The mechanism of cardioprotection by S‐nitrosoglutathione monoethyl ester in rat isolated heart during cardioplegic ischaemic arrest

Abstract

1 This study was designed (i) to assess the effect of S-nitrosoglutathione monoethyl ester (GSNO-MEE), a membrane-permeable analogue of S-nitrosoglutathione (GSNO), on rat isolated heart during cardioplegic ischaemia, and (ii) to monitor the release of nitric oxide (-NO) from GSNO-MEE in intact hearts using endogenous myoglobin as an intracellular -NO trap and the hydrophilic N-methyl glucamine dithiocarbamate-iron During aerobic reperfusion, denitrosylation of the MbNO complex slowly occurred as shown by the decrease in ESR spectral intensity. GSNO-MEE treatment did not affect ubisemiquinone radical formation during reperfusion. 5 GSNO-MEE (20,l`-) treatment elevated the myocardial cyclic GMP during ischaemia (47 + 3 in control vs. 153 + 34 pmol g-' dry wt. after 35 min ischaemia, P< 0.05). The cyclic GMP levels decreased in the control group during ischaemia from 100 + 6 after induction of cardioplegia to 47 + 3 pmol g' dry wt. at the end of ischaemic duration. 6 Glycogen levels were lower in GSNO-MEE (20 pmol 1-1)-treated hearts throughout the ischaemic duration (26.7 + 3.1 in control vs. 19.7 + 2.4 pmol g dry-' wt. in GSNO-MEE-treated group at the end of ischaemic duration), because of rapid depletion of glycogen during induction of cardioplegia. During ischaemia, the amounts of glycogen consumed in both groups were similar. Equivalent amounts of lactate were produced in both groups (148 + 4 in control vs. 141 + 4 umol g' dry wt. in GSNO-MEEtreated group after 35 min in ischaemia). 7 The mechanism(s) of myocardial protection by GSNO-MEE against ischaemic injury may involve preischaemic glycogen reduction and/or elevated cyclic GMP levels in myocardial tissue during ischaemia.

Cardioprotection and mitochondrial S-nitrosation: Effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia–reperfusion injury

“…Notably, the protection elicited by SNO-MPG was not abrogated by inclusion of the sGC inhibitor ODQ in the incubations ( Figure 2B), indicating no role for classical NO • / cGMP signaling in the mechanism of protection. This result contrasts with previous studies showing that the cardioprotective effect of GSNO was cGMP dependent [31,42]. At 20 μM, the parent thiol of SNO-MPG (i.e.…”

“…Low molecular weight SNOs such as GSNO and S-nitroso-cysteine (SNOC) have previously been used as S-nitrosating agents [23,25], and are known to elicit cardioprotection [31], but are pleiotropic in their actions. Therefore, it was hypothesized that administration of a low molecular weight SNO that accumulates preferentially in mitochondria would deliver cardioprotection at low doses.…”

Reaction of S-Nitrosoglutathione with the Heme Group of Deoxyhemoglobin

“…It has previously been demonstrated that nitrosylmyoglobin is formed during perfusion of the intact rat heart with GSNO (18). GSNO is a potent protective agent against reperfusion injury in this model and it is tempting to speculate that myocyte myoglobin may play a role in the release of nitric oxide from GSNO (19,20).…”

Nitrosation of Uric Acid by Peroxynitrite

“…In addition, the nitrated product may prove valuable to the rational design of a new class of mechanism-based, anti-ischemic drugs that mimic the properties of endogenous uric acid. It is possible that a mimic of the nitrated uric acid product could be utilized to alleviate myocardial ischemic syndromes following ischemia/ reperfusion, cardioplegic ischemic arrest, coronary artery thrombosis after thrombolysis, and restenosis after transluminal coronary angioplasty (63,64). The uric acid nitrosation product may play a pivotal role in human pathophysiology by releasing ⅐NO, which could decrease vascular tone and increase tissue blood flow (65,66).…”