The mechanism of the late preconditioning effect of 3-nitropropionic acid

Abstract

The aim of the present study was to investigate the mechanism of effect of 3-nitropropionic acid-(3-NP) induced late preconditioning in rat heart. For this purpose 20-30 min before 3-NP (20 mg/kg, i.p.) injection, the rats were treated intraperitoneally with 5-hydroxydecanoate (40 mg/kg, 5-HD, mitochondrial K(ATP)-channel blocker), L-NAME (100 mg/kg, NOS inhibitor), N-2-mercaptopropionylglycine (100 mg/kg, MPG, free radical scavenger), or superoxide dismutase+catalase (10000+10000 IU/kg, SOD+CAT). Control rats received saline only without 3-NP pretreatment. After two days, hearts were isolated and perfused at a constant pressure in a Langendorff apparatus. 15-min global ischemia followed by 30-min reperfusion was applied to all hearts. Pretreatment of 3-NP significantly reduced infarct size, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) levels, and incidence of ventricular tachycardia (VT) compared with the control group receiving saline only. 5-HD, L-NAME, MPG, or SOD+CAT treatment statistically reversed 3-NP-induced reduction in infarct size. Although CK-MB, LDH levels, and incidence of VT were also reduced by L-NAME, MPG, or SOD+CAT treatment, only 5-HD significantly inhibited beneficial effects of 3-NP on all of the parameters above. These results showed that mito-K(ATP) channels play a pivotal role in late preconditioning effect of 3-NP in the isolated rat heart. However, other mediators such as reactive oxygen species and NO may be, at least in part, involved in mechanisms of this effect.

Delayed pre‐conditioning by 3‐nitropropionic acid prevents 3,4‐methylenedioxymetamphetamine‐induced 5‐HT deficits

“…1999, 2001; Turan et al. 2006; Basgut et al. 2008), we addressed whether this is also true in our model.…”

“…Because delayed pre‐conditioning caused by 3NP in the heart is partially reversed by the non‐specific nitric oxide synthase (NOS) inhibitor, L‐NAME (Ockaili et al. 1999; Basgut et al. 2008), the contribution nitric oxide (NO) was investigated.…”

The Second Window of Preconditioning (SWOP) Where Are We Now?

“…Hoag and coworkers [147] noted that glibenclamide or 5-HD administered prior to heat stress did not abrogate the delayed preconditioning effect, whereas when these K ATP channel blockers were given before the κ-opioid agonist, U50488H, the delayed preconditioning effect was abolished [42]. More recently, the co-administration of 5-HD with 3-nitropropionic acid (a succinate dehydrogenase inhibitor) was found to reduce myocardial infarct size 48 h later in a Langendorff-perfused rat heart model [150], supporting evidence for a trigger role of the K ATP channel. Curiously, Patel and co-workers found that delayed cardioprotection elicited by either IPC [151] or the δ-opioid agonist, SNC-121 [53], could be blocked by HMR1098 (a sarcolemmal K ATP channel antagonist), if the latter was administered prior to the preconditioning stimulus, but not if it was administered prior to infarction, suggesting a trigger role for the sarcolemmal K ATP channel in delayed preconditioning.…”

Mitochondria are sources of metabolic sink and arrhythmias

“…A protective role for mitoK ATP channel activation against arrhythmias has been inferred by experiments demonstrating that mitoK ATP channel blockers consistently abolished the anti-arrhythmic phenotype provided by preconditioning stimuli, such as ischemic preconditioning (Vegh & Parratt, 2002; Rajesh et al , 2004), adenosine (Headrick et al , 2003), delta opioid agonists (Fryer et al , 2000; Fischbach et al , 2003), estrogen (Das & Sarkar, 2006), 3-nitropropionic acid (Basgut et al , 2008), nitroglycerin (Baharvand et al , 2009), noradrenaline (Imani et al , 2008), or endothelin receptor agonists (Das et al , 2007). It is important to note, however, that mitoK ATP channel blockade during other preconditioning stimuli; namely, bradykinin (Driamov et al , 2004), low-flow ischemia (Driamov et al , 2004), peroxynitrite (Kiss et al , 2008), and estradiol (Tsai et al , 2002) failed to attenuate the anti-arrhythmic protection of these stimuli.…”