Cardiovascular Therapeutics

Cardiovascular Therapeutics / 2020 / Article

Review Article | Open Access

Volume 2020 |Article ID 2478781 |

William A. Pettinger, Edwin K. Jackson, "α 2-Adrenoceptors: Challenges and Opportunities—Enlightenment from the Kidney", Cardiovascular Therapeutics, vol. 2020, Article ID 2478781, 9 pages, 2020.

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

Academic Editor: Victor Garcia
Received20 Jan 2020
Accepted03 Mar 2020
Published01 May 2020


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.

1. Background

While pursuing the hidden antihypertensive mechanism of methyldopa (Aldomet) [1, 2], we examined the effects of methyldopa’s metabolites methyldopamine and methylnorepinephrine on reversing melanocyte stimulating hormone- (MSH-) induced darkening of frog (Rana pipiens) skin. In these experiments, the skin of the rear thigh of Rana pipiens was draped over a 1.2 cm cylinder and light reflectance from a parallel light source was quantified by a photometer; then, MSH was applied. Microscopically, MSH treatment causes a rapid migration of tiny black granules from the dense core granules to completely blacken the skin within a few minutes. Epinephrine, via α-adrenoceptors, causes a reverse migration of the granules back into the dense core granules and a tremendous increase in the reflected light in several minutes. We found methyldopamine and methylnorepinephrine to be 30 to 100 times as potent as the naturally occurring dopamine and norepinephrine metabolites of DOPA in reversing MSH-induced darkening of frog skin [3]. That was the basis for discovery of α2-ARs and the functional classification of α-adrenoceptors [4, 5]. Since those early days, three human α2-AR subtypes, referred to as α2A-AR, α2B-AR, and α2C-AR, have been cloned. Despite having only approximately 50% amino acid sequence identity, these three α2-AR isoforms have similar structures, pharmacology, and signaling mechanisms, yet differ in tissue distribution (see Aantaa and coworkers [6] for review).

Subsequent to the skin-lightening experiments, a large population of α2-ARs were discovered in normal kidneys [7], the function of which was unknown. An excess of these receptors was found in kidneys of all genetically hypertensive rat strains and further augmented when rats ingested a high-sodium diet [810]. Overexpression of α2-ARs was also present in prazosin (selective α1-AR antagonist) pretreated normal rats [11]; this surplus of α2-ARs occupied the anatomic and functional domain unique to α1-ARs in membrane enclosed postjunctional sites (Figure 1). Thus, these extra α2-ARs mediate sympathetic nerve-induced sodium retention which is ordinarily unique to α1-ARs. We suggest that similar multiplication and acquisition of increased or unique function of α2-ARs occur as mechanisms of various clinical phenomena. While we focus here on excessive expression of α2-ARs and potential roles they might play in hypertension, therapeutic renal denervation, temporary severe orthostasis, and prazosin’s efficacy in stress disorders, we also mention the related issue of bone fractures in race horses.

Essential hypertension in humans is due to excess dietary sodium coupled with the very common genetic predisposition to inappropriate retention of sodium by the kidneys. Sympathetic nerve activation induces sodium retention by the kidney, but its role in hypertension causality was unclear, and for good reason. In vivo studies in humans and in animals were rendered irrelevant because of lowering of systemic arterial pressure by sympathetic blocking agents such as quanethidine and by receptor blocking agents such as phentolamine or prazosin. Decrement in perfusion pressure, as in renal artery stenosis, increases tubular reabsorption of sodium by two mechanisms: one is activation of the renin-angiotensin-aldosterone-sodium retaining mechanism; the second one involves increased tubular reabsorption of sodium independent of aldosterone when renal perfusion pressure is reduced and conversely decreased tubular sodium reabsorption when renal pressure is increased (i.e., renal pressure-natriuresis mechanism). Acute reduction of systemic arterial pressure thus interferes with results of studies of these drugs in vivo, so in vitro perfusion techniques were essential to study these mechanisms. However, technical problems of kidney perfusion precluded use of these techniques as well.

