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Molecules 2017, 22(5), 752; doi:10.3390/molecules22050752

The Adenosinergic System as a Therapeutic Target in the Vasculature: New Ligands and Challenges

1
LAQV/REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-047 Porto, Portugal
2
Laboratory of Pharmacology, Department of Drug Science, Faculty of Pharmacy, University of Porto, 4050-047 Porto, Portugal
*
Author to whom correspondence should be addressed.
Academic Editor: Francisco Ciruela
Received: 17 March 2017 / Revised: 24 April 2017 / Accepted: 2 May 2017 / Published: 6 May 2017
(This article belongs to the Special Issue Adenosine Receptors)
View Full-Text   |   Download PDF [305 KB, uploaded 6 May 2017]

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. View Full-Text
Keywords: adenosine receptors; nucleoside transporters; vasculature adenosine receptors; nucleoside transporters; vasculature
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Sousa, J.B.; Diniz, C. The Adenosinergic System as a Therapeutic Target in the Vasculature: New Ligands and Challenges. Molecules 2017, 22, 752.

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