O11 | In vitro and in vivo effects of dapagliflozin on adenosine diphosphate induced platelet aggregation response in Göttingen minipigs
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O11 | In vitro and in vivo effects of dapagliflozin on adenosine diphosphate induced platelet aggregation response in Göttingen minipigs. / Hinz, Kathrin; Lyhne, Mille Kronborg; Debes, K. P.; Reimann, Maria Josefine; Flethøj, M.; Bruun, Camilla Vibeke Sichlau; Ludvigsen, Trine Pagh; Kirchhoff, J.; Jespersen, Thomas; Pedersen, H. D.; Møller, J. E.; Olsen, Lisbeth Høier.
I: Journal of Veterinary Pharmacology and Therapeutics, Bind 46, Nr. S1, O11, 2023, s. 33.Publikation: Bidrag til tidsskrift › Konferenceabstrakt i tidsskrift › Forskning › fagfællebedømt
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T1 - O11 | In vitro and in vivo effects of dapagliflozin on adenosine diphosphate induced platelet aggregation response in Göttingen minipigs
AU - Hinz, Kathrin
AU - Lyhne, Mille Kronborg
AU - Debes, K. P.
AU - Reimann, Maria Josefine
AU - Flethøj, M.
AU - Bruun, Camilla Vibeke Sichlau
AU - Ludvigsen, Trine Pagh
AU - Kirchhoff, J.
AU - Jespersen, Thomas
AU - Pedersen, H. D.
AU - Møller, J. E.
AU - Olsen, Lisbeth Høier
PY - 2023
Y1 - 2023
N2 - Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) including dapagliflozin (DAPA) reduce cardiovascular morbidity and mortality in human patients with heart failure. The underlying mech-anisms of the beneficial cardiovascular effects are incompletely un-derstood. Previous in vitro study has suggested inhibitory effect of SGLT2i on human platelet activity, and the effect was enhanced by adding endothelial derived factors (nitric oxide (NO) and prostacy-clin (PGI)). The aim of the present study was to investigate if DAPA inhibited porcine adenosine diphosphate (ADP) induced platelet ag-gregation response, and if NO and PGI enhanced the inhibitory ef-fect. Moreover, platelet aggregation response in a porcine model of ischemic myocardial injury (MI) was investigated after 6–7 weeks of oral DAPA therapy.Patients and Methods: Platelet rich plasma (PRP) from 12 healthy Göttingen Minipigs was incubated with low (0.4 μM) and high (30 μM) concentrations of DAPA alone and in combination with NO and PGI. Platelet aggregation response was induced using 10 μM ADP. In ad-dition, platelet aggregation was induced in PRP from 26 Göttingen Minipigs with experimental induced ischemic MI and randomized for daily oral DAPA (10 mg/pig (n = 13)) or placebo (n = 13) treatment for 6– 7 weeks using 5, 10 and 20 μM ADP. Platelet aggregation response was analyzed using light transmission aggregometry and maximal aggregation response (Max), velocity of aggregation (Vel) and area under the aggregation curve (AUC) as outcomes.Results: DAPA did not inhibit ADP induced platelet aggregation response in healthy Göttingen Minipigs alone nor in combination with NO and PGI. Unexpected a mild stimulating effect of DAPA was found using both low (Max (p < .0001); AUC (p = .0005); Vel (p < .0001)) as well as high (Max (p = .03); AUC (p = .03); Vel (p < .0004)) DAPA concentrations. For Max the stimulatory effect further in-creased when DAPA was combined with NO and PGI (low (p = .02) and high (p = .03) DAPA concentrations). The ADP induced platelet aggregation response in PRP from Göttingen Minipigs with ischemic MI and daily DAPA treatment was not different from the placebo group.Conclusions: The SGLT2i DAPA did not inhibit ADP induced platelet aggregation in vitro in healthy nor in vivo in Göttingen Minipigs with experimental induced ischemic MI. Unexpectedly DAPA slightly increased the ADP induced aggregation response in vitro. Further studies are needed to elucidate potential differences between por-cine and human platelet biology regarding SGLT2i effect.Acknowledgements: The study was funded by the LIFEPHARM Center at University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary and Animal Sciences and Novo Nordisk A/S.
AB - Introduction: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) including dapagliflozin (DAPA) reduce cardiovascular morbidity and mortality in human patients with heart failure. The underlying mech-anisms of the beneficial cardiovascular effects are incompletely un-derstood. Previous in vitro study has suggested inhibitory effect of SGLT2i on human platelet activity, and the effect was enhanced by adding endothelial derived factors (nitric oxide (NO) and prostacy-clin (PGI)). The aim of the present study was to investigate if DAPA inhibited porcine adenosine diphosphate (ADP) induced platelet ag-gregation response, and if NO and PGI enhanced the inhibitory ef-fect. Moreover, platelet aggregation response in a porcine model of ischemic myocardial injury (MI) was investigated after 6–7 weeks of oral DAPA therapy.Patients and Methods: Platelet rich plasma (PRP) from 12 healthy Göttingen Minipigs was incubated with low (0.4 μM) and high (30 μM) concentrations of DAPA alone and in combination with NO and PGI. Platelet aggregation response was induced using 10 μM ADP. In ad-dition, platelet aggregation was induced in PRP from 26 Göttingen Minipigs with experimental induced ischemic MI and randomized for daily oral DAPA (10 mg/pig (n = 13)) or placebo (n = 13) treatment for 6– 7 weeks using 5, 10 and 20 μM ADP. Platelet aggregation response was analyzed using light transmission aggregometry and maximal aggregation response (Max), velocity of aggregation (Vel) and area under the aggregation curve (AUC) as outcomes.Results: DAPA did not inhibit ADP induced platelet aggregation response in healthy Göttingen Minipigs alone nor in combination with NO and PGI. Unexpected a mild stimulating effect of DAPA was found using both low (Max (p < .0001); AUC (p = .0005); Vel (p < .0001)) as well as high (Max (p = .03); AUC (p = .03); Vel (p < .0004)) DAPA concentrations. For Max the stimulatory effect further in-creased when DAPA was combined with NO and PGI (low (p = .02) and high (p = .03) DAPA concentrations). The ADP induced platelet aggregation response in PRP from Göttingen Minipigs with ischemic MI and daily DAPA treatment was not different from the placebo group.Conclusions: The SGLT2i DAPA did not inhibit ADP induced platelet aggregation in vitro in healthy nor in vivo in Göttingen Minipigs with experimental induced ischemic MI. Unexpectedly DAPA slightly increased the ADP induced aggregation response in vitro. Further studies are needed to elucidate potential differences between por-cine and human platelet biology regarding SGLT2i effect.Acknowledgements: The study was funded by the LIFEPHARM Center at University of Copenhagen, Faculty of Health and Medical Sciences, Department of Veterinary and Animal Sciences and Novo Nordisk A/S.
U2 - 10.1111/jvp.13177
DO - 10.1111/jvp.13177
M3 - Conference abstract in journal
VL - 46
SP - 33
JO - Journal of Veterinary Pharmacology and Therapeutics
JF - Journal of Veterinary Pharmacology and Therapeutics
SN - 0140-7783
IS - S1
M1 - O11
T2 - 15th International Congress of the European Association for Veterinary Pharmacology and Toxicology held Bruges, Belgium, July 2–5, 2023
Y2 - 2 July 2023 through 5 July 2023
ER -
ID: 370487059