Owasoyo J O, Jay M, Gillespie M N
College of Pharmacy, Division of Pharmacology, University of Kentucky, Lexington 40536-0082.
Toxicol Appl Pharmacol. 1988 Jan;92(1):86-94. doi: 10.1016/0041-008x(88)90230-x.
Excessive cigarette smoking is recognized as a major risk factor for ischemic heart disease. Although the mechanism by which smoking enhances this risk is not known, multiple lines of indirect evidence suggest that an adverse effect of nicotine on the interaction between neutrophils and the myocardium may play a central pathogenic role. Accordingly, this study employed an isolated rabbit heart preparation perfused at a constant flow rate with physiologic salt solution containing autologous neutrophils to test the hypotheses that nicotine promotes myocardial neutrophil uptake and that an augmented myocardial neutrophil burden intensifies the actions of stimulated neutrophils on the coronary circulation. Addition of 10(-7) M nicotine to the perfusion medium caused an abrupt and sustained sequestration of 111In-labeled neutrophils by isolated rabbit hearts. In contrast, preincubation of neutrophils in 10(-7) M nicotine without inclusion of the alkaloid in the perfusion medium failed to promote neutrophil uptake. Nicotine neither enhanced myocardial neutrophil sequestration induced by perfusion with hypoxic medium nor potentiated neutrophil chemotactic responses evoked by leukotriene B4, the putative mediator of hypoxia-induced myocardial neutrophil uptake. In addition, nicotine failed to influence either baseline levels or the hypoxia-induced accumulation of immunoreactive leukotriene B4 detected in myocardial biopsies. The inflammatory cell stimulant, formylmethionyl-leucyl-phenylalanine (fMLP), increased coronary vascular resistance in neutrophil-perfused hearts but not in hearts perfused with neutrophil-free medium. The magnitude of the fMLP-induced coronary response was augmented when the myocardial neutrophil burden was increased by the addition of nicotine to the perfusion medium or by perfusion with hypoxic medium. These observations suggest that nicotine promotes myocardial neutrophil uptake by mechanisms that do not relate to enhanced release and/or effects of endogenous leukotriene B4 and that sequestration of neutrophils intensifies their actions on the coronary circulation.
过度吸烟被认为是缺血性心脏病的主要危险因素。尽管吸烟增加这种风险的机制尚不清楚，但多条间接证据表明，尼古丁对中性粒细胞与心肌之间相互作用的不良影响可能起着核心致病作用。因此，本研究采用以恒定流速灌注含自体中性粒细胞的生理盐溶液的离体兔心标本，以检验尼古丁促进心肌摄取中性粒细胞以及增加的心肌中性粒细胞负荷会增强受刺激的中性粒细胞对冠脉循环作用的假设。向灌注培养基中添加10(-7)M尼古丁会导致离体兔心突然且持续地滞留111In标记的中性粒细胞。相比之下，将中性粒细胞在10(-7)M尼古丁中预孵育但灌注培养基中不包含该生物碱，则无法促进中性粒细胞摄取。尼古丁既没有增强缺氧培养基灌注诱导的心肌中性粒细胞滞留，也没有增强白三烯B4（缺氧诱导心肌摄取中性粒细胞的假定介质）诱发的中性粒细胞趋化反应。此外，尼古丁对心肌活检中检测到的免疫反应性白三烯B4的基线水平或缺氧诱导的积累均无影响。炎性细胞刺激剂甲酰甲硫氨酰-亮氨酰-苯丙氨酸（fMLP）会增加中性粒细胞灌注心脏的冠脉血管阻力，但对无中性粒细胞灌注的心脏无此作用。当通过向灌注培养基中添加尼古丁或用缺氧培养基灌注来增加心肌中性粒细胞负荷时，fMLP诱导的冠脉反应幅度会增大。这些观察结果表明，尼古丁通过与内源性白三烯B4的释放增强和/或作用无关的机制促进心肌摄取中性粒细胞，并且中性粒细胞的滞留会增强它们对冠脉循环的作用。