Renal excretory function is dependent on high oxygen tension in the perfusate and oncotic effects of albumin to prevent severe edema in isolated, perfused kidneys. Previous studies failed because bubbling of oxygen denatured and precipitated albumin which clogged arterioles. We overcame these technical problems using the reverse phase of pediatric dialysis coils for oxygenation of albumin/ficol (oncotic activity) perfusates which sustained rat kidney functioning for hours [1113]. For a schematic diagram of the perfusion apparatus, see the article by Smyth and coworkers [12].

In this isolated perfused rat kidney model, we found that subpressor sympathetic nerve activation promoted sodium retention which was blocked by the α1-AR antagonist prazosin; however, the α2-AR antagonist yohimbine had no effect. This is not surprising since α1-ARs are considered the primary postjunctional α-AR subtype mediating noradrenergic neurotransmission via a signaling mechanism that involves coupling to phospholipase C via Gq/11 with subsequent production of inositol trisphosphate, diacylglycerol, and calcium release from the endoplasmic or sarcoplasmic reticulum [14]. However, after three days of prazosin administration, prazosin was no longer effective; yohimbine (α2-AR antagonist) infusion was required to block sympathetic nerve-induced sodium retention [11]. Of particular interest was that α2-AR density in the kidney had doubled after three days of prazosin administration. Thus, α1-AR blockade induces synthesis of new α2-ARs which then occupy the otherwise exclusive postjunctional domain and function of α1-ARs (Figure 1). Inasmuch as changes in sodium excretion in response to renal nerve stimulation were studied at frequencies and intensities of renal sympathetic nerve stimulation below those causing vascular resistance increases, the synthesis of new α2-ARs affecting sodium excretion likely occurred in the postjunctional membranes of renal epithelial cells; however, we hypothesize that this phenomenon is more general and occurs in other tissues as well (e.g., vascular tissues). Notably, norepinephrine (NE) infusion did not cause sodium retention. Thus, a barrier encompasses the sympathetic nerve terminal/α1-AR linkage which impedes access of circulating NE to the innervated α1-ARs mediating sodium retention. From these observations, it appears that normally functioning α1-ARs are suppressive to α2-AR synthesis. In fact, in genetic hypertensive rats where excess α2-ARs exist, there is a defect in α1-AR signaling [15]. It should thus be no surprise that overexpression of α2-ARs in genetic hypertension (or essential hypertension) mediates excess sodium retention as part of the fundamental cause of hypertension [16]. Currently, the mechanism by which α1-ARs suppress the expression of α2-ARs is unknown, and it is imperative to investigate this mechanism in future studies. We speculate that activation of the inositol trisphosphate/calcium/diacylglycerol axis by α1-ARs in the postjunctional cell leads to either reduced production of α2-ARs, decreased trafficking of α2-ARs to the postjunctional membrane, or increased degradation of α2-ARs.

The complexity of α2-AR-mediated signaling is illustrated further by the contrasting effects of α2-AR activation on sodium retention/excretion by kidneys under different hormonal influences. For example, vasopressin infusion causes water and sodium retention [17], and when this hormone predominates, α2-AR activation causes sodium excretion. Alternatively, in the presence of furosemide, adenylate cyclase is activated, sodium excretion is increased, and α2-AR activation induces sodium retention [12, 18]. We suspect that α2-AR signaling is context dependent in many other tissues, for example, the brain. Most importantly, isolated kidney perfusion techniques were critical in discovery of increased synthesis and redistribution of α2-ARs which may explain diverse clinical phenomena as described below.

2. Hypertension

High blood pressure is arguably the most important public health problem in the world today. If the kidney has an impaired capacity to excrete sodium (i.e., a shift to the right of the pressure-natriuresis curve) and dietary sodium intake is excessive, an increase in arterial pressure is required to cause natriuresis to restore sodium balance [19]. Thus, hypertension is caused mainly by excess dietary sodium coupled with impaired renal excretion of sodium, often genetically determined in rats and in humans. Millions of people in unacculturated environs do not ingest excess salt and do not have hypertension, strokes, obesity, diabetes, and rarely heart attacks or heart failure [20, 21]. An intact sympathetic nervous system supports high blood pressure [22] and several antihypertensive drugs work through inhibition thereof. Renal sympathetic nerves increase sodium retention by two mechanisms: one is α1-AR-mediated retention of sodium [17, 23] and the second is via β-adrenoceptor activation of the renin-aldosterone-sodium retaining mechanism [2428].

