C. Depre et al., PROTECTION AGAINST ISCHEMIC-INJURY BY NONVASOACTIVE CONCENTRATIONS OFNITRIC-OXIDE SYNTHASE INHIBITORS IN THE PERFUSED RABBIT HEART, Circulation, 92(7), 1995, pp. 1911-1918
Background The functional and metabolic effects of inhibitors of nitri
c oxide (NO) synthase on ischemic hearts have not been investigated. T
his work was designed to perform such a study in isolated perfused rab
bit hearts submitted to low-flow ischemia. Methods and Results After a
30-minute equilibration period, the hearts were submitted to low-flow
ischemia for 60 minutes followed by reperfusion for 30 minutes. Funct
ional and metabolic parameters were followed in hearts perfused with o
r without inhibitors of NO synthase or NO precursors, which were added
15 minutes before ischemia but were absent during reperfusion. Ischem
ic contracture was delayed and reduced in hearts perfused with 1 mu mo
I/L L-N-monomethylarginine (L-NMMA) or 1 mu mol/L L-N-arginine methyle
ster, two inhibitors of NO synthase, but not with D-N-monomethylargini
ne, the inactive enantiomer of L-NMMA. The protection was suppressed b
y addition to the perfusate containing L-NMMA of 1 mmol/L L-arginine o
r 0.1 mmol/L sodium nitroprusside but not by addition of 10 mu mol/L 8
-bromo cGMP, a cGMP analogue. The functional protection by 1 mu mol/L
L-NMMA was related to a stimulation of glycolysis from exogenous gluco
se and a preservation of the glycogen stores. This resulted in a bette
r maintenance of high-energy phosphates and a lower acidosis as measur
ed by P-31 nuclear magnetic resonance spectroscopy. During reperfusion
, functional recovery was more than doubled, and enzyme release was ha
lved in L-NMMA-treated hearts compared with controls. The functional a
nd metabolic protection was maximal at 1 nmol/L to 1 mu mol/L L-NMMA,
ie, below the vasoactive concentrations of the inhibitor. Conclusions
Nonvasoactive concentrations of NO synthase inhibitors protect the hea
rt against ischemic damage; this relates to a stimulation of glycolysi
s from exogenous glucose.