Pretreatment with Naltrindole Demonstrates Cardioprotection in an Acute In Vivo Model of Ischemia/Reperfusion Injury
Location
Philadelphia, PA
Start Date
11-5-2022 1:00 PM
End Date
11-5-2022 4:00 PM
Description
Myocardial infarctions (MI) remain prevalent in the U.S. with over one million cardiac events every year. Previous research indicates delta opioid receptor activation mimics pharmacologic preconditioning by reducing infarct size post-MI. However, our results have shown that naltrindole (NTI), a selective delta opioid receptor antagonist, elicits unexpected cardioprotective effects ex-vivo when given prior to 30min global ischemia (I) followed by 45min reperfusion (R). We aim to determine the cardioprotective effects of NTI in an in-vivo model.
Female Sprague-Dawley rats (~250g) were assigned to control (0.9% NaCl, n=15) or (0.2mg/kg NTI, n=15). Thereafter, LD NTI (0.4-1.0 mg/kg, n=3) and high dose (HD, 4.0-8.0 mg/kg, n=5) were added to the study to measure cardiac function via a pressure transducer. Rats were anesthetized with ketamine-xylazine (90 mg/kg, 9mg/kg). NTI was infused (0.4mL/min) through the jugular vein over 5 mins (pretreatment) before I(30min)/R(3hrs) via proximal left anterior descending coronary artery. Hearts were stained with Superimperse blue dye and 1% triphenyltetrazolium chloride to determine infarct size. Data were analyzed via ANOVA Student Newman Keuls post-hoc analysis and unpaired t-tests, p<0.05 was considered statistically significant.
HD NTI (n=5) significantly depressed dP/dt max (6167±489 mmHg/s vs. 3714±645 mmHg/s), dP/dt min (-7015±942 mmHg/s vs. -4034±776 mmHg/s), and heart rate (261±20 BPM vs. 208±3 BPM) at the end of pretreatment compared to LD NTI (0.4-1.0 mg/kg, n=3 all p<0.05). This preconditioning effect correlated with decreased infarct size. HD NTI exhibited ~60% reduction in infarct size (21±7 %; n=4, p<0.01) vs. control (57±2 %; n=15) and LD NTI (55±4 %; n=18). These results mirrored ex-vivo studies, although a 20x dose was needed in-vivo to presumably overcome compensatory neurohormonal responses. Results suggest that NTI pretreatment can protect against I/R injury. Future studies will further examine 15 and 30 mg/kg dosage of NTI to examine potential effects on infarct size reduction.
Embargo Period
5-26-2022
Pretreatment with Naltrindole Demonstrates Cardioprotection in an Acute In Vivo Model of Ischemia/Reperfusion Injury
Philadelphia, PA
Myocardial infarctions (MI) remain prevalent in the U.S. with over one million cardiac events every year. Previous research indicates delta opioid receptor activation mimics pharmacologic preconditioning by reducing infarct size post-MI. However, our results have shown that naltrindole (NTI), a selective delta opioid receptor antagonist, elicits unexpected cardioprotective effects ex-vivo when given prior to 30min global ischemia (I) followed by 45min reperfusion (R). We aim to determine the cardioprotective effects of NTI in an in-vivo model.
Female Sprague-Dawley rats (~250g) were assigned to control (0.9% NaCl, n=15) or (0.2mg/kg NTI, n=15). Thereafter, LD NTI (0.4-1.0 mg/kg, n=3) and high dose (HD, 4.0-8.0 mg/kg, n=5) were added to the study to measure cardiac function via a pressure transducer. Rats were anesthetized with ketamine-xylazine (90 mg/kg, 9mg/kg). NTI was infused (0.4mL/min) through the jugular vein over 5 mins (pretreatment) before I(30min)/R(3hrs) via proximal left anterior descending coronary artery. Hearts were stained with Superimperse blue dye and 1% triphenyltetrazolium chloride to determine infarct size. Data were analyzed via ANOVA Student Newman Keuls post-hoc analysis and unpaired t-tests, p<0.05 was considered statistically significant.
HD NTI (n=5) significantly depressed dP/dt max (6167±489 mmHg/s vs. 3714±645 mmHg/s), dP/dt min (-7015±942 mmHg/s vs. -4034±776 mmHg/s), and heart rate (261±20 BPM vs. 208±3 BPM) at the end of pretreatment compared to LD NTI (0.4-1.0 mg/kg, n=3 all p<0.05). This preconditioning effect correlated with decreased infarct size. HD NTI exhibited ~60% reduction in infarct size (21±7 %; n=4, p<0.01) vs. control (57±2 %; n=15) and LD NTI (55±4 %; n=18). These results mirrored ex-vivo studies, although a 20x dose was needed in-vivo to presumably overcome compensatory neurohormonal responses. Results suggest that NTI pretreatment can protect against I/R injury. Future studies will further examine 15 and 30 mg/kg dosage of NTI to examine potential effects on infarct size reduction.