Thus, it is remarkable that α1-AR and β-adrenoceptor blocking agents, when used alone, have very low efficacy during long-term usage in hypertension treatment. Why? For prazosin, the reason is that excess α2-ARs and new function thereof occur with blockade of α1-ARs [11] for three days of treatment with prazosin (Figure 1). In this context, prazosin is remarkably effective for several days in lowering blood pressure [29, 30] and relief of symptoms in congestive heart failure. However, the substitution of α2-ARs functionally for α1-ARs impairs the efficacy of prazosin. We suspect that similar excess and translocation of α2-ARs occur on blood vessels, especially on veins, the reservoir of blood needed to sustain cardiac output, and hence blood pressure, in the upright position.

The low antihypertensive efficacy of β-adrenoceptor blockers when used alone is because the dominant controller of renin release is a pressor-volume mechanism [31] independent of β-adrenoceptors. However, when the sympathetic nervous system is reflexly activated by peripheral acting antihypertensive drugs, β-adrenoceptor blockade of excess renin release is a powerful blood pressure lowering mechanism [2628]. Extensive blood pressure lowering in severely hypertensive patients leads to passive tubular retention of sodium that can be overpowering leading to severe edema, even cardiac tamponade [32], details of which are described by Pettinger [33]. Moreover, severe preglomerular arteriolar hypertrophy coupled with the magnitude of blood pressure reduction decreases glomerular filtration rate causing uremia. This syndrome is known as the pseudorenal artery stenosis syndrome (PRASS) [33]. It is important because extremely elevated serum creatinine and urea in this syndrome could precipitate needless hemodialysis for the remainder of a patient’s life. By simply adjusting medications, kidney function can be restored. It is of particular note that reversal of arteriolar hypertrophy should be a goal of hypertension treatment [33].

With regard to hypertension, sex is an important biological variable with premenopausal women having a lower blood pressure compared to age-matched men [34]. Interestingly, we found that one gene for the overexpression of α2-AR-specific mRNA is on the Y-chromosome and one or more are on somatic chromosome(s) [35, 36]. This relationship is one additional association supportive of overexpression of α2-ARs in causality of human hypertension. Incidentally, in order for increased α2-ARs to sustain a tonal retention of sodium, our model presumes an endogenous factor stimulatory to a renal adenylate cyclase pool/isoform that is linked to sodium excretion by the kidneys. Who will discover this remarkable substance?

