Adenosine regulation of mesenteric vasodilation

I n 1929, Drury and Szent Gyorgi extracted adenosine (ADO) from different tissues and observed striking cardiovascular responses to injections of this purified adenine nucleoside.’ Nearly 40 years ago, Berne et al. proposed that myocardial generation of ADO was a major metabolic mechanism regulating blood flow in the circulation of the heart.2-4 Subsequently, Burnstock led the way in identifying discrete receptors for adenine nucleosides and nucleotides5 In his widely accepted terminology, the Pl purinergic receptor has a greater affinity for ADO than for the nucleotides, and the P2 purinoceptor has a higher affinity for adenosine 5’-triphosphate (ATP) and diphosphate than for ADO. The Pl purinoceptor has two subtype receptors; binding to the Al subtype inhibits adenylate cyclase, and binding to the A2 receptor subtype activates enzymatic synthesis of intracellular 5’cyclic adenosine monophosphate (CAMP).‘,’ A2 receptor activation on vascular smooth muscle (VSM) cells, causing intracellular CAMP accumulation, has been proposed as a general mechanism underlying the precapillary vasodilator effect of ADO8 in different vascular beds, including the mesenteric.’ However, other putative second messenger mechanisms have also been implicated in ADO-induced vasodilation.‘0-‘2 These include stimulation of a G proteinI inhibition of Ca2+ influx into VSM myoplasm, ‘**” inhibition of a phosphatidylinositol-dependent kinase,‘” opening of K+ channels to hyperpolarize VSM cells,” and generation of endothelial nitric oxide, I8 although there is evidence against the last mechanism.” Based on extrapolation of findings from other muscle systems, one can predicate a model for ADO vasodilation in mesenteric VSM cells (Figure 1). ADO binding to the A2 receptor subtype on the cell surface activates adenylate cyclase via a stimulatory G protein. The ensuing accumulation of CAMP and activation of a protein kinase closes the sarcolemmal Ca’+ slow channel, thereby attenuating the inward diffusion of Ca’+ from the extracellular compartment. CAMP accumulation also enhances Ca2+adenosine triphosphatase extrusion of Ca2+ from the myoplasm into the sarcoplasmic reticulum and the extracellular space. The decrease in myoplasmic [Ca”] relaxes VSM cells and dilates the blood vessel. For nearly all of the 20th century, Barcroft’s notion has dominated the explanation of physiological regulation of vasodilation.20 According to his concept, the altered chemical environment produced by tissue metabolism relaxes nearby VSM to elicit an increase in local blood flow. Despite the demonstration of other regulatory mechanisms, local metabolic factors have been viewed as especially important in the control of blood flow through the intestinal vasculature.” Particularly telling evidence favoring the metabolic theory has been generated from studies of intestinal vascular autoregulatory responses in which the challenge of either a diminished blood flow or an increased oxygen demand evokes a localized hyperemia of the gut. Examples of such intestinal autoregulatory phenomena include postprandial hyperemia,22 pressure-flow autoregulation,‘j reactive hyperemia,24 autoregulatory escape,” and poststimulation hyperemia.” However, it should be noted that nearly all research in this area has tended to focus narrowly on single-mediator candidates without much consideration of associated regulatory systems. Three major criteria for validating candidate local regulators of mesenteric hyperemias are: (1) the substance must be present in intestinal tissue in measurable quantities that increase with either a diminished blood flow or an enhanced local metabolism; (2) when administered, the substance exogenously must relax mucosal resistance vessels and must increase blood flow through mucosal, nutrient capillaries; and (3) the substance should have effective antagonists of either its VSM receptors or its biosynthetic enzymes.‘0727 Confidence in the putative vasodilator regulator would also be increased if it had been shown to fulfill the role of vasodilator metabolite in at