Nishikawa Y, Stepp D W, Chilian W M
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Am J Physiol Heart Circ Physiol. 2000 Aug;279(2):H459-65. doi: 10.1152/ajpheart.2000.279.2.H459.
We tested the hypothesis that nitric oxide (NO) inhibits endothelium-derived hyperpolarizing factor (EDHF)-induced vasodilation via a negative feedback pathway in the coronary microcirculation. Coronary microvascular diameters were measured using stroboscopic fluorescence microangiography. Bradykinin (BK)-induced dilation was mediated by EDHF, when NO and prostaglandin syntheses were inhibited, or by NO when EDHF and prostaglandin syntheses were blocked. Specifically, BK (20, 50, and 100 ng. kg(-1). min(-1) ic) caused dose-dependent vasodilation similarly before and after administration of N(G)-monomethyl-L-arginine (L-NMMA) (3 micromol/min ic for 10 min) and indomethacin (Indo, 10 mg/kg iv). The residual dilation to BK with L-NMMA and Indo was completely abolished by suffusion of miconazole or an isosmotic buffer containing high KCl (60 mM), suggesting that this arteriolar vasodilation is mediated by the cytochrome P-450 derivative EDHF. BK-induced dilation was reduced by 39% after inhibition of EDHF and prostaglandin synthesis, and dilation was further inhibited by combined blockade with L-NMMA to a 74% reduction in the response. This suggests an involvement for NO in the vasodilation. After dilation to BK was assessed with L-NMMA and Indo, sodium nitroprusside (SNP, 1-3 microgram. kg(-1). min(-1) ic), an exogenous NO donor, was administered in a dose to increase the diameter to the original control value. Dilation to BK was virtually abolished when administered concomitantly with SNP during L-NMMA and Indo (P < 0.01 vs. before SNP), suggesting that NO inhibits EDHF-induced dilation. SNP did not affect adenosine- or papaverine-induced arteriolar dilation in the presence of L-NMMA and Indo, demonstrating that the effect of SNP was not nonspecific. In conclusion, our data are the first in vivo evidence to suggest that NO inhibits the production and/or action of EDHF in the coronary microcirculation.
一氧化氮（NO）通过冠状动脉微循环中的负反馈途径抑制内皮衍生超极化因子（EDHF）介导的血管舒张。采用频闪荧光微血管造影术测量冠状动脉微血管直径。当NO和前列腺素合成受到抑制时，缓激肽（BK）诱导的血管舒张由EDHF介导；而当EDHF和前列腺素合成被阻断时，则由NO介导。具体而言，在给予N(G)-单甲基-L-精氨酸（L-NMMA，3 μmol/min，经冠状动脉内注射10分钟）和吲哚美辛（Indo，10 mg/kg，静脉注射）之前和之后，BK（20、50和100 ng·kg(-1)·min(-1)，经冠状动脉内注射）均引起剂量依赖性血管舒张。用咪康唑或含高钾（60 mM）的等渗缓冲液灌注后，L-NMMA和Indo存在时对BK的残余舒张作用完全消除，提示这种小动脉血管舒张由细胞色素P-450衍生物EDHF介导。抑制EDHF和前列腺素合成后，BK诱导的舒张作用降低39%，联合L-NMMA阻断后舒张作用进一步受到抑制，反应降低74%。这提示NO参与了血管舒张过程。在用L-NMMA和Indo评估对BK的舒张反应后，给予外源性NO供体硝普钠（SNP，1 - 3 μg·kg(-1)·min(-1)，经冠状动脉内注射），剂量足以使血管直径增加至原始对照值。在L-NMMA和Indo存在的情况下，与SNP同时给药时，对BK的舒张作用几乎完全消除（与给予SNP之前相比，P < 0.01），提示NO抑制EDHF诱导的舒张。在L-NMMA和Indo存在时，SNP不影响腺苷或罂粟碱诱导的小动脉舒张，表明SNP的作用并非非特异性。总之，我们的数据首次提供了体内证据，表明NO在冠状动脉微循环中抑制EDHF的产生和/或作用。
