Role of α2-Adrenoceptors in Hypertension: Focus on Renal Sympathetic Neurotransmitter Release, Inflammation, and Sodium Homeostasis

Hering, Lydia; Rahman, Masudur; Potthoff, Sebastian A.; Rump, Lars Christian; Stegbauer, Johannes

doi:10.3389/fphys.2020.566871

Cited by 20 publications

(19 citation statements)

References 110 publications

(184 reference statements)

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“…Adrenoceptor alpha 2A (ADRA2A) is known for its involvement in the regulation of neurotransmitter release and modulation of sympathetic nervous system activity (30,31). Its functions extend beyond the central nervous system, encompassing diverse physiological functions such as cardiovascular regulation and smooth muscle contraction (30,31). For cellular responses, ADRA2A inhibits adenylate cyclase, leading to decreased cyclic adenosine monophosphate (cAMP) levels and modulation of various intracellular pathways, including protein kinase A (PKA), PKC, and the MAPK pathways (30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer

Moreno,

Ohara,

Craig

et al. 2024

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient cohorts revealed downregulation of adrenoceptor alpha 2A (ADRA2A) in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients.In vitroexperiments demonstrated thatADRA2Atransgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.

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Section: Discussionmentioning

confidence: 99%

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer

Moreno,

Ohara,

Craig

et al. 2024

Preprint

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“…Interestingly, ARs are distributed distinctly in the arterial and venous systems and play a key role in coordinating the arterial and venous circulation. Most arteries and large veins (e.g., vena cava) are mainly regulated by α1/α2-ARs, while peripheral veins are regulated by α2B-ARs[25; 31; 32; 33]. The high abundance of α2B-ARs in the peripheral veins highlights their involvement in the constriction of these peripheral veins.…”

Section: Discussionmentioning

confidence: 99%

Centhaquine Increases Stroke Volume and Cardiac Output in Patients with Hypovolemic Shock

Khanna,

Vaidya,

Shah

et al. 2024

Preprint

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Background: Centhaquine is a resuscitative agent that acts on alpha-2B adrenergic receptors to enhance venous return in hypovolemic shock. The effect of centhaquine on cardiac output in patients with hypovolemic shock has not been reported. Methods: Trans-thoracic echocardiography was utilized to measure stroke volume (SV), cardiac output (CO), left ventricular outflow tract-velocity time integral (LVOT-VTI), left ventricular outflow tract diameter (LVOTd), heart rate (HR), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (FS) and inferior vena cava (IVC) diameter before (0 min) and after centhaquine (0.01 mg/kg, iv infusion over 60 min) treatment (60 min, 120 min, and 300 min) in 12 randomly selected patients with hypovolemic shock enrolled in a prospective, multicenter, open-label phase IV clinical study (NCT05956418) of centhaquine in patients with hypovolemic shock. Results: A significant increase in SV (mL) was observed after 60, 120, and 300 minutes of centhaquine treatment. CO (mL/min) increased significantly at 120 and 300 min despite a decrease in HR at these times. A significant increase in IVC diameter and LVOT-VTI (mL) at these time points was observed, which indicated increased venous return. The LVEF and FS did not change, while the mean arterial pressure (MAP, mmHg) increased in patients after 120 and 300 minutes of centhaquine treatment. Positive correlations between IVC diameter and SV (R2 = 0.9556) and between IVC diameter and MAP (R2 = 0.8928) were observed, which indicated the effect of centhaquine mediated increase in venous return on SV, CO, and MAP. Conclusions: Centhaquine mediated increase in venous return appears to play a critical role in enhancing SV, CO, and MAP in patients with hypovolemic shock; these changes could be pivotal for reducing shock-mediated circulatory failure, promoting tissue perfusion, and improving patient outcomes. Trial registration: The phase IV trial reported in this study has Clinical Trials Registry, India; ctri.icmr.org.in, CTRI/2021/01/030263; clinicaltrials.gov,NCT05956418.

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“…Thus, diabetic nephropathy originates renal dysfunction that may induce increased renal vascular resistance and, subsequently, chronic kidney damage, that runs in hypertension and vascular altered homeostasis. In this sense, the adrenergic system plays a crucial role, since sympathetic nerves extensively innervate the kidney [ 33 , 34 ]. Renal nerves follow the renal arteries and innervate not only the vasculature but also the juxtaglomerular apparatus and the basement membrane of epithelial cells within the nephron.…”

Section: Discussionmentioning

confidence: 99%

Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT1D Receptor Activation via NO Pathway

Fernández-González

García-Pedraza

Ordóñez

et al. 2023

IJMS

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Renal vasculature, which is highly innervated by sympathetic fibers, contributes to cardiovascular homeostasis. This renal sympathetic outflow is inhibited by 5-HT in normoglycaemic rats. Considering that diabetes induces cardiovascular complications, we aimed to determine whether diabetic state modifies noradrenergic input at renal level and its serotonergic modulation in rats. Alloxan diabetic rats were anaesthetized (pentobarbital; 60 mg/kg i.p.) and prepared for in situ autoperfusion of the left kidney to continuously measure systemic blood pressure (SBP), heart rate (HR), and renal perfusion pressure (RPP). Electrical stimulation of renal sympathetic outflow induces frequency-dependent increases (Δ) in RPP (23.9 ± 2.1, 59.5 ± 1.9, and 80.5 ± 3.5 mm Hg at 2, 4, and 6 Hz, respectively), which were higher than in normoglycaemic rats, without modifying HR or SBP. Intraarterial bolus of 5-HT and 5-CT (5-HT1/5/7 agonist) reduced electrically induced ΔRPP. Only L-694,247 (5-HT1D agonist) reproduced 5-CT inhibition on sympathetic-induced vasoconstrictions, whereas it did not modify exogenous noradrenaline-induced ΔRPP. 5-CT inhibition was exclusively abolished by i.v. bolus of LY310762 (5-HT1D antagonist). An inhibitor of guanylyl cyclase, ODQ (i.v.), completely reversed the L-694,247 inhibitory effect. In conclusion, diabetes induces an enhancement in sympathetic-induced vasopressor responses at the renal level. Prejunctional 5-HT1D receptors, via the nitric oxide pathway, inhibit noradrenergic-induced vasoconstrictions in diabetic rats.

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Role of α2-Adrenoceptors in Hypertension: Focus on Renal Sympathetic Neurotransmitter Release, Inflammation, and Sodium Homeostasis

Cited by 20 publications

References 110 publications

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer

Centhaquine Increases Stroke Volume and Cardiac Output in Patients with Hypovolemic Shock

Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT1D Receptor Activation via NO Pathway

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