Impaired Function of Prejunctional Adenosine A₁ Receptors Expressed by Perivascular Sympathetic Nerves in DOCA-Salt Hypertensive Rats

Abstract

Increased sympathetic nervous system activity contributes to deoxycorticosterone acetate (DOCA)-salt hypertension in rats. ATP and norepinephrine (NE) are coreleased from perivascular sympathetic nerves. NE acts at prejunctional a 2 -adrenergic receptors (a 2 ARs) to inhibit NE release, and a 2 AR function is impaired in DOCA-salt rats. Adenosine, an enzymatic ATP degradation product, acts at prejunctional A 1 adenosine receptors (A 1 Rs) to inhibit NE release. We tested the hypothesis that prejunctional A 1 R function is impaired in sympathetic nerves supplying mesenteric arteries (MAs) and veins (MVs) of DOCAsalt rats. Electrically evoked NE release and constrictions of blood vessels were studied in vitro with use of amperometry to measure NE oxidation currents and video microscopy, respectively. Immunohistochemical methods were used to localize tyrosine hydroxylase (TH) and A 1 Rs in perivascular sympathetic nerves. TH and A 1 Rs colocalized to perivascular sympathetic nerves. Adenosine and N 6 -cyclopentyl-adenosine (CPA, A 1 R agonist) constricted MVs but not MAs. Adenosine and CPA (0.001-10 mM) inhibited neurogenic constrictions and NE release in MAs and MVs. DOCA-salt arteries were resistant to adenosine and CPA-mediated inhibition of NE release and constriction. The A 2A adenosine receptor agonist CGS21680 (C 23 H 29 N 7 O 6 .HCl.xH 2 O) (0.001-0.1 mM) did not alter NE oxidation currents. We conclude that there are prejunctional A 1 Rs in arteries and both pre-and postjunctional A 1 Rs in veins; thus, adenosine selectively constricts the veins. Prejunctional A 1 R function is impaired in arteries, but not veins, from DOCA-salt rats. Sympathetic autoreceptor dysfunction is not specific to a 2 ARs, but there is a more general disruption of prejunctional mechanisms controlling sympathetic neurotransmitter release in DOCA-salt hypertension.

Macrophage depletion lowers blood pressure and restores sympathetic nerve α2-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats

“…Thus, a possible mechanism of O 2 Ϫ disruption of ␣ 2 R function is through receptor-G protein-effector uncoupling. This proposed general mechanism is supported by our recent data showing that the function of prejunctional A 1 adenosine receptors on periarterial sympathetic nerves is also impaired in DOCA-salt hypertensive rats (56).…”

Enhanced function of inhibitory presynaptic cannabinoid CB1 receptors on sympathetic nerves of DOCA–salt hypertensive rats

“…By contrast, presynaptic α 2 - [22,31,34,44] and β 2 -adrenoceptors [30] and adenosine A 1 heteroreceptors [37] rather increase hypertension. The differential behaviour of α 2 (or A 1 ) as opposed to CB 1 receptors is indeed surprising since each of the three receptors is G i/o proteincoupled [1].…”

“…The higher sympathetic tone is at least partially due to an impaired function of inhibitory presynaptic α 2 -adrenoceptors [22,31,34,44] and adenosine A 1 heteroreceptors [37] and an increased function of facilitatory presynaptic β 2 -adrenoceptors [30]. We can exclude the possibility that a reduction of renal mass affects our results, since unilateral nephrectomy was performed both in the hypertensive and normotensive animals.…”

“…Presynaptic receptors located on sympathetic nerve endings participate in the development and maintenance of the enhanced sympathetic activity, as shown in, e.-g., the model of deoxycorticosterone acetate (DOCA)-salt hypertension in rats. Thus, an impaired function of inhibitory presynaptic α 2 -adrenoceptors [23,31,34] and adenosine A 1 heteroreceptors [37] and an increased function of facilitatory presynaptic β 2 -adrenoceptors [30] have been shown.…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…Inhibitory prejunctional purinergic modulation of vascular sympathetic neurotransmission in SHR is diminished via both adrenoceptors and A 1 receptors (Kamikawa et al, 1980(Kamikawa et al, , 1983Jackson, 1987;Illes et al, 1989;Yu et al, 1997;Park et al, 2010a). There is also impaired function of prejunctional A 1 receptors on perivascular sympathetic nerves in deoxycorticosterone acetate (DOCA)-salt hypertensive rats (Sangsiri et al, 2013).…”