Inhibition of inducible nitric oxide synthase after myocardial ischemia increases coronary flow.
BACKGROUND
The role of nitric oxide synthase in myocardial ischemia-reperfusion injury is complex. Our hypothesis was that inducible nitric oxide synthase has a role in the regulation of coronary flow after ischemia.


METHODS
Four groups of isolated blood-perfused rabbit hearts underwent sequential periods of perfusion, ischemia, and reperfusion (20, 30, and 20 minutes). Two groups underwent 40 minutes of perfusion. Ischemic groups received saline vehicle, N omega-nitro-L-arginine methyl ester (L-NAME) or the highly specific inducible nitric oxide synthase inhibitor 1400W in low or high doses during reperfusion. Two nonischemic groups were treated with saline vehicle or 1400W during the last 20 minutes of perfusion. Left ventricular developed pressure and coronary flow were measured after each perfusion period. Ventricular levels of myeloperoxidase and cyclic guanosine monophosphate were measured at the end of the second perfusion period.


RESULTS
Coronary flow was significantly increased in both 1400W groups versus L-NAME (p < 0.001) and in high-dose 1400W versus control (p < 0.001). Coronary flow was not significantly different between the nonischemic groups. Left ventricular developed pressure was not significantly different among the ischemic groups or between the two nonischemic groups. There were no differences in cyclic guanosine monophosphate levels in any of the ischemic hearts. Myeloperoxidase levels were significantly elevated in L-NAME versus high-dose 1400W, nonischemic 1400W, and nonischemic saline groups (p < 0.02).


CONCLUSIONS
Highly selective inhibition of inducible nitric oxide synthase results in increased coronary flow after ischemia but not after continuous perfusion. This occurs with decreased neutrophil accumulation and a trend toward increased contractility without elevation of cyclic guanosine monophosphate levels.
Parrino
P E
PE
Department of Surgery, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Laubach
V E
VE
Gaughen
J R
JR
Shockey
K S
KS
Wattsman
T A
TA
King
R C
RC
Tribble
C G
CG
Kron
I L
IL
D000818:Animals; D003326:Coronary Circulation / Q000502:physiology*; D006152:Cyclic GMP / Q000032:analysis; D005260:Female; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D009195:Peroxidase / Q000032:analysis; D011817:Rabbits
D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D006152:Cyclic GMP