Further evidence for an important role of renal α2-ARs in hypertension is provided by studies in the spontaneously hypertensive rat (SHR), a genetic model of hypertension with excessive expression of renal α2-ARs. Despite normal plasma and kidney levels of angiotensin II, as well as normal expression of angiotensin II type 1 receptors (AT1Rs) in the kidney, this model of genetic hypertension is fully dependent on the renin-angiotensin system for development and maintenance of an elevated blood pressure [37]. Why? The reason is in part due to the increased sensitivity of the renal microcirculation to angiotensin II-induced vasoconstriction [3742]. Importantly, α2-ARs are Gi-coupled receptors that upon activation release large quantities of βγ G-protein subunits from the Gi ternary complex (i.e., αiβγ), and AT1Rs are Gq-coupled receptors that upon stimulation release αq G-protein subunits from the Gq ternary complex (i.e., αqβγ). As discussed by Selbie and Hill [43] and Philip and coworkers [44], when βγ subunits bind to specific isoforms of phospholipase C (PLC), the ability of αq to activate the enzymatic activity of PLC is remarkably enhanced. PLC, in part via activation of protein kinase C (PKC), then promotes renal vasoconstriction. In SHR kidneys, but not kidneys from genetically normotensive rats, this signaling “cross-talk” or “coincident signaling” is engaged when α2-ARs are stimulated with the selective agonist UK 14,304 and AT1Rs are simultaneously activated with angiotensin II [4548]. Likely, the enhanced expression of renal α2-ARs in SHR kidneys provides an enlarged membrane-localized pool of βγ subunits which tethers the scaffolding protein receptor for activated C kinase 1 (RACK1) to the cell membrane [49]. RACK1 then organizes an efficient signaling complex (Figure 2) consisting of βγ subunits released from α2-ARs, αq subunits released from AT1Rs, PLC, and PKC [49]. The importance of α2-AR/Gi-mediated release of βγ in this mechanism is highlighted by recent findings that Gi-coupled receptors are particularly effective in releasing active βγ subunits. In contrast, other G-proteins (e.g., Gq and G13) tend to restrain the signaling capabilities of βγ subunits released from their corresponding αβγ complexes [50]. In addition to the coincidence signaling mechanism described above, α2-AR-mediated release of αi from the αiβγ ternary complex may also contribute to the enhanced renovascular response to angiotensin II in SHR kidneys (Figure 2). Indeed, αi inhibits the adenylate cyclase/cAMP pathway [51], which may explain why the ability of prostacyclin (activates adenylate cyclase) to inhibit angiotensin II-induced renal vasoconstriction is impaired in SHR kidneys [52, 53]. Taken together, the evidence suggests that α2-ARs importantly contribute to the enhanced vasoconstrictive effects of angiotensin II in SHR kidneys. Further support for this model is that inhibition of α2-AR signaling with pertussis toxin, a toxin that blocks Gi-mediated signaling [54], normalizes renovascular responses to angiotensin II in SHR kidneys and chronically reverses hypertension in SHR [55, 56], despite the fact that pertussis toxin activates renin release [57]. The model shown in Figure 2 was tested using pressor levels of angiotensin II with renovascular responses (or in some experiments contractile responses to isolated preglomerular vascular smooth muscle cells) as the outcome measure and, therefore, applies to sympathetic regulation of renal vascular smooth muscle cells; however, we hypothesize that similar coincident signaling involving α2-ARs may occur in renal epithelial cells and may contribute directly to sodium retention and hypertension independent of renovascular changes (Figure 2).

3. Renal Denervation for Hypertension

To the extent that α1-AR-mediated sodium retention is a basic mechanism of hypertension, destruction of sympathetic nerves to the kidney should lower blood pressure. Indeed, catheter-based renal denervation (RDN) has shown promise as a treatment for resistant hypertension [58, 59]. However, the phase 3 Symplicity HTN-3 trial in patients with resistant hypertension failed to achieve its primary efficacy endpoint; this outcome has dampened initial enthusiasm regarding the utility of RDN [60]. Why the disappointing results? Several hypotheses have been proposed including operator inexperience, suboptimal design of the ablation catheter, and need for better patient selection [61]. However, another consideration is that perhaps like prazosin, RDN prevents the tonic influence of α1-ARs to suppress the synthesis of α2-ARs. Thus, RDN likely would upregulate the expression of renal α2-ARs in the renal sympathetic neuroeffector junction. Upregulated α2-ARs may express agonist-independent (constitutive or intrinsic) activity [62] or could be activated by circulating catecholamines. In support of this hypothesis, studies by Vallon and coworkers [63] revealed that in the setting of subacute RDN, activation of α2-ARs sensitizes kidneys to the detrimental effects of angiotensin II and nitric oxide synthase inhibition.

4. Injury from Falls in the Elderly and Orthostatic Hypotension

Falling is a frequent cause of serious injury and death in the elderly and orthostatic hypotension often causes falling. With prazosin, blood pressure drops in the standing position because of blockade of postsynaptic α1-ARs. In this context, postural hypotension can be severe during the first few days of prazosin treatment or reinitiation of treatment [29, 30]. Prazosin and other α1-AR antagonists are used frequently to reduce urethral tone in prostatic obstruction in elderly men, in stress disorders and in treatment of hypertension. Fortunately, severe orthostasis is temporary, and we attribute reversal thereof to stimulation of newly expressed α2-ARs that occupy the otherwise exclusive postjunctional domain of α1-ARs. The exaggerated temporary orthostasis is due to two mechanisms: one is reduced retention of sodium and water by the kidney causing volume contraction in venous reservoirs; the second mechanism is due to a decrease in venous tone which occurs during the time interval before multiplication and assumption of α1-AR function by newly synthesized α2-ARs.

