT联合使用均未改变静息冠状动脉血流，也未损害运动期间血流的正常增加，这表明当K⁺(ATP)通道完整时，NO和腺苷依赖性机制对于维持冠状动脉血流并非必需。联合阻断K⁺(ATP)通道和腺苷可使静息冠状动脉血流降至27±3mL/min（P<0.05），但运动仍使血流增加至45±5mL/min（P<0.05）。随后添加LNNA进一步使静息冠状动脉血流降至20±2mL/min，并显著减弱运动诱导的冠状动脉血管舒张（冠状动脉血管传导性，静息时为0.20±0.03mL·min⁻¹·mmHg⁻¹，运动最剧烈时为0.24±0.04mL·min⁻¹·mmHg⁻¹；P = 0.22），以至于静息和运动时的冠状动脉血流均低于对照静息水平。这些发现表明，K⁺(ATP)通道对于在静息和运动时维持冠状动脉血管舒张至关重要，但当K⁺(ATP)通道被阻断时，腺苷和NO在运动期间均发挥作用以增加冠状动脉血流。在联合阻断K⁺(ATP)通道和腺苷受体的情况下，NO能够产生在所有血管舒张系统完整时运动引起的冠状动脉血管舒张的约四分之一。
