Ischemia-Induced Norepinephrine Release, but not Norepinephrine-Derived Free Radicals, Contributes to Myocardial Ischemia - Reperfusion Injury

Abstract

t is generally accepted that excess levels of norepinephrine (NE) could lead to myocardial injury. [1][2][3][4] Prolonged myocardial ischemia causes a large amount of NE to be released from the sympathetic nerve terminals via non-exocytotic local metabolic mechanism independently of central sympathetic activation, and this excessive NE may promote myocardial injury. 5 Reperfusion following prolonged ischemia would prevent progression of ischemic cell necrosis, whereas reperfusion itself causes myocardial injury, the phenomenon known as reperfusion injury. [6][7][8][9][10] Increased interstitial concentration of NE during ischemia may be involved in the pathogenesis of reperfusion injury, because NE is a source of free radicals. [11][12][13] Previous studies have shown that auto-oxidation of NE results in the generation of highly reactive ·OH radicals. 12,13 Thus, the pathogenesis of catecholamine-induced myocardial injury in the setting of reperfusion following prolonged ischemia is multifactorial, but the relative role of this NE-derived free radical formation in increasing the size of the infarct after reperfusion remains unclear. Accordingly, we studied the effects of cardiac denervation on free radical formation and infarct size in rats with reperfusion following prolonged ischemia and compared them with those of -adrenoceptor blockade. Methods Experimental AnimalThe experimental procedures were approved by the guidelines for animal experimentation at Toyama Medical and Pharmaceutical University. A total of 48 male Wistar rats weighing 300-350 g were used for induction of myocardial ischemia as described previously. 14 Briefly, the rats were anesthetized with sodium pentobarbital (30 mg/kg, ip), and a left thoracotomy was performed to exteriorize the heart. The left coronary artery was ligated 2-3 mm from its origin with a suture of 5-0 prolene (Ethicon, Inc, Somerville, NJ, USA) for 30 min, and then the ligature was released.The animals were divided into 3 groups: control, phenol, and atenolol. The following protocols were performed: (i) determination of hemodynamics and infarct size (control = 8, phenol =6, atenolol =6), (ii) determination of interstitial NE concentrations during ischemia and reperfusion (control =7, phenol =4, atenolol =4), and (iii) electron paramagnetic resonance (EPR) study (control =6, phenol =7). One week before coronary ligation, regional cardiac denervation was performed by painting a solution of 10% phenol in ethanol on the left ventricular (LV) epicardium around the proximal region of the left coronary artery. 15 The 1-selective adrenoceptor blockade, atenolol (0.5 mg/kg), was Background Norepinephrine (NE)-derived free radicals may contribute to myocyte injury after ischemiareperfusion, so the influence of sympathetic denervation on myocardial ischemia -reperfusion injury was investigated in the present study. Methods and ResultsCardiac sympathetic denervation was produced in Wistar rats by a solution of 10% phenol 1 week before ischemia. Atenolol (0.5 mg/kg) was intravenously a...

Ischemic Preconditioning Attenuates Postischemic Leukocyte - Endothelial Cell Interactions Role of Nitric Oxide and Protein Kinase C

“…19 Numerous attempts have been made to elucidate the mechanisms behind preconditioning, but results have suggested nearly as many possible mediators as there have been attempts. These possible mediators include NO, 20 acetylcholine, 21 catecholamines, 22 angiotensin II, 23 bradykinin, 24 adenosine, 25 and reactive oxygen species (ROS). 26,27 Although the roles of NOS/NO and PKC in IPC in the heart and many other organs have been extensively discussed, [28][29][30] only few studies have investigated skeletal muscle [31][32][33] and the microcirculatory leukocyte-endothelium interaction.…”

Early Administration of Fluvastatin, but not at the Onset of Ischemia or Reperfusion, Attenuates Myocardial Ischemia-Reperfusion Injury Through the Nitric Oxide Pathway Rather Than Its Antioxidant Property

“…Nonomura et al, however, showed no significant relation between oxidative stress and IR injury in rats treated with cardiac sympathetic denervation. 25 Thus, the role of oxidative stress in IR injury remains to be elucidated.…”

Influence of .BETA.-Adrenoceptor Blockade on the Myocardial Accumulation of Fatty Acid Tracer and Its Intracellular Metabolism in the Heart After Ischemia-Reperfusion Injury

“…Previous studies have shown that -blockade reduced infarct size in the heart after more prolonged coronary occlusion. 30,31 Further studies are required to investigate whether changes in FA metabolism by -blockade may accelerate recovery from myocardial stunning.…”