Associate editor: C.C.Y. PangPharmacology of adenosine receptors in the vasculature
Introduction
Adenosine is a ubiquitous molecule that has an effect on many mammalian cells. This nucleoside appears to play a pivotal role in a number of physiological and pathophysiological conditions. One of the primary roles of adenosine within the cardiovascular system appears to be the direct regulation of both cardiac and vascular functions. Adenosine also has an indirect effect on the cardiovascular system by virtue of its effects on the autonomic nervous system, as well as on mast cells and platelets. There has been considerable interest in the subclassification of adenosine receptors because of their widespread actions in mammalian cells. Obviously, characterization of a heterogeneous population of receptors for adenosine could provide an opportunity for the development of novel compounds that could be of therapeutic value.
Adenosine is released from cells as a result of metabolism, and its release can increase dramatically from cells that are metabolically stressed. This essentially means that this molecule can be released from a variety of cells throughout the body, as a result of increased metabolic rates, in concentrations that can have a profound impact on blood vessel function and, consequently, blood flow. Therefore, it has to be recognized that this molecule can have a very promiscuous effect on blood vessel function throughout the body.
It is also recognized that the actions of this nucleoside on the vasculature are most prominent when oxygen demand is high and there is a reduction in oxygen tension at the site in question. Therefore, it is not surprising that adenosine has been found to be an important regulator of blood vessel tone under hypoxic conditions where high concentrations of adenosine are attained. In addition, it is interesting to observe that in certain vascular beds, adenosine has a biphasic response, and can produce both contraction and relaxation, the response being dependent on basal blood vessel tone.
Over the last three decades, it has become known that the physiological actions of adenosine are transmitted via membrane-bound receptors coupled to G-proteins located on the effector cells.
Section snippets
Adenosine formation and catabolism
It is recognized that adenosine is formed at both intracellular and extracellular sites by two distinct pathways that involve two different substrates, namely, AMP and S-adenosylhomocysteine (Sparks & Bardenheuer, 1986). The enzymatic hydrolysis of each of these two substrates yields adenosine as a by-product. Since both enzymes are fairly abundant in the body, it means that both pathways are potentially of equal importance.
There are essentially three systems that can account for inactivation
Adenosine receptor subtype and signal transduction
Adenosine receptors were first divided into two subtypes, based on their ability to inhibit or stimulate the activity of adenylyl cyclase (Burnstock, 1978). Currently, four subtypes of adenosine receptors in mammalian cells have been characterized and cloned. These are referred to as the adenosine A1, A2A, A2B, and A3 receptors Tucker & Linden, 1993, Linden, 1994, Fredholm et al., 1994, Olah & Stiles, 1995, Fredholm et al., 2000. Although a subtype labeled as the adenosine A4 receptor has been
Coronary artery
The importance of vasodilator effects of adenosine has long been established in the coronary arteries of many species, including rabbit (Hisajima et al., 1986), guinea-pig (Ueeda et al., 1991), bovine (Conti et al., 1993), dog (Cox et al., 1994), porcine (Niiya et al., 1994), and rat (Harrison et al., 1996). There is also consensus that the adenosine A2 receptors mediate the vasorelaxant effect of adenosine in this vascular bed Ueeda et al., 1991, Merkel et al., 1993, Conti et al., 1993.
Adenosine receptors in human blood vessels
Adenosine receptors in human blood vessels have been characterized using pharmacological and biochemical techniques. Certainly, specific high-affinity-binding sites to NECA have been demonstrated in cerebral microvessels and pial vessels. The reported Bmax and Kd values for the high-affinity sites for NECA in these preparations were ∼ 1.3 pmol per mg of protein and 250 nM, respectively (Kalaria & Harik, 1988). Furthermore, effectively, no binding sites could be demonstrated for CHA (selective A1
Functional role of different subtypes of adenosine receptors in control of microcirculation
A number of reports in the literature have described the vasodilator role of adenosine receptors in a number of microvasculature beds. In rat skeletal muscle, adenosine dilates the arterioles and venules of the spinotrapezius muscle (Mian & Marshall, 1991). Topical applications of adenosine produced graded dilatations of all sections of arterial and venous trees, with the terminal arterioles and collecting venules being the most responsive (Mian & Marshall, 1991). In addition, hypoxia appeared
Arterial circulation
Activation of adenosine receptors results in a reduction in blood pressure, and associated with this is a reduction in arterial resistance Nekooeian & Tabrizchi, 1996, Tabrizchi, 1997. The arterial dilatation is predominately mediated via the activation of adenosine A2 receptors (Tabrizchi, 1997). Interestingly, it has been reported that the arterial vasodilator action of APNEA is not due to the stimulation of adenosine A2 receptors Fozard & Carruthers, 1993a, Fozard & Carruthers, 1993b and
Functional effects of adenosine and its analogues on the cardiovascular system in pathophysiological conditions
Adenosine is released from metabolically active cells, with the primary aim of tonic and cellular protection during stress conditions. Therefore, it would not be surprising to find that adenosine levels become elevated in a dysfunctional cardiovascular system. Long-term treatment of rats with the nonselective adenosine receptor antagonist 1,3-dipropyl-8-sulphonphenylxanthine has been reported to produce hypertension and morphological alteration of small arteries, with the lumen width being
Conclusion
It is clear that the effects of adenosine in blood vessels are mediated by membrane-bound receptors that are linked to G-proteins. Adenosine concentrations appear to be low during resting conditions, but can be substantially elevated during hypoxia and ischaemia and by increased mechanical and biochemical work. It is apparent that there are at least three subtypes of receptors that mediate the direct effects of adenosine in blood vessels, these being A1, A2A, and A2B subtypes. The functional
Acknowledgements
Research conducted in Reza Tabrizchi’s laboratory is supported, in part, by a grant-in-aid from the Heart and Stroke Foundation of Newfoundland & Labrador and New Brunswick.
References (153)
- et al.
Differential vasodilatory action of 2-octynyladenosine (YT-146), an adenosine A2 receptor agonist, in the isolated rat femoral artery and vein
Eur J Pharmacol
(1995) - et al.
Inhibition of N-, P/Q- and other types of Ca2+ channels in rat hippocampal nerve terminals by the adenosine A1 receptor
Eur J Pharmacol
(1997) - et al.
Cloning, characterisation and chromosomal assignment of the human adenosine A3 receptor (ADORA3) gene
Neurosci Res
(1997) - et al.
Rat heart mitochondria release adenosine
Biochem Biophys Res Commun
(1983) - et al.
Is adenosine deaminase involved in adenosine transport?
Med Hypotheses
(1990) - et al.
Acute hemodynamic effects of endogenous adenosine in patients with chronic heart failure
Am Heart J
(1998) - et al.
Effect of adenosine on pulmonary circulation of rabbits
Gen Pharmacol
(1999) - et al.
Cyclic AMP efflux is regulated by occupancy of adenosine receptor in pig aortic smooth muscle cells
J Biol Chem
(1990) - et al.
Interactions of the bovine brain A1-adenosine receptor with recombinant G protein α-subunits. Selectivity for rGiα-3
J Biol Chem
(1991) - et al.
Studies of 5′-nucleotidase in the perfused rat heart. Including measurement of the enzyme in perfused skeletal muscle and liver
J Biol Chem
(1976)