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New Findings: What is the central question of this study?Does acute exposure to high molecular weight advanced glycation end products (HMW‐AGEs) alter cardiomyocyte contractile function?What is the main finding and its importance?Ventricular cardiomyocytes display reduced Ca2+ influx, resulting in reduced contractile capacity, after acute exposure to HMW‐AGEs, independent of activation of their receptor. Given that HMW‐AGEs are abundantly present in our Western diet, a better understanding of underlying mechanisms, especially in patients already displaying altered cardiac function, should be gained for these compounds. Sustained elevated levels of high molecular weight advanced glycation end products (HMW‐AGEs) are known to promote cardiac dysfunction. Recent data suggest that acutely elevated levels of AGEs occur in situations of increased oxidative stress. Whether this increase might have detrimental effects on cardiac function remains unknown. In this study, we investigated whether acute exposure to HMW‐AGEs affects cardiomyocyte function via activation of their receptor (RAGE) signalling pathway. Single cardiomyocytes from the left ventricle of adult male rats were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Functional experiments were performed in cardiomyocytes pre‐incubated with or without an anti‐RAGE antibody. Unloaded cell shortening and L‐type Ca2+ current amplitude were evaluated in the presence or absence of HMW‐AGEs (200 μg ml−1). Expression of RAGE, c‐Jun N‐terminal kinase (JNK) and phosphorylated JNK (pJNK) were assessed by western blot. Experiments were performed at room temperature. After 4 min application of HMW‐AGEs, unloaded cell shortening was significantly reduced. This impaired contractile function was related to reduced Ca2+ influx. These alterations were also observed in cardiomyocytes pre‐incubated with anti‐RAGE antibody. Our study demonstrates that acute exposure to elevated levels of HMW‐AGEs leads to direct and irreversible cardiomyocyte dysfunction, independent of RAGE activation. [ABSTRACT FROM AUTHOR]