EGFR-TKI, erlotinib, causes hypomagnesemia, oxidative stress, and cardiac dysfunction: attenuation by NK-1 receptor blockade.
Journal of cardiovascular pharmacology(2015)
摘要
To determine whether the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib may cause hypomagnesemia, inflammation, and cardiac stress, erlotinib was administered to rats (10 mg · kg(-1)· d(-1)) for 9 weeks. Plasma magnesium decreased progressively between 3 and 9 weeks (-9% to -26%). Modest increases in plasma substance P (SP) occurred at 3 (27%) and 9 (25%) weeks. Neutrophil superoxide-generating activity increased 3-fold, and plasma 8-isoprostane rose 210%, along with noticeable appearance of cardiac perivascular nitrotyrosine. The neurokinin-1 (NK-1) receptor antagonist, aprepitant (2 mg · kg(-1) · d(-1)), attenuated erlotinib-induced hypomagnesemia up to 42%, reduced circulating SP, suppressed neutrophil superoxide activity and 8-isoprostane elevations; cardiac nitrotyrosine was diminished. Echocardiography revealed mild to moderately decreased left ventricular ejection fraction (-11%) and % fractional shortening (-17%) by 7 weeks of erlotinib treatment and significant reduction (-17.5%) in mitral valve E/A ratio at week 9 indicative of systolic and early diastolic dysfunction. Mild thinning of the left ventricular posterior wall suggested early dilated cardiomyopathy. Aprepitant completely prevented the erlotinib-induced systolic and diastolic dysfunction and partially attenuated the anatomical changes. Thus, chronic erlotinib treatment does induce moderate hypomagnesemia, triggering SP-mediated oxidative/inflammation stress and mild-to-moderate cardiac dysfunction, which can largely be corrected by the administration of the SP receptor blocker.
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