Cardioprotection and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischemia-reperfusion.
The effects of two nitric oxide (NO) donors were evaluated in a 6-h model of feline myocardial ischemia-reperfusion. After 80 min of a 90-min ischemic period, SIN-1 or C87-3754 or their respective controls (i.e., 0.9% NaCl or C88-3934, a control compound which does not release NO) were given i.v. as a bolus (0.1 mg/kg) and infused at 1 mg/kg/h for the entire 4.5-h reperfusion period. Administration of the active NO donors significantly decreased the necrotic area/area-at-risk ratio from 29 +/- 3% in the vehicle group to 9 +/- 2 and 11 +/- 5% in the SIN-1 and C87-3754 groups, respectively (P less than .001). The inactive NO donor C88-3934 failed to reduce infarct size (31 +/- 3%). Neither NO donor reduced the accumulation of neutrophils in the necrotic area when compared to their respective control groups, but both agents significantly attenuated coronary endothelial dysfunction as shown by a vasorelaxation to acetylcholine of 62 +/- 2 and 64 +/- 3% in the SIN-1- and C87-3754-treated arteries, as compared to only a 27 +/- 3 and 34 +/- 4% vasorelaxation in the vehicle and inactive NO donor groups, respectively (P less than .001). Our studies show that SIN-1 and C87-3754 exert beneficial effects in a 6-h model of myocardial ischemia-reperfusion. Both NO donors decreased myocardial necrosis and decreased the reperfusion-induced endothelial dysfunction without significantly altering the pressure-rate index (i.e., an index of myocardial oxygen demand).
Siegfried
M R
MR
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Erhardt
J
J
Rider
T
T
Ma
X L
XL
Lefer
A M
AM
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002415:Cats; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009569:Nitric Oxide / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D013558:Sydnones / Q000494:pharmacology* / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000494:pharmacology
D011450:Prostaglandin Endoperoxides, Synthetic; D013558:Sydnones; D014665:Vasodilator Agents; C072857:3-(cis-2,6-dimethylpiperidino)sydnonimine; D009569:Nitric Oxide; D000001:Calcimycin; C002385:linsidomine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D008981:Molsidomine; D000109:Acetylcholine