Cardioprotective effects of ingliforib, a novel glycogen phosphorylase inhibitor.
Interventions such as glycogen depletion, which limit myocardial anaerobic glycolysis and the associated proton production, can reduce myocardial ischemic injury; thus it follows that inhibition of glycogenolysis should also be cardioprotective. Therefore, we examined whether the novel glycogen phosphorylase inhibitor 5-Chloro-N-[(1S,2R)-3-[(3R,4S)-3,4-dihydroxy-1-pyrrolidinyl)]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (ingliforib; CP-368,296) could reduce infarct size in both in vitro and in vivo rabbit models of ischemia-reperfusion injury (30 min of regional ischemia, followed by 120 min of reperfusion). In Langendorff-perfused hearts, constant perfusion of ingliforib started 30 min before regional ischemia and elicited a concentration-dependent reduction in infarct size; infarct size was reduced by 69% with 10 microM ingliforib. No significant drug-induced changes were observed in either cardiac function (heart rate, left ventricular developed pressure) or coronary flow. In open-chest anesthetized rabbits, a dose of ingliforib (15 mg/kg loading dose; 23 mg.kg(-1).h(-1) infusion) selected to achieve a free plasma concentration equivalent to an estimated EC(50) in the isolated hearts (1.2 microM, 0.55 microg/ml) significantly reduced infarct size by 52%, and reduced plasma glucose and lactate concentrations. Furthermore, myocardial glycogen phosphorylase a and total glycogen phosphorylase activity were reduced by 65% and 40%, respectively, and glycogen stores were preserved in ingliforib-treated hearts. No significant change was observed in mean arterial pressure or rate-pressure product in the ingliforib group, although heart rate was modestly decreased postischemia. In conclusion, glycogen phosphorylase inhibition with ingliforib markedly reduces myocardial ischemic injury in vitro and in vivo; this may represent a viable approach for both achieving clinical cardioprotection and treating diabetic patients at increased risk of cardiovascular disease.
Tracey
W Ross
WR
Pfizer Global Research and Development, MS8220-3125, Eastern Point Rd., Groton, CT 06340, USA. w_ross_tracey@groton.pfizer.com
Treadway
Judith L
JL
Magee
William P
WP
Sutt
Jill C
JC
McPherson
R Kirk
RK
Levy
Carolyn B
CB
Wilder
Donald E
DE
Yu
Li J
LJ
Chen
Yue
Y
Shanker
Ravi M
RM
Mutchler
Alison K
AK
Smith
Andrew H
AH
Flynn
David M
DM
Knight
Delvin R
DR
D000818:Animals; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D011759:Pyrrolidines; D006003:Glycogen; D024981:Glycogen Phosphorylase; C483083:ingliforib