Protective Effects of FK409, a Novel Nitric Oxide Donor, Against Postischemic Myocardial Dysfunction in Guinea-Pig Hearts

Abstract

Effects of FK409 were investigated in perfused guinea-pig Langendorff hearts subjected to ischemia and reperfusion. Nitric oxide electrode, fluorometry, and 31P nuclear magnetic resonance imaging were used to monitor changes in cellular high-phosphorous energy and nitric oxide and Ca2+ content in the heart together with simultaneous recordings of left ventricular developed pressure. After cardioplegic arrest with St. Thomas' Hospital solution, normothermic (37 degrees C) global ischemia was induced for 40 min, and hearts were reperfused for 40 min. FK409 at 10(-8) M, which has a minimum inotropic effect on nonischemic hearts, was added to the cardioplegic solution. Treatment with FK409 reduced left ventricular developed pressure during and after ischemia and improved postischemic recovery of left ventricular developed pressure from 55.4% at 40 min of reperfusion in FK409-free hearts up to 80.4% in hearts treated with FK409 (p < 0.01). Flow rate at 1.5 min after treatment with the cardioplegic solution was 27.7 ml/min in hearts treated with FK409 compared with 21.2 ml/min in drug-free hearts (p < 0.01). Treatment with FK409 significantly effected preservation of tissue level of beta-adenosine triphosphate at the end of ischemia or reperfusion. During ischemia, arrested with the cardioplegic solution, intracellular Ca2+ accumulation and nitric oxide release were reduced. At the end of ischemia in FK409-treated hearts, nitric oxide release was 86% greater than in drug-free hearts without reference to the Ca2+ concentration. In cardiac surgery, normothermic arrested hearts are subject to damage by oxygen free radicals in reperfusion injury. Therefore, nitric oxide exogenously supplied by FK409 was responsible for the cardioprotective action, presumably by acting directly as an oxygen radical scavenger during reperfusion. A specific nitric oxide donor, like FK409, may have therapeutic use as a nitric oxide-mediated vasorelaxant and additional protective action for reperfusion-injury hearts.

Protective effects of EGCg or GCg, a green tea catechin epimer, against postischemic myocardial dysfunction in guinea-pig hearts

“…2). In another of our studies of guinea-pig hearts, the NO supplied by serotonin derivatives with antioxidative activity from safflower oil (Hotta et al, 2002), or the specific NO donor FK409, had a cardioprotective action, presumably by scavenging cytosolic superoxide anion (Cao et al, 2001). In addition to the most potent antioxidant effect, EGCg or GCg, like the NO donor, may have therapeutic use as an NO-mediated vasorelaxant (Huang et al, 1999;Sanae et al, 2002) and have additional protective action in myocardial ischemia-reperfusion-induced injury.…”

“…Hence, GCg showed a more prolonged hypotensive effect on rabbits than EGCg. Each catechin (GCg or EGCg), like the NO donor, FK409 (Cao et al, 2001) and two serotonin derivatives from safflower seeds with potent antioxidative activity (Hotta et al, 2002), may have therapeutic use as an NO-mediated vasorelaxant, and may have an additional protective action in myocardial ischemia-reperfusion-induced injury. Therefore, in the present study, we attempted to define the cardioprotective effects of EGCg or catechin epimer GCg, a more diluted concentration than that of EGCg, on sequential changes in contractility or stiffness of the left ventricle, and the cellular metabolism of high phosphorous energy in isolated guinea-pig Langendorff hearts subjected to normothermic global ischemia and subsequent reperfusion.…”

Protective Effects of Cyclo(L-Leu-L-Tyr) against Postischemic Myocardial Dysfunction in Guinea-Pig Hearts

“…The role of superoxide (O 2 Ϫ ), NO, and peroxynitrite (ONOO Ϫ ) in myocardial ischemiareperfusion injury and preconditioning was reviewed by Fredinardy and Schulz. 34) In another of our studies on guineapig hearts, NO supplied by the NO donor FK409, 35) serotonin derivatives from safflower oil, 19) or the strongest antioxidative tea catechins (EGCg and GCg), 26,27) had cardioprotective actions, presumably by scavenging cytosolic superoxide anions. Immunoblotting analysis showed that endothelial nitric oxide synthese ((e)-NOS) was present in mitochondria and ONOO -itself also inhibited [Ca 2ϩ ] m influx.…”

Protective Effects of Fluvoxamine against Ischemia/Reperfusion Injury in Isolated, Perfused Guinea-Pig Hearts

“…The effluent was removed from a level above the heart with a peristaltic pump, leaving the heart submerged in a fixed volume of the perfusate. In the ischemia-reperfusion experiments, 31 P-NMR spectra were monitored along with simultaneous recordings of ventricular pressure, as described previously [16][17][18][19] and paced at a rate of 3-4 Hz stimulation via a 3 M KCl agar electrode. 31 P-NMR spectra were obtained at 161.8 MHz on a GSX 400 spectrometer (JEOL Datum Co., Ltd., Tokyo, Japan) equipped with a 9.4-Tesla vertical-bore magnet.…”

“…The increase in 5-HT levels during ischemia has been implicated in the endothelial release of NO from another receptor (5-HT 1B or 5-HT 2B receptors) in the heart. 38) NO exogenously supplied by a specific NO donor, such as FK409, 17) or the antioxidative 5-HT derivatives isolated from safflower 18) were shown to be responsible for the cardioprotective action observed, presumably by acting directly as oxygen radical scavengers during reperfusion. These NO donors may have potential therapeutic use as NO-mediated vasorelaxers and afford additional protection to reperfusioninjury hearts.…”