Generation of
reactive oxygen species is a major, well-known cause of
heart injury induced by
ischemia-reperfusion. This injury is manifested through
myocardial stunning, reperfusion and lethal
reperfusion injury of cardiocytes. The pyridoindole
stobadine has been shown to exhibit significant
antioxidant,
free-radical scavenging and hypoxic-tissue-protecting properties. The present study examined the effects of
stobadine and two novel derivatives, SMe1 and
SMe1EC2, which exhibit improved pharmacodynamic and toxicity profiles, on the functional properties and reperfusion dysrhythmias of the isolated rat heart in
ischemia-reperfusion conditions. All experiments were performed on isolated Langendorff-perfused hearts isolated from 3-month-old male Wistar rats. After 15 min of stabilization, the hearts were subjected to a 30-minute period of global no-flow
ischemia, followed by a 30-minute reperfusion period.
Stobadine, SMe1 and
SMe1EC2 were applied at a concentration of 1 x 10(-5) 10 min before the onset of
ischemia, and during reperfusion through the perfusion medium. As compared to the untreated group, addition of
SMe1EC2 during reperfusion significantly increased left ventricular developed pressure, decreased pathologically elevated left ventricular end-diastolic pressure and enhanced recovery of the
stunned myocardium after
ischemia. Both SMe1 and
stobadine failed to influence these parameters; however, all derivatives tested inhibited serious life-threatening reperfusion dysrhythmias such as
ventricular tachycardia and
ventricular fibrillation. Our findings suggest that
SMe1EC2 promotes an improved recovery of the left ventricular function following
ischemia compared to either
stobadine or SMe1. However, both
SMe1EC2 and SMe1 manifested a significant anti-dysrhythmic effect comparable with that of
stobadine and partially reduced
myocardial ischemia-reperfusion-induced injury.