Original article The ischemic metabolite lysophosphatidylcholine increases rat coronary arterial tone by endothelium-dependent mechanisms Rui Zhang a , Ni Bai b , Jeremy So a , Ismail Laher b , Kathleen M. MacLeod a , Brian Rodrigues a, ⁎ a Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 b Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 abstract article info Article history: Received 31 October 2008 Received in revised form 6 March 2009 Accepted 30 March 2009 Available online 15 April 2009 Keywords: Lysophosphatidylcholine Vascular tone Cardiac ischemia/reperfusion Endothelium-derived hyperpolarizing factor Nitric oxide Endothelin-1 Lysophosphatidylcholine (LPC), a hydrolysis product of phospholipid degradation, accumulates in the ischemic myocardium. Using isolated hearts or rat coronary septal arteries, we tested the impact of LPC in modulating basal function or the responses to vasoactive agents. Sustained perfusion of hearts with LPC augmented coronary perfusion pressure (CPP) and reduced left ventricular developed pressure (LVDP). By mechanisms that have yet to be identified, these effects on CPP and LVDP were exaggerated when LPC was removed from the perfusate. Although LPC (or its washout) had no direct effect on vascular tone in the isolated coronaryartery, it selectively potentiated the receptor-coupled vasoconstrictor response to U-46619, a thromboxane A 2 mimetic. Interestingly, when LPC was washed out, the potentiation to U-46619 was even more pronounced. Both the immediate and residual effects of LPC were endothelium-dependent. EDHF was likely the sole mediator responsible for the direct effects of LPC on U-46619-vasoconstriction, whereas the augmented vasoconstrictor responses following LPC washout may in part be related to an increase in ET-1, and a striking reduction in the bioavailability of NO. Our data suggest that in addition to reducing the accumulation of LPC to prevent ischemia-reperfusion (I/R) damage, efforts targeting an improved endothelium-dependent regulation of vascular tone could be an attractive approach to limit the cardiac damage induced by I/R. © 2009 Elsevier Inc. All rights reserved. 1. Introduction A prolonged period of ischemia (I) followed by restoration of blood flow (reperfusion, R) causes myocardial injury. In ischemic myocytes, oxygen deficiency induces rapid cessation of mitochondrial oxidative phosphorylation, with resultant loss of ATP production [1]. A compensatory increase in anaerobic glycolysis promotes lactate accumulation, reduces intracellular pH, and induces calcium overload [2]. In the post-ischemic state, reperfusion for a short duration with oxygen-rich blood results in a dramatic increase in fatty acid (FA) utilization, a compensatory effect for functional recovery of the myocardium. However, this augmented utilization of FA may further uncouple glycolysis and glucose oxidation, increase proton accumula- tion, and ultimately accelerate cell damage, leading to functional impairment [3]. Similar to cardiomyocytes, the coronary vasculature is also a target of I/R injury. Clinically, on reperfusion, microvascular defects are still evident (no-reflow), preventing nutrient delivery to the cardiomyo- cytes. Experimentally, I/R enhances coronary tone [4], either as a consequence of augmented vasoconstrictor release [4], and/or a markedly impaired endothelium-dependent relaxation (EDR) [5]. To explain the latter, multiple mechanisms have been suggested including excess production of oxygen free radicals[6], attenuated bioavailability of NO [7], and neutrophil-mediated inflammatory damage [8]. Lysophosphatidylcholine (LPC), a hydrolysis product of phospho- lipid degradation, accumulates in the ischemic myocardium in hearts from different animal species [9,10] as well as humans [11]. As a temporal relationship exists between the accumulation of LPC and electrophysiological changes with ventricular arrhythmias [11], con- siderable effort has been devoted to examine the role of LPC in cardiomyocyte I/R injury. However, exogenous LPC also elevates coronary vascular resistance in isolated perfused rat hearts [12] and selectively impairs EDR in isolated porcine large coronary arteries [13,14]. We recently demonstrated that in addition to its direct effect on the rat mesenteric arterial bed, LPC exerts residual effects on vascular reactivity long after washout of this lysolipid [15]. Specifi- cally, there was a robust potentiation of the vasoconstrictor response to phenylephrine. Should this residual effect of LPC in modulating responses to vasoconstrictors also be evident in the coronary vasculature, cardiac injury would be expected to be accelerated when added onto the prevailing cardiomyocyte injury. In the current Journal of Molecular and Cellular Cardiology 47 (2009) 112–120 ⁎ Corresponding author. Faculty of Pharmaceutical Sciences, UBC 2146 East Mall, Vancouver, B.C., Canada V6T 1Z3. Tel.:+1 604 822 4758; fax: +1 604 822 3035. E-mail address: rodrigue@interchange.ubc.ca (B. Rodrigues). 0022-2828/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yjmcc.2009.03.026 Contents lists available at ScienceDirect Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc