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Pre-clamp cardioprotection by protein kinase C (PKC) inhibitor improves left ventricular function following canine
C E Anagnostopoulos1, C P Connery, H Dumont
1St. Luke's-Roosevelt Hospital Center at Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Insights
Protein kinase C (PKC) inhibition with SPC-100270 protected canine myocardium from ischemic/reperfusion injury (IRI). This PK inhibitor significantly improved ejection fraction post-cardiac arrest, suggesting therapeutic potential.
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Protein kinase C (PKC) is implicated in neutrophil activation and calcium homeostasis.
- PKC activity contributes to myocardial damage during ischemic/reperfusion injury (IRI).
Purpose of the Study:
- To assess the efficacy of the protein kinase inhibitor SPC-100270 in a canine model of myocardial IRI.
- To evaluate SPC-100270's protective effects on cardiac function following ischemic insult.
Main Methods:
- A double-blind study involving 19 coonhound dogs subjected to cardiopulmonary bypass (CPB).
- Animals received either SPC-100270 or a vehicle control before 60 minutes of cardiac arrest.
- Ejection fraction (EF) was measured via echocardiography post-reperfusion.
Main Results:
- 5 out of 9 dogs treated with SPC-100270 exhibited an EF > 20% (range 27%-44%).
- None of the 10 control dogs achieved an EF > 20% (range 0%-16%).
- SPC-100270 significantly increased the likelihood of maintaining EF > 20% (p=0.01).
Conclusions:
- SPC-100270 demonstrates significant cardioprotective effects against IRI in a canine model.
- Inhibition of PKC with SPC-100270 may be a viable strategy to mitigate myocardial damage.
- Further research into SPC-100270 for IRI treatment is warranted.
Abstract:
Since protein kinase C (PKC) has been proven to be a mediator of neutrophil activation and of intracellular calcium homeostasis, its inhibition could protect the myocardium from the deleterious effects of ischemic/reperfusion inury (IRI). The principal objective of this study was to evaluate the efficacy of the PK inhibitor SPC-100270 (2S,3S)-2-amino, 3-octadecanediol in a canine model of IRI. A double-blind study was conducted in which 19 coonhound dogs received either SPC-100270 or a vehicle before going on cardiopulmonary bypass (CPB). After 60 minutes of global normothermic (37 degree C) cardiac arrest (cross-clamp time 65-81 minutes for SPC-100270 and 65-72 minutes for control) and discontinuation of CBP, an epicardial short axis view echocardiogram was performed and reviewed by a double-blinded observer to determine the ejection fraction (EF). EF value exceeded 20% in 5 out of 9 SPC-100270 animals (27%-44%) and in 0 of 10 controls (0%-16%). These data show that SPC-10027 significantly (p=0.01 by Fisher's Exact Test) increased the probability that the animals would exhibit an EF greater than 20%.