Endothelial and Neuronal Nitric Oxide Activate Distinct Pathways on Sympathetic Neurotransmission in Rat Tail and Mesenteric Arteries

Abstract

Nitric oxide (NO) seems to contribute to vascular homeostasis regulating neurotransmission. This work aimed at assessing the influence of NO from different sources and respective intracellular pathways on sympathetic neurotransmission, in two vascular beds. Electrically-evoked [3H]-noradrenaline release was assessed in rat mesenteric and tail arteries in the presence of NO donors or endothelial/neuronal nitric oxide synthase (NOS) inhibitors. The influence of NO on adenosine-mediated effects was also studied using selective antagonists for adenosine receptors subtypes. Location of neuronal NOS (nNOS) was investigated by immunohistochemistry (with specific antibodies for nNOS and for Schwann cells) and Confocal Microscopy. Results indicated that: 1) in mesenteric arteries, noradrenaline release was reduced by NO donors and it was increased by nNOS inhibitors; the effect of NO donors was only abolished by the adenosine A1 receptors antagonist; 2) in tail arteries, noradrenaline release was increased by NO donors and it was reduced by eNOS inhibitors; adenosine receptors antagonists were devoid of effect; 3) confocal microscopy showed nNOS staining in adventitial cells, some co-localized with Schwann cells. nNOS staining and its co-localization with Schwann cells were significantly lower in tail compared to mesenteric arteries. In conclusion, in mesenteric arteries, nNOS, mainly located in Schwann cells, seems to be the main source of NO influencing perivascular sympathetic neurotransmission with an inhibitory effect, mediated by adenosine A1 receptors activation. Instead, in tail arteries endothelial NO seems to play a more relevant role and has a facilitatory effect, independent of adenosine receptors activation.

Vascular Sympathetic Neurotransmission and Endothelial Dysfunction

“…The influence of endothelium in noradrenaline release has also been previously demonstrated [49,50]. This conclusion was obtained not only in arteries without endothelium but also in a model of endothelial dysfunction (i.e, essential hypertensive arteries), which is shown in Table 1.…”

“…There is evidence demonstrating that NO can modulate sympathetic neurotransmission modifying vascular smooth muscle tone, in various vascular beds, such as in coronary [57,58], mesenteric [50,59,60] and pulmonary arteries [61][62][63]. Indeed, and as illustrated in Figure 1,a NO donor, DEA-NONOATE (10 μM) altered noradrenaline release (measured as explained above, i.e., by determining the amount of 3 H overflow using liquid scintillation spectrometry) in differential mode depending on the vascular territory: an increase of noradrenaline release occurs in tail artery contrasting to mesenteric territory where noradrenaline release is reduced.…”

“…Another relevant data are related with NO source, i.e., the type of NOS that generates NO (Figure 1): in tail arteries, NO production is ascribed mainly to eNOS isoform, particularly to eNOS oxygenase domain with residual activity of the eNOS reductase domain [50], while in mesenteric arteries, nNOS, with both reductase and oxygenase domains being equally active, seems to be the most relevant isoform producing NO.…”

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

“…Several studies described the occurrence of a neuromodulatory role ascribed to adenosine receptor subtypes activation in sympathetic nerve fibers located in the adventitia layer of pulmonary [ 155 ], mesenteric [ 156 , 157 , 158 ], aorta [ 159 ], tail [ 3 , 4 , 154 , 160 , 161 , 162 ] and renal [ 163 , 164 ] arteries as well as in veins such as mesenteric veins [ 165 , 166 , 167 ]. For example, adenosine A 2 receptors, known to facilitate noradrenaline release, may have a profound impact in vascular remodeling, by enhancing noradrenaline levels in the synaptic cleft.…”

“…For example, adenosine A 2 receptors, known to facilitate noradrenaline release, may have a profound impact in vascular remodeling, by enhancing noradrenaline levels in the synaptic cleft. On the other hand, the idea that endothelium could influence neurotransmission [ 155 ] was recently supported by findings where endogenous adenosine (derived from endothelium) altered neurotransmission (mesenteric and tail arteries) [ 161 ]. Endothelium-derived adenosine was also described to activate prejunctional adenosine receptors, mainly A 1 and A 2A , which modulate neurotransmission influencing vascular tonus [ 154 ].…”