Impaired function of prejunctional adenosine receptors on perivascular sympathetic nerves in salt-sensitive hypertension

Hypertension is a major public problem that will affect more than 1.6 billion people worldwide by 2025. Essential hypertension is associated with sympathetic nerve hyperactivity and 50% of the patients are salt sensitive. Deoxycorticosterone acetate (DOCA)-salt rat model is a low rennin form of hypertension with transient salt and water retention and is a model of salt-sensitive human hypertension. Norepinephrine (NE) and ATP are the major cotransmitters relased from perivascular sympathetic nerve varicosities supplying arteries and veins. NE and ATP regulate pheripheral arterial resistance and venous capacitance. Release of NE and ATP is precisely regulated by prejnctional autoreceptors. NE acts on the α2-adrenergic receptors (α 2AR) to inhibit NE and ATP release and the α2AR function is impaired in DOCA-salt rats. ATP is hydrolyzed to adenosine which activates prejunctional adenosine A1 receptors (A1Rs) and A 2ARs to modulate NE and ATP release. This work determined role of prejunctional A1Rs and A2ARs in adrenergic transmission. I also tested the hypothesis that prejunctional A1R and A2AR function is impaired in sympathetic nerves supplying mesenteric arteries and veins of DOCA-salt rats. Electricall-evoked NE release and constriction of blood vessel were measured in vitro by using amperometry and video microscopy. Drug effects on the kinetics of NE oxidtion currents were measured. My results show that prejunctional A1Rs couple to inhibition of NE release and A1R function is impaired in periarterial nerves of DOCA-salt rats. I also showed that prejunctional A2ARs couple to stimulation of adenosine transporter in perivenous sympathetic nerves and this receptor function is also compromised in DOCA-salt hypertension. These data suggests that the perivascular sympathetic nerve varicosities are an important target for the pathophysiology of salt sensitive hypertension. Furthermore, sympathetic autoreceptor dysfunction is not specific to α2-adrenergic receptors, but there is a more general disruption of prejunctional mechanisms controlling sympathetic neurotransmitter release. Finally, the data illustrate differential autoreceptor dysfunction in arteries and veins of DOCA-salt hypertension.