Relation of cyclic nucleotide ratios to ischemic and reperfusion injury in nitric oxide-donor treated rat hearts.
Nitric oxide (NO) donors given during ischemia possibly protect the myocardium by increasing tissue cyclic guanosine monophosphate (cGMP) and decreasing cytosolic Ca2+ levels. However, NO donors also elevate ischemic cyclic adenosine monophosphate (cAMP) levels, which exacerbates ischemic-reperfusion injury. The authors propose that suppression of this NO donor-induced increase in cAMP would improve the cardioprotective properties of these compounds. Langendorff perfused rat hearts were treated with sodium nitroprusside (SNP, 0.1 mM ) or glyceryl trinitrate (GTN, 1.0 microM ) and/or adenylyl cyclase (SQ, 50 microM ) or guanylyl cyclase (ODQ, 30-300 microM ) inhibitors during 40-min low-flow (0.2 ml/min) ischemia. Control reperfusion rate-pressure product (RPP) recoveries were 47 +/- 3% (n = 9) and improved to 59 +/- 1% (n = 11) (p < 0.05) with SNP treatment. Ischemic ODQ treatment decreased RPP recovery to 33 +/- 3% (n = 10) (p < 0.05). ODQ eliminated the cardioprotective effects of SNP (RPP recovery: 40 +/- 5% [n = 7] vs. 59 +/- 1% [p < 0.05]). Adenylyl cyclase inhibition improved RPP recovery from 59 +/- 1% (SNP) to 72 +/- 4% (SNP + SQ) (n = 11) (p < 0.05). The authors conclude that (a) suppression of the NO donor-induced elevations in ischemic cGMP levels (ODQ) worsened reperfusion RPP, (b) suppression of the NO donor-induced elevation in ischemic cAMP levels (SQ) further improved reperfusion RPP in NO donor-treated hearts, and (c) the severity of ischemic-reperfusion injury in the NO donor-treated heart was inversely related to ischemic-tissue cGMP levels and often directly related to the ischemic-tissue cAMP-to-cGMP ratio.
Du Toit
E F
EF
Department of Human and Animal Physiology, University of Stellenbosch, Stellenbosch, South Africa.
Meiring
J
J
Opie
L H
LH
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use*; D009599:Nitroprusside / Q000494:pharmacology / Q000627:therapeutic use; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans
D000889:Anti-Arrhythmia Agents; D020030:Nitric Oxide Donors; D009712:Nucleotides, Cyclic; D009599:Nitroprusside; D005905:Glyburide