Differential inhibition of noradrenaline release mediated by inhibitory A 1 -adenosine receptors in the mesenteric vein and artery from normotensive and hypertensive rats C. Rocha-Pereira, J.B. Sousa, M.S. Vieira-Rocha, P. Fresco, J. Gonçalves, C. Diniz ⇑ REQUIMTE/FARMA, Departamento de Ciências do Medicamento, Laboratório de Farmacologia, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, Portugal article info Article history: Received 28 September 2012 Received in revised form 17 January 2013 Accepted 6 February 2013 Available online 13 February 2013 Keywords: Adenosine receptors Sympathetic nerves Mesenteric artery Mesenteric vein Hypertension Prejunctional abstract Mesenteric arteries and veins are densely innervated by sympathetic nerves and are crucial in the regu- lation of peripheral resistance and capacitance, respectively, thus, in the control of blood pressure. Pre- synaptic adenosine receptors are involved in vascular tonus regulation, by modulating noradrenaline release from vascular postganglionic sympathetic nerve endings. Some studies also suggest that adeno- sine receptors (AR) may have a role in hypertension. We aim at investigating the role of presynaptic aden- osine receptors in mesenteric vessels and establish a relationship between their effects (in mesenteric vessels) and hypertension, using the spontaneously hypertensive rats (SHR) as a model of hypertension. Adenosine receptor-mediated modulation of noradrenaline release was investigated through the effects of selective agonists and antagonists on electrically-evoked [ 3 H]-noradrenaline overflow. CPA (A 1 AR selective agonist: 1–100 nM) inhibited tritium overflow, but the inhibition was lower in SHR mesenteric vessels. IB-MECA (A 3 AR selective agonist: 1–100 nM) also inhibited tritium overflow but only in WKY mesenteric veins. CGS 21680 (A 2A AR selective agonist: up to 100 nM) failed to facilitate noradrenaline release in mesenteric veins, from both strains, but induced a similar facilitation in the mesenteric arteries. NECA (non-selective AR agonist: 1, 3 and 10 lM), in the presence of A 1 (DPCPX, 20 nM) and A 3 (MRS 1523, 1 lM) AR selective antagonists, failed to change tritium overflow. In summary, the modulatory effects mediated by presynaptic adenosine receptors were characterized, for the first time, in mesenteric vessels: a major inhibition exerted by the A 1 subtype in both vessels; a slight inhibition mediated by A 3 receptors in mesenteric vein; a facilitation mediated by A 2A receptors only in mesenteric artery (from both strains). The less efficient prejunctional adenosine receptor mediated inhibitory effects can contribute to an increase of noradrenaline in the synaptic cleft (both in arteries and veins), which might conduce to increased vascular reactivity. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction The mesenteric circulation plays an important role in the main- tenance of systemic blood pressure and regulation of tissue blood flow (Takenaga and Kawasaki, 1999). It is well established that ele- vated blood pressure is associated with enhanced sympathetic nerve activity in both human hypertension (Matsukawa et al., 1993) and spontaneously hypertensive rats (SHR) (Judy et al., 1976; Lundin et al., 1984). Nevertheless, the sympathetic neurons innervating arteries and veins differ in their location in the ganglia and in their electrophysiological properties (Browning et al., 1999) suggesting a differential sympathetic neural control of mesenteric arteries and veins. Sympathetic nerves innervating the splanchnic circulation are particularly important (King et al., 2007): arteries and veins from the mesenteric bed are densely innervated by sym- pathetic nerve endings and are crucial in the regulation of the peripheral resistance and capacitance, respectively (Greenway, 1983; Pang, 2001; Park et al., 2007; Rothe, 1983). For instance, an increase in mesenteric venomotor tone leads to an increase in venous return and cardiac output with a profound impact on over- all hemodynamics (Greenway, 1983). Moreover, it is well accepted that veins are more sensitive than arteries to the vasoconstrictor effects of sympathetic nerve stimulation (Hottenstein and Kreulen, 1987; Luo et al., 2004; Park et al., 2007). Adenosine is a potent regulator of vascular tone, exerting its ef- fects either directly on vascular smooth muscle cells or through prejunctional modulation of perivascular sympathetic neurotrans- mission (Burnstock and Kennedy, 1986; Olsson and Pearson, 1990). 0197-0186/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuint.2013.02.010 ⇑ Corresponding author. Address: Faculdade de Farmácia, Departamento de Ciências do Medicamento, Laboratório de Farmacologia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-047 Porto, Portugal. Tel.: +351 220428608. E-mail address: cdiniz@ff.up.pt (C. Diniz). Neurochemistry International 62 (2013) 399–405 Contents lists available at SciVerse ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/nci