Further analysis of the inhibition by agmatine on the cardiac sympathetic outflow: Role of the α 2 -adrenoceptor subtypes

Cobos-Puc, Luis E.; Aguayo-Morales, Hilda; Ventura-Sobrevilla, Janeth M.; Luque-Contreras, Diana; Chin-Chan, Miguel

doi:10.1016/j.ejphar.2017.03.009

Cited by 3 publications

(1 citation statement)

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“…There are already approved medications that target α 2 -adrenoreceptor antagonistically like Yohimbine or Idazoxan, but they lack specificity for α 2A -adrenoreceptor 32 and two studies described the occurrence or worsening of RP in patients under Yohimbine treatment 37,38 . Two research compounds, BRL 44408 and BRL 48962, have been shown to specifically target α 2A -adrenoreceptors in in vitro models but lack any data in vivo 39 .…”

Section: Discussionmentioning

confidence: 99%

ADRA2AandIRX1are putative risk genes for Raynaud’s phenomenon

Hartmann

Yasmeen

Denaxas

et al. 2022

Preprint

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BackgroundRaynaud’s phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers in fingers and toes triggered by cold or emotional stress. Despite its high reported heritability, no causal genes have been robustly identified, limiting mechanistic understanding and treatment options.AimTo investigate the genetic architecture of RP to better understand its aetiology and identify new potential therapeutic targets.MethodsWe conducted a genome-wide association study including 9,084 RP cases and 435,357 controls, based on diagnoses from electronic health records, among participants of the UK Biobank study. We identified candidate causal variants and genes using Bayesian fine-mapping and colocalization with gene expression across 49 tissues. We performed phenome-wide association analyses for all significant RP loci and computed genetic correlations followed by latent causal variable analyses between RP and a total of 205 selected phenotypes.ResultsWe identified eight unreported genomic regions associated with the risk of RP atp<5×10−8and assignedADRA2A(rs7090046, odds ratio (OR) per allele: 1.27; 95%-CI: 1.23-1.31; p<2.52×10−47) andIRX1(rs11748327, OR: 1.20; 95%-CI: 1.16-1.23, p<9.71×10−28) as the candidate causal genes at the two strongest loci. Higher expression ofADRA2Ain tibial artery andIRX1in skeletal muscle was thereby associated with a higher RP risk. We identified a likely causal detrimental effect of low fasting glucose levels on RP risk (rG=-0.12; p-value=0.01), while significant positive genetic correlations with reported comorbidities like migraine, depression, or peripheral artery disease are likely explained by shared risk factors.ConclusionOur results provide the first robust evidence for a strong genetic contribution to RP, highlighting a so far underrated role of α2A-adrenoreceptor signalling, encoded atADRA2A, as an important mechanism for hypersensitivity to catecholamine-induced vasospasms even at thermoneutral conditions.

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Section: Discussionmentioning

confidence: 99%

ADRA2AandIRX1are putative risk genes for Raynaud’s phenomenon

Hartmann

Yasmeen

Denaxas

et al. 2022

Preprint

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Pharmacological profile of agmatine: An in-depth overview

Rafi,

Rafiq,

Farhan

2024

Neuropeptides

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Cardiovascular Effects Mediated by Imidazoline Drugs: An Update

Cobos-Puc

Aguayo-Morales

2019

CHDDT

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Clonidine is a centrally acting antihypertensive drug. Hypotensive effect of clonidine is mediated mainly by central a2-adrenoceptors and/or imidazoline receptors located in a complex network of the brainstem. Unfortunately, clonidine produces side effects such as sedation, mouth dry, and depression. Moxonidine and rilmenidine, compounds of the second generation of imidazoline drugs, with fewer side effects, display a higher affinity for the imidazoline receptors compared with a2-adrenoceptors. The antihypertensive action of these drugs is due to inhibition of the sympathetic outflow primarily through central I1-imidazoline receptors in the RVLM, although others anatomical sites and mechanisms/receptors are involved. Agmatine is regarded as the endogenous ligand for imidazoline receptors. This amine modulates the cardiovascular function. Indeed, when is administered in the RVLM mimic the hypotension of clonidine. Recent findings have shown that imidazoline drugs also exerts biological response directly on the cardiovascular tissues, which can contribute to their antihypertensive response. Currently, new imidazoline receptors ligands are in development. In the present review, we provide a brief update on the cardiovascular effects of clonidine, moxonidine, rilmenidine, and the novel imidazoline agents since representing an important therapeutic target for some cardiovascular diseases.

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Further analysis of the inhibition by agmatine on the cardiac sympathetic outflow: Role of the α 2 -adrenoceptor subtypes

Cited by 3 publications

References 40 publications

ADRA2AandIRX1are putative risk genes for Raynaud’s phenomenon

ADRA2AandIRX1are putative risk genes for Raynaud’s phenomenon

Pharmacological profile of agmatine: An in-depth overview

Cardiovascular Effects Mediated by Imidazoline Drugs: An Update

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