α ₂-Adrenoceptors: Challenges and Opportunities—Enlightenment from the Kidney

Abstract

It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered α2-adrenoceptors (α2-ARs) in skin-lightening experiments in the frog. Now α2-ARs lurk on the horizon involving hypertension causality, renal denervation for hypertension, injury from falling in the elderly and prazosin’s mechanism of action in anxiety states such as posttraumatic stress disorder (PTSD). Our goal here is to focus on this horizon and bring into clear view the role of α2-AR-mediated mechanisms in these seemingly unrelated conditions. Our narrative begins with an explanation of how experiments in isolated perfused kidneys led to the discovery of a sodium-retaining process, a fundamental mechanism of hypertension, mediated by α2-ARs. In this model system and in the setting of furosemide-induced sodium excretion, α2-AR activation inhibited adenylate cyclase, suppressed cAMP formation, and caused sodium retention. Further investigations led to the realization that renal α2-AR expression in hypertensive animals is elevated, thus supporting a key role for kidney α2-ARs in the pathophysiology of essential hypertension. Subsequent studies clarified the molecular pathways by which α2-ARs activate prohypertensive biochemical systems. While investigating the role of α1-adrenoceptors (α1-ARs) versus α2-ARs in renal sympathetic neurotransmission, we noted an astonishing result: in the kidney α1-ARs suppress the postjunctional expression of α2-ARs. Here, we describe how this finding relates to a broader understanding of the role of α2-ARs in diverse disease states. Because of the capacity for qualitative and quantitative monitoring of α2-AR-induced regulatory mechanisms in the kidney, we looked to the kidney and found enlightenment.

The affinity and selectivity of α‐adrenoceptor antagonists, antidepressants and antipsychotics for the human α2A, α2B, and α2C‐adrenoceptors and comparison with human α1 and β‐adrenoceptors

“…α2‐Adrenoceptors are subdivided into α2A, α2B, and α2C‐subtypes. With receptors being present in the heart, blood vessels, and kidney, 8 α2‐adrenoceptors are important in blood pressure control (an interplay between α1, α2, and β‐adrenoceptors) and including central and peripheral α2‐effects. In addition, many α2‐adrenoceptors present in the brain also have clinical roles in anaesthesia and psychiatric treatments 9 with both pre‐ and post‐synaptic effects on neurotransmission 10‐13 …”

The effects of clonidine and yohimbine in the tail flick and hot plate tests in the naked mole rat (Heterocephalus glaber)

“…The involvement of opioid (5,6), cholinergic (8,9) and GABA (11,12) receptor pathways in NMR pain mechanisms has been reported. Noradrenergic receptor system involvement in nociception is reported in other animals such as; rats (13), pigs (14), dog and cats (15), Speke's hinged tortoise (16), small ruminants (17), and frog (18). To our knowledge, the involvement of the noradrenergic receptor system in antinociception against thermal stimuli has not been previously studied in the NMR hence the basis of this study.…”

Role of α- and β-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease

“…Interestingly α1-adrenoceptor blockade can induce synthesis of new α2-adrenoceptors, which subsequently override the post-junctional domain and function of α1-adrenoceptor antagonists. This effect has mostly been investigated in the context of treatment of hypertension and renal vascular denervation, as α2-adrenoceptors have been found to overcome sympathetic stimulation and increase sodium excretion from renal tubules [ 28 ]. In addition to α1-adrenoceptors, β-adrenoceptors mediate many of the effects of norepinephrine released from the sympathetic nervous system and epinephrine released from the adrenal medulla through the Gs family of G proteins that activate adenylyl cyclase [ 5 , 6 , 29 ].…”