The Novel Cardioprotective Effects of Naltrindole to Mitigate Rigor During Ischemia
Date of Award
7-2024
Degree Type
Thesis
Degree Name
Master of Science in Biomedical Sciences
First Advisor
Dr. Lindon Young
Second Advisor
Qian Chen Ph.D
Third Advisor
Kelsey Kjosness Ph.D
Abstract
Introduction: Previously, naltrindole (NTI) produced robust cardioprotective effects in both ex-vivo and in-vivo rat myocardial ischemia (MI) injury, and attenuated phorbol 12-myristate 13- acetate (PMA) induced polymorphonuclear leukocytes (PMNs) superoxide (SO) release by a novel mechanism of action (MOA) devoid of opioid receptors. To test this hypothesis, we conducted PMN SO release and isolated perfused MI assays using KB-R7943 (KB), a reverse mode Na+/Ca2+ exchange inhibitor. KB should attenuate PMN SO release, MI infarct size, and improve left ventricular end diastolic pressure (LVEDP). Methods: PMNs and hearts isolated from anesthetized male Sprague Dawley rats. PMN SO release was stimulated using PMA (100 nM) ± NTI 10-200 μM, KB 5-20 μM, naloxone (NX)100-200 μM or vehicle control and measured spectrophotometrically. Cell viability was determined using 0.2% Trypan blue exclusion. NTI 1.25-5 μM, KB 10-20 μM, or NX 10 μM was given to perfused hearts, just prior to global I(30 min)/R(45 min). A pressure transducer measured LV function, and infarct size determined using 1% triphenyltetrazolium chloride staining. Data analyzed using ANOVA and Fishers post-hoc analysis, with p<0.05 considered statistically significant. Results: KB (20 μM, n=7) and NTI (200 μM, n=7) significantly reduced PMN SO release by 40.2 ± 7.8% and 53.5 ± 6.2% respectively when compared to vehicle (n=10), whereas NX 10-200 μM, (n=3) did not. NTI 5 μM and KB 20 μM reduced infarct size by 4.8 ± 3%, (n=5, p<0.05) and 2.9 ± 2%, (n=5, p<0.05) respectively compared to vehicle 14.1 ± 2%, (n=9). NTI 5 μM and KB 20 μM significantly reduced final LVEDP to 32.4 ± 11 mmHg, (n=5) and 22.8 ± 4 mmHg, (n=5) (both p<0.05) respectively compared to vehicle 72.4 ± 6 mmHg, (n=9), whereas NX 10 μM 54.2 ± 8% did not (n=3). Conclusion: The novel MOA of NTI cardioprotecton is mediated via a reduction in [Ca2+]in, and may benefit patients undergoing MI procedures.
Recommended Citation
Stinson, Cameron, "The Novel Cardioprotective Effects of Naltrindole to Mitigate Rigor During Ischemia" (2024). PCOM Biomedical Studies Student Scholarship. 238.
https://digitalcommons.pcom.edu/biomed/238