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  • The cardiotoxicity of NSAIDs except

    2020-08-03

    The cardiotoxicity of NSAIDs, except for aspirin, are well reported in many studies, and the food and drug administration (FDA) of the USA warned about the cardiovascular toxicities of NSAIDs [6]. NSAID treatment is associated with elevated blood pressure, stroke, and myocardial infarction [6,7]. Although cardiotoxicity was reported more among COX2 selective NSAIDs, it was shown that even nonselective NSAIDs increase the risk of developing cardiovascular events [8]. However, the exact mechanism by which NSAIDs exhibit cardiovascular events is not fully understood. It is suggested that NSAIDs decrease aldosterone excretion through inhibition of aldosterone glucuronidation and hence may increase the anti-diuretic effect of aldosterone and lead to elevated blood pressure [9]. In addition, inhibition of COX2 might disturb the cardioprotective pgs, such as pgI2 and H2 [10]. ARA metabolites, which are produced through cytochrome P450 (CYP450) enzymes influence cardiovascular homeostasis. Human CYP4A11 and CYP1A2 metabolize ARA to 20-hydroxyecostearonic Vacuolin-1 (20-HETE) [11], which is a vasoconstrictor [12], platelet activator [13] and naturetic in the kidney [14]. On the other hand, human CYP2C9 and CYP2J2 metabolize ARA to epoxyeicosatrienoic acids (EETs) [11], which are vasodilators and are considered cardioprotective agents [15]. Disturbance of ARA-CYP450 metabolites was associated with cardiovascular diseases, such as hypertension [16], and anticancer doxorubicin induced cardiotoxicity [17]. In addition, Lee et al. [13], found that 20-HETE was elevated 120 fold in the plasma of rofecoxib treated mice, which was associated with decreased bleeding time. Furthermore, it was recently reported that the selective COX2 inhibitors meloxicam and rofecoxib altered the ARA-CYP450 metabolites and elevated 20-HETE levels in the cardiac tissues of treated rats [18].
    Materials and methods
    Results After 14 days of NSAID administration, the physical appearance of all groups was obviously normal and the average body weight of the groups was not significantly different. However, abnormal fat in the liver was observed only in the hepatic samples of mefenamic acid, ibuprofen and meloxicam treated mice (Fig. 1). Fig. 2 shows the effects of NSAIDs on the expression of ARA-cyp450 genes in mouse kidneys. Expression of the EET synthesizing gene cyp2c29 was induced by NSAIDs by more than 2 fold compared to the control group. Expression of cyp2j5 was reduced in the kidneys after diclofenac (1.03 fold), mefenamic acid (1.4 fold), ibuprofen (2.1 fold) and meloxicam (5.7 fold) treatment compared to the control group. Only meloxicam showed a statistically Vacuolin-1 significant difference on renal cyp2j5 gene expression (p value > 0.05). In addition, NSAIDs significantly downregulated the expression of the EET metabolizing gene epdhx2 by more than 2.5 fold compared to the control group (p value < 0.05). On the other hand, NSAIDs significantly downregulated expression of 20-HETE synthesizing cyp4a12 and cyp1a2 compared to the control group (p value < 0.05), with the strongest effect seen in mefenamic acid treatment (Fig. 2). Among the tested NSAIDs, mefenamic acid and meloxicam influenced renal expression of ARA-metabolizing cyp450 genes more strongly than diclofenac and ibuprofen. Collectively, NSAIDs increased the ratio of gene expression of EETs compared to 20-HETE synthesizing enzymes in the kidney samples.