. Acute adenosinergic cardioprotection in ischemic-reperfused hearts. Am J Physiol Heart Circ Physiol 285: H1797-H1818, 2003; 10.1152/ajpheart.00407. 2003.-Cells of the cardiovascular system generate and release purine nucleoside adenosine in increasing quantities when constituent cells are "stressed" or subjected to injurious stimuli. This increased adenosine can interact with surface receptors in myocardial, vascular, fibroblast, and inflammatory cells to modulate cellular function and phenotype. Additionally, adenosine is rapidly reincorporated back into 5Ј-AMP to maintain the adenine nucleotide pool. Via these receptor-dependent and independent (metabolic) paths, adenosine can substantially modify the acute response to ischemic insult, in addition to generating a more sustained ischemia-tolerant phenotype (preconditioning). However, the molecular basis for acute adenosinergic cardioprotection remains incompletely understood and may well differ from more widely studied preconditioning. Here we review current knowledge and some controversies regarding acute cardioprotection via adenosine and adenosine receptor activation.adenosine; adenosine receptor activation; ischemia; reperfusion injury THE HEART possesses its own intrinsic protective responses, including the adenosine receptor system, which enhance resistance to ischemic insult. An understanding of the mechanisms involved in these responses not only informs us of how the heart reacts to injurious stimuli, but may provide avenues for developing novel protective strategies applicable in the setting of ischemia-reperfusion. The purine nucleoside adenosine was attributed with cardioregulatory functions almost 75 years ago (64), and since then has emerged as a crucially important control substance in essentially every tissue of the body. In the heart adenosine not only plays a role in regulating growth and differentiation, angiogenesis, coronary blood flow, cardiac conduction and heart rate, substrate metabolism, and sensitivity to adrenergic stimulation (23,67,68,73,74,260,271,283), but may play a role as an endogenous determinant of ischemic tolerance (189,225,245,259,311,312,318). From a therapeutic viewpoint, adenosine-based therapies protect against ischemic injury in a variety of animal models (72,177,208,265,288) and in human cardiac tissue (34, 36, 37,240,296). However, much remains unclear regarding the roles and mechanisms of action of adenosine in producing acute protection against ischemia and reperfusion. Generation of Endogenous Adenosine During InsultEndogenous adenosine levels increase rapidly with ischemic insult (104,109,285,286) to mediate a retaliatory response. This protective pool of adenosine can be formed via dephosphorylation of 5Ј-AMP by intra-and extracellular 5Ј-nucleotidases and from S-adenosylhomocysteine (SAH) via SAH hydrolase. Extracellular adenosine is rapidly taken into cells via a facilitative transporter (131). Within cells it is either deaminated by adenosine deaminase or rephosphorylated to 5Ј-AMP via adenosine kinase. O...

Despite minimal model characterisation Langendorff perfused murine hearts are increasingly employed in cardiovascular research, and particularly in studies of myocardial ischaemia and reperfusion. Reported contractility remains poor and ischaemic recoveries variable. We characterised function in C57/BL6 mouse hearts using a ventricular balloon or apicobasal displacement and assessed responses to 10-30 min global ischaemia. We examined the functional effects of pacing, ventricular balloon design, perfusate filtration, [Ca"] and temperature. Contractility was high in isovolumically functioning mouse hearts (measured as the change in pressure with time (+dP/dt), 6000-7000 mmHg s-I) and was optimal at a heart rate of -420 beats min-', with the vasculature sub-maximally dilated, and the cellular energy state high. Post-ischaemic recovery (after 40 min reperfusion) was related to the ischaemic duration: developed pressure recovered by 82 f YO, 73 f 4u/, 68 f 3%, 57 f 2% and 41 f 5% after 10, 15, 20, 25 and 30 min ischaemia, respectively. Ventricular compliance and elastance were both reduced post-ischaemia. Post-ischaemic recoveries were lower in the apicobasal model (80 +-4 YO, 58 k 7 YO, 40 +-3 %, 32 +-7 % and 25 2 5 YO) despite greater reflow and lower metabolic rate (pre-ischaemic myocardial O2 consumption (Vo2,,,,) 127 f 15 vs. 198 k 17 p l O2 min-' g-'), contracture, enzyme and purine efflux. Electrical pacing slowed recovery in both models, small ventricular balloons (unpressurised volumes C 50-60 p1) artificially depressed ventricular function and recovery from ischaemia, and failure to filter the perfusion fluid to C 0.45 pm depressed pre-and post-ischaemic function. With attention to these various experimental factors, the buffer perfused isovolumically contracting mouse heart is shown to be stable and highly energised, and to possess a high level of contractility, The isovolumic model is more reliable in assessing ischaemic responses than the commonly employed apicobasal model. Experimental Physiology (200 1) 86.6, 703-7 16.

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