Orthostatic hypotension is often severe in patients with excess circulating NE in pheochromocytoma, an apparent oxymoron. In the past this was attributed to volume contraction from venoconstriction which could, of course, be a contributing factor. However, this hypotension can also be explained with the model of the sympathetic nerve/α-adrenoceptor junction and its protective barrier discovered in the isolated kidney perfusion model. In this regard, pioneering work by Solomon Langer [64] and Klaus Starke [65] demonstrated the existence of prejunctional α2-ARs that are inhibitory to NE release. In pheochromocytoma, high levels of circulating NE have access to these presynaptic α2-ARs that are inhibitory to NE release. Thus, α2-AR-mediated inhibition of NE release in the standing position may also contribute to orthostatic hypotension in pheochromocytoma.

5. Posttraumatic Stress Disorder (PTSD) and Anxiety

Propranolol [6669], prazosin [7072], and combinations thereof [68] are widely used drugs for treatment of PTSD. Even so, management of PTSD remains problematic, and novel pharmacotherapies are badly needed. One approach to develop new PTSD drugs would be to elucidate the mechanisms of action by which currently available drugs relieve symptoms and exploit that knowledge to advance better treatments. In this regard, even though prazosin is often used to manage PTSD, its mechanism of action remains obscure. Interestingly, in the brain α2-ARs mediate suppression of anxiety such that withdrawal of treatment with α2-AR agonists (e.g., clonidine and methyldopa) precipitates anxiety and sleeplessness [73, 74]. Since prazosin administration increases α2-ARs in the kidney which assumes additional activity in sodium retention, a similar phenomenon may occur in the brain. Thus, we hypothesize that the efficacy of prazosin in PTSD is mediated at least partially by upregulation of α2-ARs. This is a testable hypothesis that if proven true would indicate a new avenue of research for effective PTSD treatments.

6. Furosemide in Race Horse Deaths: α2-AR Blockers to the Rescue

In the same laboratory where α2-ARs were discovered along with their substitution for α1-ARs following prazosin administration, microdissection/microchemical techniques simultaneously pursued correlates of the physiological studies involving the adenylate cyclase inhibitory role of excess α2-ARs. Thus, the renal adenylate cyclase stimulatory mechanism of furosemide was discovered in which furosemide was shown to increase urinary cyclic AMP excretion by approximately 5-fold [12]. Although distinct from furosemide’s generally accepted mechanism of diuretic activity, i.e., inhibition of the Na+-K+-2Cl symporter (see Jackson [75] for review), it is interesting that activation of Gi-linked α2-ARs reduces both cyclic AMP and sodium excretion in furosemide-treated kidneys.

Normally, the operation of the Na+-K+-2Cl symporter in the thick ascending limb provides for a transepithelial potential difference (PD) of about 10 mV (lumen positive with respect to the interstitium). This lumen positive PD drives the reabsorption of Ca2+ (which being a cation is repulsed by a positive PD) via the paracellular pathway. Loop diuretics, such as furosemide, bind to and inhibit the Na+-K+-2Cl symporter, which destroys the lumen positive PD and thereby reduces the driving force for Ca2+ reabsorption. This is why loop diuretics increase Ca2+ excretion leading to hypocalcemia [75]. Low serum Ca2+ levels stimulate parathyroid hormone (PTH) release, which mobilizes Ca2+ from bone leading to decreased bone density. However, the aforementioned mechanism does not rule out the possibility that furosemide increases Ca2+ mobilization from bone via an additional, and more direct, mechanism involving stimulation of adenylate cyclase in osteoblasts/osteoclasts, similar to PTH. Currently, huge doses of furosemide are used repeatedly in race horses to prevent lung hemorrhage. Via the aforementioned mechanisms, furosemide in race horses would be expected to absorb excess calcium from bone causing osteoporosis and predisposition to leg fracture, which may explain the large number of deaths in race horses due to leg fracture. Indeed, loop diuretics are also known to promote osteoporosis in humans [76, 77].

