Relation of Cyclic Nucleotide Ratios to Ischemic and Reperfusion Injury in Nitric Oxide–Donor Treated Rat Hearts

Abstract

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.

Nitric oxide in myocardial ischemia/reperfusion injury

“…Indeed, the myocardial cGMP concentration did not increase significantly during 40 min of low flow ischemia in isolated buffer-perfused rat hearts [43] and 90 min low flow ischemia in in situ pig hearts [44]. In contrast, the cGMP concentration was increased in ischemic areas compared to normoperfused areas of patients with coronary artery disease [45,46].…”

Magnetic resonance study of the transmembrane nitrite diffusion

“…Several chemical and enzymatic mechanisms of nitrite conversion to NO have been reported [8][9][10][11], supporting an important role of nitrite as a source of NO production and thus, it is expected that NO 2 -may exert cardioprotection in a manner similar to one observed with NO donors [12][13][14]. NO can protect the heart [15], and knockout of endothelial NO synthase (NOS) has been reported to render the hearts of mice more sensitive to ischemic insults [16,17].…”

Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia–reperfusion damage

“…• donors protect against ischemia-reperfusion (I͞R) damage in in vitro models of infarction (22)(23)(24). In addition, knockout of endothelial NOS renders the hearts of mice more sensitive to ischemic insults, with increased infarct size and diminished cardiac function compared with wild type (25,26).…”

“…NO • also may have direct beneficial effects on cardiomyocytes. The protective effects of NO • donors are associated with elevations in cGMP and activation of cGMPdependent protein kinases; however, the final effector of this signal transduction pathway is uncertain (22). In addition, it has been suggested that NO • may provide protection by modifying mitochondrial respiration by means of interaction with specific complexes of the respiratory chain, resulting in alterations in cellular ATP concentration (47,48).…”