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Does acute treatment of dapagliflozin reduce cardiac infarct size through direct cardiac effects or reductions in blood glucose levels?
Cardiovascular Diabetology volume 19, Article number: 141 (2020)
In a recent article in this Journal, Lahnwong and co-workers , reported that acute pre-treatment of dapagliflozin just 15 min before start LAD occlusion reduced infarct size to a large extent in Wistar rats. These results are remarkable considering that most studies examining acute treatment with a SGLT2 inhibitor reported no effect on cardiac infarct size; only following chronic treatment (> > 1 d) do SGLT2i’s significantly reduce infarct size . The question therefore arises what sets this study apart?
The answers may be found in the anesthetic regimen: animals were anesthetized with Zoletil and xylazine . It is known that α2-adrenergic agonists such as xylazine or medetomidine acutely raise blood glucose to hyperglycemic values [3, 4] in non-fasted animals, through inhibition of insulin release from pancreatic β cells. Numerous studies have demonstrated that hyperglycemia is strongly associated with increased infarct size . We therefore postulate that the intravenously administered dapagliflozin quickly lowered the high blood glucose levels in these animals, thereby explaining the reduction in infarct size by dapagliflozin in this experimental condition. It is therefore unfortunate that no information is provided by the authors on blood glucose, insulin, and ketone levels. We believe that in the search of potential cardioprotective mechanisms of SGLT2i’s, the nutritional status of the animal (fed versus fasted) and the substrate and hormone levels in the blood during the intervention being studied, should always be reported when examining these most promising antidiabetic drugs.
Availability of data and materials
Lhanwong S, Palee S, Apaijai N, Sriwichaiin S, Kerdphoo S, Jaiwongkam T, Chattipakom S, Chattipakom N. Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury. Cardiovasc Diabetol. 2020;19(1):91.
Andreadou I, Bell RM, Bøtker HE, Zuurbier CJ. SGLT2 inhibitors reduce infarct size in reperfused ischemic heart and improve cardiac function during ischemic episodes in preclinical models. Biochim Biophys Acta Mol Basis Dis. 2020;1866(7):165770.
Saha JK, Xia J, Grondin JM, Engle SK, Jakubowski JA. Acute hyperglycemia induced by ketamine/xylazine anesthesia in rats: mechanism and implications for preclinical models. Exp Biol Med. 2005;230:777–84.
Zuurbier CJ, Keijzers PJM, Koeman A, van Wezel HB, Hollmann MW. Anesthesia’s effects on plasma glucose and insulin and cardiac hexokinase at similar hemodynamics and without major surgical stress in rats. Anesth Analg. 2008;106:135–42.
Penna C, Andreadou I, Aragno M, Beauloye C, Bertrand L, Lazou A, Falcao-Pires I, Bell R, Zuurbier CJ, Pagliaro P, Hausenloy DJ. Effect of hyperglycemia and diabetes on acute myocardial ischemia-reperfusion injury and cardioprotection by ischemic conditioning protocols. Br J Pharmacol. 2020. https://doi.org/10.1111/bph.14993.
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Zuurbier, C.J. Does acute treatment of dapagliflozin reduce cardiac infarct size through direct cardiac effects or reductions in blood glucose levels?. Cardiovasc Diabetol 19, 141 (2020). https://doi.org/10.1186/s12933-020-01119-z
- Infarct size