High glucose contributes to aspirin insensitivity in streptozotocin-diabetic rats: a multiparametric aggregation study

Abstract

The effect of chronic hyperglycaemia on blood platelet response to acetylsalicylic acid was studied in rats with experimental diabetes. Platelet aggregation was determined in non-diabetic and streptozotocin-diabetic rats treated orally with 4 or 40 mg aspirin (ASA)/kg per day (for 8 weeks from the eighth day of diabetes) using whole blood impedance aggregometry with arachidonic acid or ADP as platelet agonists. The dose-dependent effect of ASA 'therapy' on ADP-agonized platelets was significant only in non-diabetic animals, while in diabetic rats both doses were ineffective in reducing ADP-stimulated platelet aggregation. ASA-mediated increased acetylation of platelet proteins favoured reduced platelet aggregation and slower platelet disaggregation (Pr < 0.025 or less). Interestingly, however, the occupation of platelet protein-free amino groups was significantly higher in control rats compared with diabetic rats (P < 0.001), pointing out that proteins of platelets in non-diabetic animals were more vulnerable for the ASA-induced acetylation. We conclude that chronic hyperglycaemia interferes with preventive effects of ASA on platelet reactivity. Our data validate the suggestion that the relationship between aspirin ineffectiveness and poor metabolic control, first revealed in humans, concerns also other animals' platelets and holds regardless of the model or type of diabetes.

Aspirin resistance and diabetes mellitus

“…An interaction between glycation and acetylation has been repeatedly shown [32][33][34], and increased glycation of platelet and coagulation factor proteins may interfere with the acetylation process to contribute to aspirin resistance in the presence of diabetes [35]. In vivo studies support this notion, as rats with streptozotocin-induced diabetes have a reduced platelet response to aspirin compared with nondiabetic animals, an effect related to reduced acetylation of platelet proteins [36]. If competition between acetylation and glycation of proteins affects the efficacy of aspirin in diabetes, it will be important to evaluate whether improving glycaemic control enhances the efficacy of aspirin and whether, in the presence of poor control, increased doses of aspirin are required [37,38].…”

Antioxidative enzyme and glutathione S-transferase activities in diabetic rats exposed to long-term ASA treatment

“…The rats injected with STZ were considered diabetic if their fasting blood glucose was > 200 mg/dl (Blood Glucose Sensor Electrodes, MediSense, Abbot Laboratories, Bedford, UK). Because this study was performed along with another one, devoted to the effects of long-term hyperglycemia and ASA treatment on blood platelet reactivity and platelet prostanoid metabolism, we used the same protocol of ASA administration: low and high ASA doses differed in their efficacy at hampering thromboxane generation and platelet reactivity (Watala et al, 2006). Some nondiabetic animals were injected daily with physiological saline solution (i.p.)…”

Frequency, Risk Factors, Prognosis, and Genetic Polymorphism of the Cyclooxygenase-1 Gene for Aspirin Resistance in Elderly Chinese Patients with Cardiovascular Disease

“…Several studies have shown an association between diabetes and aspirin resistance in humans and in animal models [31,32]. In most of these studies, an association between aspirin resistance and elevated HbA1c and increased fasting serum glucose levels was reported in diabetic patients [33,34,35].…”