The cardio-protective properties of Ncx-6550, a nitric oxide donating pravastatin, in the mouse.
OBJECTIVE
Determine the cardio-protective properties of a nitric oxide-releasing pravastatin (Ncx-6550), in comparison to pravastatin.


METHODS
A mouse model of myocardial infarct was used assessing tissue damage both at 2 and 24 hour post-reperfusion, administering compounds both prophylactically and therapeutically.


RESULTS
Ncx-6550 induced a significant dose-dependent (2.24-22.4 micromol/kg i.p.) cardioprotection in the two hour reperfusion protocol. In vehicle-treated mice, infarct size (expressed as fraction of area at risk; IS/AR) was 41.2 +/- 1%, and it was reduced to 22.2 +/- 0.9% and 32.6 +/- 0.9% following 22.4 and 6.72 micromol/kg Ncx-6550 (p < 0.05). 22.4 micromol/kg Ncx-6550 also increased cardiac levels of the enzyme heme oxygenase-1. Treatment of mice with pravastatin induced significant reduction of myocardial injury only at 22.4 micromol/kg (IS/AR value: 33.7 +/- 0.9%). In a 24 hour reperfusion protocol, Ncx-6550 and pravastatin were tested only at 22.4 micromol/kg i.p. being given either one hour prior to ischemia (prophylactic protocol) or one hour into reperfusion (therapeutic protocol). With either treatment scheme, Ncx-6550 produced higher cardioprotection compared to pravastatin, as reflected also by a reduction in the incidence of lethality as well as in circulating troponin I and interleukin-1beta levels.


CONCLUSIONS
These results indicate Ncx-6550 as a novel therapeutic agent with a potential for the treatment of myocardial infarct.
Di Filippo
Clara
C
Department of Experimental Medicine, Section of Pharmacology, 2nd University of Naples, Italy.
Monopoli
Angela
A
Ongini
Ennio
E
Perretti
Mauro
M
D'Amico
Michele
M
D000818:Animals; D002316:Cardiotonic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009566:Nitrates / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics / Q000494:pharmacology*; D009573:Nitrites / Q000097:blood; D017035:Pravastatin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D019210:Troponin I / Q000097:blood
C516976:1,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid 4-(nitrooxy)butyl ester; D002316:Cardiotonic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D019210:Troponin I; D051547:Heme Oxygenase-1; D017035:Pravastatin