How does loop diuretic-induced bone disease relate to α2-ARs? Inasmuch as α2-ARs inhibit the adenylate cyclase/cAMP pathway, one would predict that α2-AR agonists might reduce osteopenia/osteoporosis. However, as with the kidney, the effects of α2-AR signaling in bone also appear to be context dependent since the published data suggest that α2-AR antagonists, rather than agonists, protect against bone loss. For example, female mice with double knockout of α2A-ARs and α2C-ARs present a surprising phenotype characterized by (1) increased bone mass; (2) reduced bone resorption; (3) augmented bone formation; (4) increased and better connected and more plate-shaped trabeculae in the femur and vertebrae; (5) increased cortical thickness in the vertebrae; and (6) increased tibial and femoral strength [78]. Moreover, the α2-AR agonist clonidine stimulates resorptive activity of osteoclasts in culture [78]. Recent studies in humans show that single nucleotide polymorphisms located in the α2A-AR gene are associated with osteoporosis and significantly increase α2A-AR mRNA levels in human bone samples by stabilizing mRNA [79]. Together, these findings encourage the pursuit of α2-AR antagonists for prevention and treatment of osteopenia/osteoporosis, including disease promoted by loop diuretics.

7. Conclusion

Because of directly measurable effects of neuroregulatory control mechanisms in the kidney, we discovered a tonal mechanism of α1-AR suppression of synthesis, redistribution, and function of α2-ARs that appears applicable to several clinical phenomena. These include the basic mechanism of hypertension, unexpectedly low efficacy of renal denervation for hypertension, severe injury from falling, especially in the elderly, and a mechanism of action for prazosin in stress disorders (PTSD). These kidney experiments also revealed the context-dependent effects of α2-ARs [80, 81], which are likely due to the complex signaling mechanisms engaged by these receptors. From a public health viewpoint, the causal role of altered α2-AR regulation in hypertension via retention of excess sodium appears very promising. Millions of people ingesting 20 times the real minimum daily requirement for sodium [33] have no hypertension which is obviously genetically determined; they are salt-resistant. A drug which would convert salt-sensitive hypertension to salt-resistance by interfering selectively with the α2-AR-sodium retaining mechanism could be paradigm shifting. It could prevent heart attacks and failure, strokes and aortic ruptures, many cases of renal failure and dementias, remarkable goals indeed. Coincidentally, the discovery of α2-ARs may lead to a possible treatment for osteopenia/osteoporosis, including disease promoted by loop diuretics, thus reducing the incidence of bone fractures in humans and animals. Although not discussed here, potential uses for α2-AR drugs keep expanding and include glaucoma, ocular hypertension, rosacea, preeclampsia, chronic pain, anesthesia, autonomic dysfunction, attention-deficit hyperactivity disorder, opioid withdrawal, diabetes, neuropsychiatric disorders, and migraines. We conclude that hypotheses concerning potential biologic mechanisms of α2-ARs are guideposts of major future and continuing discoveries. The discovery of α2-ARs, their altered regulation, and their potential roles reviewed herein are examples of such guideposts.

Additional Points

A very recent article by Nemet and workers (Cell. 2020; 180(5):862-877) establishes that phenylacetic acid, a gut microbial metabolite, is absorbed and converted by the liver to phenylacetylglutamine. The authors also show that phenylacetylglutamine is an α2-adrenoceptor agonist that activates platelet α2-adrenoceptors to enhance thrombosis potential. In patients, levels of this unique α2-adrenoceptor agonist associate with heart attacks, strokes, and death. These recent findings reveal yet another critically important role of the α2-adrenoceptor system in human disease.

Conflicts of Interest

The authors declare that they have no conflicts of interest.


This work was supported by HL030339 to WAP and HL035909, HL040319, HL014192, HL055314, and HL069846 to EKJ. WAP was a Burroughs Wellcome scholar in Clinical Pharmacology, and EKJ was an American Heart Association established investigator.


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