Delayed Cardioprotection Afforded By Nitroglycerin Is Mediated By α-CGRP Via Activation Of Inducible Nitric Oxide Synthase

Delayed Cardioprotection Afforded by Nitroglycerinis Mediated by a-CGRP via Activation ofInducible Nitric Oxide SynthaseTransient ischemia followed by reperfusion renders the heart very resistant to subsequent ischemic insult, which is defined as ischemic preconditioning (IPC). It has been shown that the cardioprotective effects of ischemic preconditioning can be mimicked pharmacologically with clinically relevant agents, termed as pharmacological preconditioning. Growing evidence has suggested that endogenous active substances, including nitric oxide (NO), play an important role in mediation of delayed cardioprotection afforded by ischemia or pharmacological preconditioning. Calcitonin gene-related peptide (CGRP), a principal transmitter in capsaicin-sensitive sensory nerves, has been shown to participate in mediation of preconditioning. Previous investigations have demonstrated that delayed preconditioning induced by nitroglycerin is mediated by endogenous calcitonin gene-related peptide (CGRP) via NO-cGMP pathway. However, nitrate compounds have half-lives of only 2-8 min. It is obvious that the initial NO released by nitroglycerin is not a direct mediator of delayed preconditioning. There is evidence thatnitroglycerin can increase inducible nitric oxide synthase (iNOS) expression and that nitroglycerin-induced delayed preconditioning is completely abrogated in the iNOS gene-knockout mice. In the present study, we examined whether CGRP-mediated delayed preconditioning induced by nitroglycerin is involved in activation of inducible nitric oxide synthase (iNOS).Method: Male Wistar rats were subjected to left main coronary artery occlusion for 1 h and reperfusion for 3 h. Infarct size, the plasma level of cGMP and CGRP, and the expression of CGRP isoforms (α-CGRP and β-CGRP) mRNA in lumbar dorsal root ganglia were measured.Rats weighing 220 - 250 g were randomly divided into 6 groups: ischemia/reperfusion (I/R); nitroglycerin, rats were pretreated with nitroglycerin (120 μg/kg, i.v.) 24 h before I/R; aminoguanidine, rats were pretreated with aminoguanidine (300 mg/kg, i.p.) 1 h before I/R; aminoguanidine plus nitroglycerin, rats were pretreated with nitroglycerin 24 h and aminoguanidine 1 h before I/R; dexamethasone, rats were pretreated with dexamethasone (5mg/kg, i.p.) 25 h before the experiment; and dexamethasone plus nitroglycerin, after pretreatment with dexamethasone for 1 h, the rats were treated with nitroglycerin 24 h before I/R.Result: Pretreatment with nitroglycerin (120 μg/kg, i.v.) markedlyreduced infarct size. Nitroglycerin caused a significant increase in the expression of α-CGRP mRNA, but not β-CGRP mRNA, concomitant with an increase in plasma concentrations of cGMP and CGRP. These effects of nitroglycerin were completely abolished by pretreatment with aminoguanidine (300 mg/kg, i.p.), a selective inhibitor of iNOS activity, or dexamethasone (5 mg/kg, i.p.), the iNOS expression inhibitor.Conclusion: The present results suggest that delayed cardioprotection afforded by nitroglycerin is mediated by the α-CGRP isoform via generation of NO derived from iNOS.