Abstract
Adenosine is an adenine base purine with actions as a modulator of neurotransmission, smooth muscle contraction, and immune response in several systems of the human body, including the cardiovascular system. In the vasculature, four P1-receptors or adenosine receptors—A1, A2A, A2B and A3—have been identified. Adenosine receptors are membrane G-protein receptors that trigger their actions through several signaling pathways and present differential affinity requirements. Adenosine is an endogenous ligand whose extracellular levels can reach concentrations high enough to activate the adenosine receptors. This nucleoside is a product of enzymatic breakdown of extra and intracellular adenine nucleotides and also of S-adenosylhomocysteine. Adenosine availability is also dependent on the activity of nucleoside transporters (NTs). The interplay between NTs and adenosine receptors’ activities are debated and a particular attention is given to the paramount importance of the disruption of this interplay in vascular pathophysiology, namely in hypertension., The integration of important functional aspects of individual adenosine receptor pharmacology (such as in vasoconstriction/vasodilation) and morphological features (within the three vascular layers) in vessels will be discussed, hopefully clarifying the importance of adenosine receptors/NTs for modulating peripheral mesenteric vascular resistance. In recent years, an increase interest in purine physiology/pharmacology has led to the development of new ligands for adenosine receptors. Some of them have been patented as having promising therapeutic activities and some have been chosen to undergo on clinical trials. Increased levels of endogenous adenosine near a specific subtype can lead to its activation, constituting an indirect receptor targeting approach either by inhibition of NT or, alternatively, by increasing the activity of enzymes responsible for ATP breakdown. These findings highlight the putative role of adenosinergic players as attractive therapeutic targets for cardiovascular pathologies, namely hypertension, heart failure or stroke. Nevertheless, several aspects are still to be explored, creating new challenges to be addressed in future studies, particularly the development of strategies able to circumvent the predicted side effects of these therapies.
Highlights
Adenosine is an adenine nucleoside involved in nucleic acid assembly that results from ATP degradation in both the intra- and extracellular environment by the action of specific enzymes, and can act as a signaling molecule by interacting with integral membrane proteins, known as adenosine receptors or purinergic P1-receptors [1]
Adenosine receptor subtypes have been grouped into two main categories: (i) subtypes that are coupled to inhibitory G proteins, such as adenosine A1 and A3 receptors and (ii) subtypes which are coupled to stimulatory G proteins, like the A2A and A2B receptors
Evidence has demonstrated that adenosine receptors are pleiotropic since they may couple with several G proteins/transduction mechanisms depending on their degree of activation or cellular/subcellular localization [2]
Summary
Adenosine is an adenine nucleoside involved in nucleic acid assembly that results from ATP degradation in both the intra- and extracellular environment by the action of specific enzymes, and can act as a signaling molecule by interacting with integral membrane proteins, known as adenosine receptors or purinergic P1-receptors [1]. Transport of adenosine across the cellular membrane is crucial since it contributes to regulate extracellular adenosine levels, and subsequently, adenosine receptor subtype activation. NTs act as important players in adenosine function by controlling local levels of adenosine in the vicinity of the adenosine receptors The effectiveness of this adenosine transport system has been demonstrated to be active in humans, and is responsible for the extremely short half-life of adenosine in human blood. Guanosine increases adenosine and inosine levels [14,15], and can, alter adenosinergic system dynamics All these players—adenosine, adenosine receptors and nucleoside transporters—constitute together the adenosinergic system that, due to the above features, can exert a “fine-tuning” modulation in multiple physiological and pathophysiological processes
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