Pharmacological evidence that metformin blocks the vasopressor responses mediated by stimulation of α 1 - and α 2 -adrenoceptors in pithed rats

Cruz, Saúl Huerta de la; Medina-Terol, Grecia J.; Beltrán-Ornelas, Jesús H.; C, Gómez; Morato-Valderrama, Yaltzir; Sánchez-López, Araceli; Centurión, David

doi:10.1016/j.ejphar.2017.12.032

Cited by 3 publications

(1 citation statement)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The majority of patients with diabetes within our cohort (73%) were treated with antihyperglycemics, including insulin, which has been shown to reduce circulating catecholamine levels in untreated, long-term diabetes (14,15). Further, a significant number of patients with diabetes (26%) were treated with metformin, which has been proposed to inhibit the activities of a1/2-adrenoceptors, thereby possibly preventing NE release/concentration within the heart (23,31,45).…”

Section: Limitationsmentioning

confidence: 99%

Enhanced Catecholamine Flux and Impaired Carbonyl Metabolism Disrupt Cardiac Mitochondrial Oxidative Phosphorylation in Diabetes Patients

Nelson

Efird

Kew

et al. 2021

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Aims: Catecholamine metabolism via monoamine oxidase (MAO) contributes to cardiac injury in models of ischemia and diabetes, but the pathogenic mechanisms involved are unclear. MAO deaminates norepinephrine (NE) and dopamine to produce H 2 O 2 and highly reactive ''catecholaldehydes,'' which may be toxic to mitochondria due to the localization of MAO to the outer mitochondrial membrane. We performed a comprehensive analysis of catecholamine metabolism and its impact on mitochondrial energetics in atrial myocardium obtained from patients with and without type 2 diabetes. Results: Content and maximal activity of MAO-A and MAO-B were higher in the myocardium of patients with diabetes and they were associated with body mass index. Metabolomic analysis of atrial tissue from these patients showed decreased catecholamine levels in the myocardium, supporting an increased flux through MAOs. Catecholaldehyde-modified protein adducts were more abundant in myocardial tissue extracts from patients with diabetes and were confirmed to be MAO dependent. NE treatment suppressed mitochondrial ATP production in permeabilized myofibers from patients with diabetes in an MAO-dependent manner. Aldehyde dehydrogenase (ALDH) activity was substantially decreased in atrial myocardium from these patients, and metabolomics confirmed lower levels of ALDH-catalyzed catecholamine metabolites. Proteomic analysis of catechol-modified proteins in isolated cardiac mitochondria from these patients identified >300 mitochondrial proteins to be potential targets of these unique carbonyls. Innovation and Conclusion: These findings illustrate a unique form of carbonyl toxicity driven by MAOmediated metabolism of catecholamines, and they reveal pathogenic factors underlying cardiometabolic disease. Importantly, they suggest that pharmacotherapies targeting aldehyde stress and catecholamine metabolism in heart may be beneficial in patients with diabetes and cardiac disease. Antioxid. Redox Signal. 35,[235][236][237][238][239][240][241][242][243][244][245][246][247][248][249][250][251]

show abstract

Section: Limitationsmentioning

confidence: 99%

Enhanced Catecholamine Flux and Impaired Carbonyl Metabolism Disrupt Cardiac Mitochondrial Oxidative Phosphorylation in Diabetes Patients

Nelson

Efird

Kew

et al. 2021

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

Effects of single and combined metformin and l-citrulline supplementation on l-arginine-related pathways in Becker muscular dystrophy patients: possible biochemical and clinical implications

et al. 2018

View full text Add to dashboard Cite

The L-arginine/nitric oxide synthase (NOS) pathway is considered to be altered in muscular dystrophy such as Becker muscular dystrophy (BMD). We investigated two pharmacological options aimed to increase nitric oxide (NO) synthesis in 20 male BMD patients (age range 21-44 years): (1) supplementation with L-citrulline (3 × 5 g/d), the precursor of L-arginine which is the substrate of neuronal NO synthase (nNOS); and (2) treatment with the antidiabetic drug metformin (3 × 500 mg/d) which activates nNOS in human skeletal muscle. We also investigated the combined use of L-citrulline (3 × 5 g/d) and metformin (3 × 500 mg/d). Before and after treatment, we measured in serum and urine samples the concentration of amino acids and metabolites of L-arginine-related pathways and the oxidative stress biomarker malondialdehyde (MDA). Compared to healthy subjects, BMD patients have altered NOS, arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) pathways. Metformin treatment resulted in concentration decrease of arginine and MDA in serum, and of homoarginine (hArg) and guanidinoacetate (GAA) in serum and urine. L-Citrulline supplementation resulted in considerable increase of the concentrations of amino acids and creatinine in the serum, and in their urinary excretion rates. Combined use of metformin and L-citrulline attenuated the effects obtained from their single administrations. Metformin, L-citrulline or their combination did not alter serum nitrite and nitrate concentrations and their urinary excretion rates. In conclusion, metformin or L-citrulline supplementation to BMD patients results in remarkable antidromic changes of the AGAT and GAMT pathways. In combination, metformin and L-citrulline at the doses used in the present study seem to abolish the biochemical effects of the single drugs in slight favor of L-citrulline.

show abstract

Potential vascular α1-adrenoceptor blocking properties of metformin in rat aorta and tail artery

Álvarez-Cámara

Ramírez‐Rosas

Medina-Terol

et al. 2019

European Journal of Pharmacology

View full text Add to dashboard Cite

Pharmacological evidence that metformin blocks the vasopressor responses mediated by stimulation of α 1 - and α 2 -adrenoceptors in pithed rats

Cited by 3 publications

References 26 publications

Enhanced Catecholamine Flux and Impaired Carbonyl Metabolism Disrupt Cardiac Mitochondrial Oxidative Phosphorylation in Diabetes Patients

Enhanced Catecholamine Flux and Impaired Carbonyl Metabolism Disrupt Cardiac Mitochondrial Oxidative Phosphorylation in Diabetes Patients

Effects of single and combined metformin and l-citrulline supplementation on l-arginine-related pathways in Becker muscular dystrophy patients: possible biochemical and clinical implications

Potential vascular α1-adrenoceptor blocking properties of metformin in rat aorta and tail artery

Contact Info

Product

Resources

About