Adenosine Endogenously Released During Early Reperfusion Mitigates Postischemic Myocardial Dysfunction by Inhibiting Platelet Adhesion

Abstract

The purpose of this study was to investigate platelet effects on postischemic heart function in conjunction with adenosine effects on intracoronary platelet adhesion. Homologous platelets were infused into the coronaries of isolated guinea pig hearts, either during low-flow ischemia or during reperfusion, and external heart work (EHW) and intracoronary platelet adhesion were determined. In most experiments, thrombin was added to the perfusate. The influence of endogenous adenosine was studied by use of the uptake blocker dipyridamole and the unspecific adenosine-receptor blocker theophylline, the A1-receptor blocker 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and the A2-receptor blocker 3,7-dimethyl-1-propargylxanthine (DMPX). The importance of nitric oxide and prostaglandin I2 (PGI2) was tested by using nitro-L-arginine (NOLAG) and indomethacin, respectively. When platelets were applied with thrombin during low-flow ischemia, EHW recovered to only 63 +/- 4% of the preischemic value, as compared with 89 +/- 3% without platelets (p < 0.05). Despite thrombin, platelets incurred no significant functional loss when applied in the first minute of reperfusion (but again in the fifth minute); however, when theophylline was also present, recovery of EHW amounted to only 42 +/- 12%. Intracoronary adhesion of platelets was negligible without thrombin, and highest during low-flow ischemia with thrombin (35 +/- 3% of the applied number). No adhesion occurred during the first minute of reperfusion, whereas in the fifth minute, adhesion was again 20.8 +/- 4%. Dipyridamole increased adenosine release and attenuated adhesion at this time. Theophylline increased adhesion in the first minute of reperfusion (33 +/- 6.4%), whereas NOLAG and indomethacin proved to be ineffective. DPCPX and DMPX each increased platelet retention during the first minute of reperfusion, their effects being additive. Intracoronary adhesion of platelets induced by thrombin in isolated hearts can reduce postischemic recovery of heart function. During reperfusion, but not during low-flow, endogenous adenosine can prevent platelet adhesion and loss of myocardial function, an action mediated both by A1- and A2-receptor-dependent mechanisms.

Acute adenosinergic cardioprotection in ischemic-reperfused hearts

“…Thus the A 1 AR is more likely to be intrinsically (and substantially) activated during ischemia-reperfusion than the A 3 . The protective function of intrinsically activated A 1 ARs has been verified by a small number of studies employing A 1 -selective antagonists (225,312,259) or antagonists displaying greater selectivity for A 1 versus A 3 receptors (245). In contrast, selective A 3 antagonism appears to have little effect on intrinsic tolerance to ischemia or hypoxia in isolated myocytes (173,267) or hearts (188).…”

“…Extracellular adenosine increases up to an order of magnitude within minutes of ischemia, and whereas it is problematic to estimate relevant interstitial adenosine concentrations, a variety of measures suggest they are more than sufficient to substantially activate cardiovascular receptors (104,109,115,285,286). This is pharmacologically validated by the effects of adenosine receptor antagonists in different models (225,245,259,311,312), keeping in mind the potential for adenosine formation to overcome effects of applied antagonism via "opening" the regulatory feedback loop between stimulus (deenergization) and signal (adenosine formation and protection) (111,123). Collectively, studies with both agonists and antagonists support substantial yet submaximal receptor activation by endogenously generated adenosine during ischemiareperfusion (see Adenosine Receptor-Mediated Cardioprotection: Which Subtypes Are Involved?).…”

“…There is also some support for intrinsic A 2 receptor-mediated protection via endogenous adenosine. For example, A 2 antagonism limits functional outcome and exacerbates platelet adhesion in vivo (259), and mixed A 1 /A 2 antagonism is also shown to be much more effective than selective A 1 AR antagonism in worsening ischemic outcomes in vivo, implicating a role for A 2 receptors (312). Effects of A 2 antagonists are restricted to in situ models consistent with A 2 receptors modulating inflammatory processes and platelet aggregation, requiring the presence of blood-borne elements.…”

“…For example, overexpression of A 1 ARs limits diastolic contracture yet appears to exert limited additional benefit postischemia (196), and post-ischemic receptor activation exerts little if any effect on indexes of reversible and irreversible myocardial damage (91,245,312). In contrast, a number of investigators reveal beneficial actions of both exogenous (86,188) and endogenous adenosine (225,259,311) in the postischemic heart.…”

“…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).…”