Alterations in sympathetic neuroeffector transmission to mesenteric arteries but not veins in DOCA-salt hypertension

Abstract

We studied hypertension-associated changes in prejunctional α 2 adrenergic receptor (α 2 -AR) function using amperometry to monitor in vitro norepinephrine (NE) measured as oxidation currents. Vasoconstriction was measured using video imaging. NE release was induced by electrical stimulation of sympathetic nerves associated with mesenteric arteries (MA) and veins (MV) of sham and DOCA-salt hypertensive rats. NE oxidation currents were larger in DOCA-salt compared to sham MA; there were no differences between currents in sham and DOCA-salt MV. Increases in NE oxidation currents followed a multi-exponential time course in sham MA. In DOCA-salt MA and sham and DOCA-salt MV, the time course was mono-exponential. Yohimbine (α 2 -AR antagonist, 1 μM), caused a mono-exponential increase in NE oxidation currents in sham and DOCA-salt MA. Yohimbine increased NE oxidation currents and constrictions more in sham compared to DOCAsalt MA and compared to MV. UK 14,304 (α 2 -AR agonist, 1.0 μM), reduced currents less in DOCAsalt MA and sham and DOCA-salt MV compared to sham MA. Prazosin (α 1 -AR antagonist, 0.1 μM) did not alter NE oxidation currents. Prazosin inhibited constrictions more in DOCA-salt compared to sham MA and almost completely blocked constrictions in sham and DOCA-salt MV. Prazosin-resistant constrictions in MA were blocked by the P2 receptor antagonist, PPADS (10 μM). Prejunctional α 2 -ARs modify NE concentrations near neuroeffector junctions in MA and MV. α 2 -AR function is most prominent in MA and is impaired in DOCA-salt MA but not MV. Purinergic transmission predominates in sham MA. NE is the dominant vasoconstrictor in DOCA-salt MA and sham and DOCA-salt MV.

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

“…Similar artery/vein differences have been established for a 2 AR function DOCA-salt hypertension (Luo et al, 2004;Park et al, 2010). a 2 AR function is partly restored in DOCA-salt rats treated with apocynin, an NADPH oxidase inhibitor (Demel et al, 2010).…”

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).…”

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

“…Detection was accomplished at a constant potential of 600 mV versus the Ag/AgCl reference. This applied potential was used to detect NE release elicited by short trains of electrical stimulation (10 Hz, 5 s, 80 V) using a bipolar focal stimulation electrode positioned on the artery surface (49,50). A control oxidation current in response to nerve stimulation was obtained in each tissue, and either UK-14304 (␣ 2AR receptor agonist) or idazoxan (␣2AR receptor antagonist) were then applied by addition to the Krebs solution.…”

“…The carbon fiber microelectrodes were prepared as previously described (49,50). The electrode was positioned on the surface of the MA using a micromanipulator.…”

“…Hypertension in the DOCA-salt model is driven by reduced renal mass (removal of one kidney), high circulating mineralocorticoid levels, and high salt intake (57). Elevated salt increases central sympathetic drive to the cardiovascular system (17,48), but there are also alterations in the local mechanisms that modulate sympathetic neurotransmission in salt-sensitive hypertension, including impaired function of ␣ 2 -adrenergic autoreceptors (␣ 2 ARs) on sympathetic nerves associated with mesenteric arteries (MAs) (41,49). ␣ 2 ARs provide negative feedback control over norepinephrine (NE) release, and MAs are part of the splanchnic circulation, a major resistance arterial bed critical for blood pressure regulation (2,28,30).…”