While previous research into the pathogenesis of ischaemic and reperfusion injuries has focussed on the cardiac myocyte, there is increasing evidence for a crucial role for coronary vascular injury in the genesis of the post-ischaemic phenotype [1-3]. Post-ischaemic vascular injury may be manifest as a transient or sustained loss of competent vessels, impairment of vascular regulatory mechanisms, and ultimately as the 'no-reflow' phenomenon (inability to sufficiently reperfuse previously ischaemic tissue despite the removal of the initial obstruction or occlusion). It is now appreciated that the earliest distinguishing feature of various forms of vascular injury (including atherosclerosis and infarction) is 'endothelial dysfunction', which is the marked reduction in endothelial-dependent relaxation due to reduced release or action of endothelial nitric oxide (NO). Importantly, vascular injury may worsen myocardial damage in vivo [4,5], significantly limiting tissue salvage and recovery. The pathogenesis of post-ischaemic vascular injury and endothelial dysfunction is incompletely understood, but has generally been considered to reflect a cardiovascular inflammatory response, neutrophils playing a key role. However, while blood-borne cells and inflammatory elements are undoubtedly involved in the 'progression' of vascular injury [6,7], accumulating evidence indicates that they are not the primary 'instigators' [8]. It should be noted that a wealth of controversial findings exists in the vascular injury literature and mechanisms involved remain unclear. Indeed, multiple mechanisms are likely to contribute to post-ischaemic vascular injury. Adenosine receptors are unique in playing a role in physical regulation of coronary function, and also in attenuating injury during and following ischaemia. While the adenosine receptor system has been extensively investigated in terms of effects on myocardial injury [9,10], little is known regarding potential effects of this receptor system on post-ischaemic coronary vascular injury. This thesis initially attempts to further our understanding of the role of adenosine in normal coronary vascular function, subsequent chapters assess the effect of ischaemia-reperfusion on vascular function, and adenosine receptor modification of vascular dysfunction in the isolated asanguinous mouse heart. Specifically, in Chapter 3 the receptor subtype and mechanisms involved in adenosine-receptor mediated coronary vasodilation were assessed in Langendorff perfused mouse and rat hearts. The study revealed that A2A adenosine receptors (A2AARs) mediate coronary dilation in the mouse vs. A2B adenosine receptors (A2BARs) in rat. Furthermore, responses in mouse involve a sensitive endothelial-dependent (NO-dependent) response and NO-independent (KATP-mediated) dilation. Interestingly, the ATP-sensitive potassium channel component predominates over NO-dependent dilation at moderate to high agonist levels. However, the high-sensitivity NO-dependent response may play an important role under physiological conditions when adenosine concentrations and the level of A2AAR activation are low. In Chapter 4 the mechanisms regulating coronary tone under basal conditions and during reactive hyperaemic responses were assessed in Langendorff perfused mouse hearts. The data support a primary role for KATP channels and NO in mediating sustained elevations in flow, irrespective of occlusion duration (5-40 s). However, KATP channels are of primary importance in mediating initial flow adjustments after brief (5-10 s) occlusions, while KATP (and NO) independent processes are increasingly important with longer (20-40 s) occlusion. Evidence is also presented for compensatory changes in KATP and/or NO mediated dilation when one pathway is blocked, and for a modest role for A2AARs in reactive hyperaemia. In Chapter 5 the impact of ischaemia-reperfusion on coronary function was examined, and the role of A1 adenosine receptor (A1AR) activation by endogenous adenosine in modifying post-ischaemic vascular function was assessed in isolated buffer perfused mouse hearts. The results demonstrate that ischaemia does modify vascular control and signficantly impairs coronary endothelial dilation in a model devoid of blood cells. Additionally, the data indicate that post-ischaemic reflow is significantly determined by A2AAR activation by endogenous adenosine, and that A1AR activation by endogenous adenosine protects against this model of vascular injury. Following from Chapter 5, the potential of A1, A2A and A3AR activation by exogenous and endogenous agonists to modulate post-ischaemic vascular dysfunction was examined in Chapter 6. Furthermore, potential mechanisms involved injury and protection were assessed by comparing effects of adenosine receptors to other 'vasoprotective' interventions, including anti-oxidant treatment, Na+/H+ exchange (NHE) inhibition, endothelin (ET) antagonism, and 2,3-butanedione monoxime (BDM). The data acquired confirm that post-ischaemic endothelial dysfunction is reduced by intrinsic A1AR activation, and also that exogenous A3AR activation potently reduces vascular injury. Protection appears unrelated to inhibition of ET or oxidant stress. However, preliminary data suggest A3AR vasoprotection may share signalling with NHE inhibition. Finally, the data reveal that coronary reflow in isolated buffer perfused hearts is not a critical determinant of cardiac injury, suggesting independent injury processes in post-ischaemic myocardium vs. vasculature. Collectively, these studies show that adenosine has a significant role in regulating coronary vascular tone and reactive hyperaemic responses via NO and KATP dependent mechanisms. Ischaemia-reperfusion modifies vascular control and induces significant endothelial dysfunction in the absence of blood, implicating neutrophil independent injury processes. Endogenous adenosine affords intrinsic vasoprotection via A1AR activation, while adenosinergic therapy via exogenous A3AR activation represents a new strategy for directly protecting against post-ischaemic vascular injury.