Jones C J, Kuo L, Davis M J, DeFily D V, Chilian W M
Department of Medical Physiology, Texas A&M University Health Science Center, College Station 77843-1114.
Circulation. 1995 Mar 15;91(6):1807-13. doi: 10.1161/01.cir.91.6.1807.
The purpose of this study was to test the hypothesis that endothelium-derived nitric oxide (NO) participates in coronary microvascular responses to adenosine and pacing-induced increases in metabolic demand by maintaining an optimal distribution of coronary resistance.
Coronary microvascular diameters were measured by stroboscopic epi-illumination and intravital microscopy in open-chest dogs (n = 20). Epicardial coronary blood velocity (CBV) was measured by Doppler flowmetry. Responses to adenosine (1 and 10 micrograms.kg-1.min-1 IC) and left atrial pacing (180 beats per minute) were recorded before and after inhibition of NO synthesis by NG-nitro-L-arginine methyl ester (L-NAME, 30 micrograms.kg-1.min-1 IC). At baseline, adenosine dilated arterioles (< 100 microns) (11 +/- 4% and 25 +/- 3% diameter changes, P < .05) more than small arteries (> 100 microns) (-4 +/- 6% and 7 +/- 3%, P < .05 for the higher dose) and increased CBV (43 +/- 31% and 118 +/- 25%, P < .05). Left atrial pacing dilated arterioles (12 +/- 2%, P < .05) and small arteries (8 +/- 3%, P < .05) and also increased CBV (68 +/- 9%, P < .05). L-NAME abolished CBV increases caused by acetylcholine (10 and 100 ng.kg-1.min-1 IC; 53 +/- 33% and 168 +/- 82% versus -12 +/- 15% and -1 +/- 14%, P < .05) but not papaverine. Small arteries were constricted by L-NAME (-8 +/- 2%, P < .05), arterioles were dilated (10 +/- 4%, P < .05), and CBV was unchanged. After L-NAME, adenosine failed to dilate arterioles further (3 +/- 3% and 2 +/- 2%; P < .05 versus prior responses), and CBV changes were attenuated (14 +/- 16% and 8 +/- 13%; P < .05 versus prior responses). Pacing also failed to dilate arterioles (-4 +/- 2%, P < .05 versus prior response), resulting in an attenuated CBV change (34 +/- 13%, P < .05 versus prior response). The possibility that adenosine stimulates NO release in canine coronary arterioles was investigated in isolated arterioles (diameters, 81 +/- 4 microns; n = 8). Adenosine caused dose-dependent dilation to maximal diameter, which was unaffected by inhibition of NO synthesis by L-NAME.
Inhibition of NO synthesis attenuates coronary dilation during adenosine infusions and during pacing-induced increases in metabolic demand. Inhibition of NO synthesis may shift the major site of coronary resistance into small arteries through autoregulatory adjustments in arterioles. These data therefore suggest that NO, by dilating predominantly small coronary arteries, promotes metabolic coronary dilation by preserving the tone and vasodilator reserve of arterioles.
本研究的目的是验证如下假设，即内皮源性一氧化氮（NO）通过维持冠状动脉阻力的最佳分布，参与冠状动脉微血管对腺苷的反应以及起搏诱导的代谢需求增加。
通过频闪落射照明和活体显微镜测量开胸犬（n = 20）的冠状动脉微血管直径。用多普勒血流仪测量心外膜冠状动脉血流速度（CBV）。在通过NG-硝基-L-精氨酸甲酯（L-NAME，30μg·kg⁻¹·min⁻¹静脉注射）抑制NO合成之前和之后，记录对腺苷（1和10μg·kg⁻¹·min⁻¹静脉注射）和左心房起搏（每分钟180次搏动）的反应。在基线时，腺苷使小动脉（<100μm）扩张（直径变化分别为11±4%和25±3%，P<.05）的程度大于小动脉（>100μm）（较高剂量时分别为-4±6%和7±3%，P<.05），并增加CBV（分别为43±31%和118±25%，P<.05）。左心房起搏使小动脉（12±2%，P<.05）和小动脉（8±3%，P<.05）扩张，并增加CBV（68±9%，P<.05）。L-NAME消除了乙酰胆碱（10和100 ng·kg⁻¹·min⁻¹静脉注射；分别为53±33%和168±82%，而-12±15%和-1±14%，P<.05）引起的CBV增加，但未消除罂粟碱引起的增加。小动脉被L-NAME收缩（-8±2%，P<.05），小动脉扩张（10±4%，P<.05），CBV无变化。在L-NAME之后，腺苷未能进一步扩张小动脉（分别为3±3%和2±2%；与先前反应相比，P<.05），CBV变化减弱（分别为14±16%和8±13%；与先前反应相比，P<.05）。起搏也未能扩张小动脉（-4±2%，与先前反应相比，P<.05），导致CBV变化减弱（34±13%，与先前反应相比，P<.05）。在分离的小动脉（直径81±4μm；n = 8）中研究了腺苷是否刺激犬冠状动脉小动脉释放NO。腺苷引起剂量依赖性扩张至最大直径，这不受L-NAME抑制NO合成的影响。
抑制NO合成可减弱腺苷输注期间以及起搏诱导的代谢需求增加期间的冠状动脉扩张。抑制NO合成可能通过小动脉的自身调节调整，将冠状动脉阻力的主要部位转移到小动脉。因此，这些数据表明，NO通过主要扩张小冠状动脉，通过维持小动脉的张力和血管舒张储备来促进代谢性冠状动脉扩张。
