Short-acting calcium antagonist clevidipine protects against reperfusion injury via local nitric oxide-related mechanisms in the jeopardised myocardium.
BACKGROUND
Calcium antagonists may, in addition to their classical actions, release nitric oxide (NO) from coronary arteries. The aim of this study was to elucidate the possible interaction between the cardioprotective effect of a short-acting calcium antagonist and NO during myocardial ischaemia and reperfusion.


METHODS
Anaesthetised pigs were subjected to 45 min ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Five groups were given vehicle (n=9), clevidipine (n=8), the NO synthase inhibitor L-NMMA (n=6), clevidipine in combination with L-NMMA (n=6) or clevidipine in combination with L-NMMA and NO precursor L-arginine (n=6) into the LAD during the last 10 min of ischaemia and the first 5 min of reperfusion.


RESULTS
There were no significant differences in LAD blood flow, mean arterial pressure, rate-pressure product or dP/dt between the groups before ischaemia or during reperfusion. The infarct size (IS) was 86+/-2% of the area at risk in the vehicle group. Clevidipine reduced the IS to 59+/-3% (P<0.001). When clevidipine was administered together with L-NMMA, the protective effect of clevidipine was abolished (IS, 87+/-3%; P<0.001 vs. clevidipine), whereas addition of L-arginine restored its cardioprotective effect (IS 60+/-3%; P<0.001 vs. vehicle). L-NMMA did not affect IS per se (88+/-5%). Endothelium-dependent coronary vasodilation induced by substance P was significantly larger in the clevidipine group than in the other groups.


CONCLUSIONS
Local administration of a calcium antagonist during the late ischaemia and early reperfusion reduces IS and preserves coronary endothelial function. The cardioprotective effect of clevidipine is suggested to be dependent on maintained local bioavailability of NO.
Gourine
A
A
Department of Cardiology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
Gonon
A
A
Sjöquist
P O
PO
Pernow
J
J
D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D013373:Substance P / Q000494:pharmacology; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D011725:Pyridines; C118563:clevidipine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D013373:Substance P; D001120:Arginine; D019001:Nitric Oxide Synthase