N-METHYL-D-ASPARTATE RECEPTOR INHIBITION PREVENTS GLUCOMETABOLIC DYSREGULATION AND CARDIAC INJURY IN NICOTINE-EXPOSED MALE RATS

Abstract

Objective: Since non-smoking nicotine exposure has been associated with cardiometabolic disorders and smoking cessation therapies are of great global and medical significance. N-methyl-D-aspartate receptor (NMDAR) activity has been implicated in diabetes. Although NMDAR is also expressed in cardiomyocytes, there is dearth of information on its activity on cardiometabolic dysfunctions and its associated mechanism yet to be fully elucidated. It is therefore hypothesized that NMDAR inhibition by low-dose ketamine would improve nicotine-induced glucometabolic deregulation and cardiac injury. Design and method: Male Wistar rats (n = 6/group) aged 10 weeks were given (p.o.) vehicle, nicotine (1.0 mg/kg) with or without ketamine (0.2 mg/kg) daily for 28 days. Oral glucose tolerance test was performed 24-hours to the end of the experiment. The insulin resistance was estimated using the homeostasis model assessment for insulin resistance (HOMA-IR). Results: Data showed that nicotine exposure led to insulin resistance, hyperinsulinemia, elevated 1-hour postload glucose, glucose intolerance, triglyceride-glucose index. Likewise, plasma and cardiac uric acid, malondialdehyde, lactate, triglyceride (TG), TG/HDL-C, oxidized glutathione (GSSG) levels, creatinine kinase (CK), lactate dehydrogenase (LDH), adenosine deaminase (ADA), xanthine oxidase (XO) activities were increased in nicotine-exposed rats. On the other hand, plasma and cardiac nitric oxide level was reduced by nicotine exposure. However, ketamine treatment also led to elevated TG, LDH, lactate, CK activity, nitric oxide, and reduced TG/HDL-C, uric acid, MDA, GSSG levels, XO and ADA activities when compared to control. However, these nicotine-induced cardiometabolic disorders were ameliorated in ketamine-treated rats. Conclusions: The results demonstrated that low-dose ketamine prevents glucose dysregulation, plasma and cardiac TG, uric acid, lactate accumulation and suppressed ADA, XO and CK activities. Therefore, these findings imply that inhibition of NMDAR by low dose-ketamine improves glucometabolic regulation and ameliorates cardiac injury through ADA/XO/CK-dependent mechanisms.