Kudej R K, Zhang X P, Ghaleh B, Huang C H, Jackson J B, Kudej A B, Sato N, Sato S, Vatner D E, Hintze T H, Vatner S F
Cardiovascular Research Institute and Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103, USA.
Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H2967-74. doi: 10.1152/ajpheart.2000.279.6.H2967.
The goal of the current study was to determine the effects of cAMP-mediated coronary reactivity in conscious pigs with stunned myocardium induced by 1.5 h coronary stenosis (CS) and 12 h coronary artery reperfusion (CAR). Domestic swine (n = 5) were chronically instrumented with a coronary artery blood flow (CBF) probe, hydraulic occluder, left ventricular pressure gauge, wall-thickening crystals in the ischemic and nonischemic zones, and a coronary sinus catheter. The hydraulic occluder was inflated to induce a CS with a stable 38 +/- 1% reduction in CBF for 1.5 h. Before flow reduction and during CAR, cAMP-induced coronary vasodilation was investigated by forskolin (20 nmol. kg(-1). min(-1)). Enhanced CBF responses [+62 +/- 9%, P < 0.05, compared with pre-CS (+37 +/- 3%)] were observed for forskolin at 12 h after CAR as well as for bradykinin and reactive hyperemia. With the use of a similar protocol during systemic nitric oxide (NO) synthase inhibition with N(omega)-nitro-L-arginine (30 mg. kg(-1). day(-1) for 3 days), the enhanced CBF responses to forskolin, bradykinin, and reactive hyperemia were not observed after CS. Isolated microvessel preparations from pigs (n = 8) also demonstrated enhanced NO production to direct stimulation of adenylyl cyclase with forskolin (+71 +/- 12%) or NKH-477 (+60 +/- 10%) and administration of 8-bromo-cAMP (+74 +/- 13%), which were abolished by protein kinase A or NO synthase inhibition. These data indicate that cAMP stimulation elicits direct coronary vasodilation and that this action is amplified in the presence of sustained myocardial stunning after recovery from CS. This enhanced cAMP coronary vasodilation is mediated by an NO mechanism that may be involved in myocardial protection from ischemic injury.
本研究的目的是确定环磷酸腺苷（cAMP）介导的冠状动脉反应性对清醒猪的影响，这些猪的心肌因1.5小时冠状动脉狭窄（CS）和12小时冠状动脉再灌注（CAR）而受到损伤。选用家猪（n = 5），长期植入冠状动脉血流（CBF）探头、液压阻塞器、左心室压力计、缺血区和非缺血区的室壁增厚晶体以及冠状窦导管。通过充气液压阻塞器诱导冠状动脉狭窄，使CBF稳定降低38±1%，持续1.5小时。在血流减少前和冠状动脉再灌注期间，通过福斯高林（20 nmol·kg⁻¹·min⁻¹）研究cAMP诱导的冠状动脉舒张。冠状动脉再灌注12小时后，观察到福斯高林以及缓激肽和反应性充血的CBF反应增强[与冠状动脉狭窄前（+37±3%）相比，增加了+62±9%，P < 0.05]。在用N（ω）-硝基-L-精氨酸（（30 mg·kg⁻¹·天⁻¹，持续3天）抑制全身一氧化氮（NO）合酶的过程中，采用类似方案，冠状动脉狭窄后未观察到福斯高林、缓激肽和反应性充血的CBF反应增强。从猪（n = 8）分离的微血管制剂也显示，用福斯高林（+71±12%）或NKH-477（+60±10%）直接刺激腺苷酸环化酶以及给予8-溴-cAMP（+74±13%）后，NO生成增加，而蛋白激酶A或NO合酶抑制可消除这种增加。这些数据表明，cAMP刺激可引起直接的冠状动脉舒张，并且在从冠状动脉狭窄恢复后存在持续性心肌损伤时，这种作用会增强。这种增强的cAMP介导的冠状动脉舒张是由一种NO机制介导的，该机制可能参与心肌对缺血性损伤的保护。
