title: Agmatine induced NO dependent rat mesenteric artery relaxation and its impairment in salt-sensitive hypertension.
abstract: l-Arginine and its decarboxylated product, agmatine are important mediators of NO production and vascular relaxation. However, the underlying mechanisms of their action are not understood. We have investigated the role of arginine and agmatine in resistance vessel relaxation of Sprague-Dawley (SD) and Dahl salt-sensitive hypertensive rats. Second or 3rd-order mesenteric arterioles were cannulated in an organ chamber, pressurized and equilibrated before perfusing intraluminally with agonists. The vessel diameters were measured after mounting on the stage of a microscope fitted with a video camera. The gene expression in Dahl rat vessel homogenates was ascertained by real-time PCR. l-Arginine initiated relaxations (EC50, 5.8±0.7mM; n=9) were inhibited by arginine decarboxylase (ADC) inhibitor, difluoromethylarginine (DFMA) (EC50, 18.3±1.3mM; n=5) suggesting that arginine-induced vessel relaxation was mediated by agmatine formation. Agmatine relaxed the SD rat vessels at significantly lower concentrations (EC50, 138.7±12.1μM; n=22), which was compromised by l-NAME (l-N(G)-nitroarginine methyl ester, an eNOS inhibitor), RX821002 (α-2 AR antagonist) and pertussis toxin (G-protein inhibitor). The agmatine-mediated vessel relaxation from high salt Dahl rats was abolished as compared to that from normal salt rats (EC50, 143.9±23.4μM; n=5). The α-2A AR, α-2B AR and eNOS mRNA expression was downregulated in mesenteric arterioles of high-salt treated Dahl hypertensive rats. These findings demonstrate that agmatine facilitated the relaxation via activation of α-2 adrenergic G-protein coupled receptor and NO synthesis, and this pathway is compromised in salt-sensitive hypertension.
authors.affiliation: Department of Biomedical Engineering, Florida International University, Miami, FL 33174, United States.
authors.forename: Tushar V
authors.initials: TV
authors.lastname: Gadkari
authors.forename: Natalie
authors.initials: N
authors.lastname: Cortes
authors.forename: Kumpal
authors.initials: K
authors.lastname: Madrasi
authors.forename: Nikolaos M
authors.initials: NM
authors.lastname: Tsoukias
authors.forename: Mahesh S
authors.initials: MS
authors.lastname: Joshi
mesh_terms: D000376:Agmatine / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D009569:Nitric Oxide; D000376:Agmatine; D001120:Arginine; D002262:Carboxy-Lyases; C019722:arginine decarboxylase
keywords: ADC; AR; Agmatine; Arginine decarboxylase; DFMA; Hypertension; Nitric oxide; PTx; adrenergic receptor; arginine decarboxylase; difluoromethylarginine; eNOS; endothelial nitric oxide synthases; l-Arginine; l-NAME; l-NG-nitroarginine methyl ester; pertussis toxin; α-2 Adreno receptor