一氧化氮、K(+)(ATP)通道和环磷酸鸟苷在兔预处理反应中的作用。

The role of nitric oxide, K(+)(ATP) channels, and cGMP in the preconditioning response of the rabbit.

作者信息

Horimoto H, Gaudette G R, Saltman A E, Krukenkamp I B

机构信息

Division of Cardiothoracic Surgery and The Institute for Molecular Cardiology, State University of New York at Stony Brook, Stony Brook, New York 11794, USA.

出版信息

J Surg Res. 2000 Jul;92(1):56-63. doi: 10.1006/jsre.2000.5845.

DOI:10.1006/jsre.2000.5845

PMID:10864483

Abstract

BACKGROUND

The role of nitric oxide (NO), K(+)(ATP) channels, and cyclic GMP (cGMP) in preconditioning is unknown.

MATERIAL AND METHODS

Isolated rabbit hearts were pretreated with the NO precursor L-arginine (L-Arg), both alone and after infusion of the NO synthetase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Guanylate cyclase inhibitor methylene blue (MB) was infused prior to L-Arg in a separate group of hearts. To contrast the mechanisms of NO preconditioning and potassium channel opener (PCO) preconditioning, we infused the PCO pinacidil after L-NAME and the PCO blocker glibenclamide before L-Arg. Control hearts had no drug infused. The LAD coronary artery was occluded for 1 h and reperfused for 1 h in all hearts. Action potential duration (APD(50)), coronary flow (CF), and left ventricular developed pressure (DP) were measured, and infarct size (IS) was determined and expressed as a percentage of the area at risk.

RESULTS

L-Arg prolonged APD(50) at 60 min of reperfusion (94 +/- 6 ms vs 69 +/- 2 ms (control) vs 70 +/- 2 ms (L-NAME) vs 74 +/- 3 ms (MB), P < 0.05). L-Arg reduced IS compared with control (24 +/- 2% vs 49 +/- 3%, P < 0.05); this was reversed by either L-NAME (53 +/- 4%, P < 0.05) or MB (43 +/- 3%, P < 0.05), but not by glibenclamide (20 +/- 4%), unlike the increase in CF during L-Arg infusion, which was blocked by glibenclamide. Pinacidil infusion decreased IS (26 +/- 2%), but this effect was blocked by L-NAME (53 +/- 7%, P < 0.05 vs pinacidil), although L-NAME did not blunt the increase in CF. There were no significant differences in DP among groups.

CONCLUSION

L-Arginine preconditions the heart through NO generation, and this response is mediated through a cGMP-dependent mechanism, but is independent of the K(+)(ATP) channels. Coronary vasodilation is mediated through a mechanism different from that responsible for cardiomyocyte preconditioning.

摘要

背景

一氧化氮（NO）、钾离子ATP通道（K(+)(ATP)通道）及环磷酸鸟苷（cGMP）在预处理中的作用尚不清楚。

材料与方法

分离的兔心脏分别单独用NO前体L-精氨酸（L-Arg）预处理，以及在注入NO合酶抑制剂N(G)-硝基-L-精氨酸甲酯（L-NAME）后用L-Arg预处理。在另一组心脏中，在L-Arg注入前先注入鸟苷酸环化酶抑制剂亚甲蓝（MB）。为对比NO预处理和钾通道开放剂（PCO）预处理的机制，我们在L-NAME注入后注入PCO匹那地尔，在L-Arg注入前注入PCO阻滞剂格列本脲。对照心脏不注入任何药物。所有心脏均将左前降支冠状动脉闭塞1小时，然后再灌注1小时。测量动作电位时程（APD(50)）、冠状动脉血流量（CF）和左心室舒张末压（DP），并测定梗死面积（IS），以危险区域面积的百分比表示。

结果

再灌注60分钟时，L-Arg使APD(50)延长（94±6毫秒，对照组为69±2毫秒，L-NAME组为70±2毫秒，MB组为74±3毫秒，P<0.05）。与对照组相比，L-Arg减小了梗死面积（24±2%对49±3%，P<0.05）；L-NAME（53±4%，P<0.05）或MB（43±3%，P<0.05）均可逆转这一作用，但格列本脲不能（20±4%），与L-Arg注入期间CF增加被格列本脲阻断不同。注入匹那地尔减小了梗死面积（26±2%），但该作用被L-NAME阻断（53±7%，与匹那地尔相比P<0.05），尽管L-NAME并未减弱CF的增加。各组间DP无显著差异。