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

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.

Vascular Sympathetic Neurotransmission and Endothelial Dysfunction

“…In vascular tissues as well as in some diseased states, such as hypertension, the bioavailability of adenosine varies [71], as presented in Table 2.…”

Deletion of murine slc29a4 modifies vascular responses to adenosine and 5‐hydroxytryptamine in a sexually dimorphic manner

“…There have been numerous studies highlighting the role of ENT4 in modulating the effects of 5‐HT in the CNS, but relatively few studies have examined its role in peripheral systems. Since both adenosine and 5‐HT have well‐documented cardiovascular effects (Fidalgo, Ivanov, & Wood, 2013; McIntosh & Lasley, 2012; Sousa & Diniz, 2017; Watts, 2016), ENT4 may play a role in regulating the effects of these agents in the vasculature. A unique aspect of ENT4 is the enhancement of substrate flux in acidic conditions, such as those associated with vascular ischemia‐reperfusion injury (Barnes et al, 2006; Tandio et al, 2019; Zhou, Duan, Engel, Xia, & Wang, 2010).…”

Differential regulation of β2-adrenoceptor and adenosine A2B receptor signalling by GRK and arrestin proteins in arterial smooth muscle

“…Collectively, these data suggest that the β 1 AR population plays at most a minor role in isoprenaline-stimulated cAMP production, with the majority role played by the β 2 AR, implying that we examined β 2 AR (rather than β 1 AR) activity in this study. VSMC are also reported to express various adenosine receptors [27], therefore we characterised their contributions to cAMP accumulation in response to the non-selective adenosine agonist NECA. Our data show that NECA-induced cAMP production was unaffected by PTx pretreatment and the A 2A R-selective agonist CGS21680 produced a weak response only at concentrations reported to interact with A 2B R [16].…”

“…Adenosine mediates vaso-relaxatory responses in a variety of vascular beds [26], and RASM cells are reported to express a number of adenosine receptor subtypes [27]. Therefore, we first characterized which receptor subtype(s) could generate cAMP.…”