title: Intravenous adenosine protects the myocardium primarily by activation of a neurogenic pathway.
abstract: Endogenous adenosine is a trigger for ischemic myocardial preconditioning (IPC). Although intravascular administration of adenosine has been used to further unravel the mechanism of protection by IPC, it is questionable whether adenosine and IPC employ the same signaling pathways to exert cardioprotection. We therefore investigated whether the active metabolic barrier of the endothelium prevents an increase in myocardial interstitial adenosine concentrations by intravenous adenosine, using microdialysis, and also the role of NO and activation of a neurogenic pathway in the cardioprotection by adenosine. In pentobarbital-anesthetized rats, area at risk and infarct size (IS) were determined 120 min after a 60-min coronary artery occlusion (CAO), using trypan blue and nitro-blue-tetrazolium staining, respectively. IPC with a single 15-min CAO and a 15-min adenosine infusion (ADO, 200 microg min(-1) i.v.) limited IS to the same extent (IS = 41 +/- 6% and IS = 40 +/- 4%, respectively) compared to control rats (IS = 63 +/- 3%, both P < 0.05). However, IPC increased myocardial interstitial adenosine levels seven-fold from 4.3 +/- 0.7 to 27.1 +/- 10.0 microM (P < 0.05), while ADO had no effect on interstitial adenosine (4.1 +/- 1.2 microM), or any of the other purines. The NO synthase inhibitor N(omega)-nitro-L-arginine (LNNA), which did not affect IS (IS = 62 +/- 3%), attenuated the protection by ADO (IS = 56 +/- 3%; P < 0.05 vs ADO, P = NS vs LNNA). The ganglion blocker hexamethonium, which had also no effect on IS (IS = 66 +/- 3%), blunted the protection by ADO (IS = 55 +/- 4%; P < 0.05 vs ADO and vs hexamethonium). These observations demonstrate that cardioprotection by ADO is dependent on NO, and is primarily mediated by activation of a neurogenic pathway.
authors.affiliation: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research Institute COEUR, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
authors.forename: Olivier C
authors.initials: OC
authors.lastname: Manintveld
authors.forename: Maaike
authors.initials: M
authors.lastname: te Lintel Hekkert
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Keijzer
authors.forename: Pieter D
authors.initials: PD
authors.lastname: Verdouw
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005730:Ganglionic Blockers / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D007262:Infusions, Intravenous; D019194:Ischemic Preconditioning; D008297:Male; D017551:Microdialysis; D009203:Myocardial Infarction / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002316:Cardiotonic Agents; D005730:Ganglionic Blockers; D019335:Nitroarginine; D009569:Nitric Oxide; D018738:Hexamethonium; D019001:Nitric Oxide Synthase; D000241:Adenosine