Exenatide induces aortic vasodilation increasing hydrogen sulphide, carbon monoxide and nitric oxide productionReportar como inadecuado




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Cardiovascular Diabetology

, 13:69

First Online: 02 April 2014Received: 17 December 2013Accepted: 15 March 2014

Abstract

BackgroundIt has been reported that GLP-1 agonist exenatide exendin-4 decreases blood pressure. The dose-dependent vasodilator effect of exendin-4 has previously been demonstrated, although the precise mechanism is not thoroughly described. Here we have aimed to provide in vitro evidence for the hypothesis that exenatide may decrease central aortic blood pressure involving three gasotransmitters, namely nitric oxide NO carbon monoxide CO, and hydrogen sulphide H2S.

MethodsWe determined the vasoactive effect of exenatide on isolated thoracic aortic rings of adult rats. Two millimetre-long vessel segments were placed in a wire myograph and preincubated with inhibitors of the enzymes producing the three gasotransmitters, with inhibitors of reactive oxygen species formation, prostaglandin synthesis, inhibitors of protein kinases, potassium channels or with an inhibitor of the Na-Ca-exchanger.

ResultsExenatide caused dose-dependent relaxation of rat thoracic aorta, which was evoked via the GLP-1 receptor and was mediated mainly by H2S but also by NO and CO. Prostaglandins and superoxide free radical also play a part in the relaxation. Inhibition of soluble guanylyl cyclase significantly diminished vasorelaxation. We found that ATP-sensitive-, voltage-gated- and calcium-activated large-conductance potassium channels are also involved in the vasodilation, but that seemingly the inhibition of the KCNQ-type voltage-gated potassium channels resulted in the most remarkable decrease in the rate of vasorelaxation. Inhibition of the Na-Ca-exchanger abolished most of the vasodilation.

ConclusionsExenatide induces vasodilation in rat thoracic aorta with the contribution of all three gasotransmitters. We provide in vitro evidence for the potential ability of exenatide to lower central aortic blood pressure, which could have relevant clinical importance.

KeywordsGlucagon-like-peptide-1 Exenatide Vasodilation Aortic rings Central blood pressure AbbreviationsBKCaLarge-conductance calcium activated potassium channel

COCarbon monoxide

CVCardiovascular

GLP-1Glucagon-like-peptide-1

GLP-1RGlucagon-Like-Peptide-1 receptor

NONitric oxide

HOHeme oxygenase

H2SHydrogen sulphide

H89N-2-p-Bromocinnamylaminoethyl-5-isoquinolinesulfonamide dihydrochloride

KATPATP-sensitive potassium channel

KvVoltage-gated potassium channel

L-NAMENω-Nitro-L-arginine methyl ester hydrochloride

3MST3-mercaptopyruvate-sulfurtransferase

NOSNitric oxide synthase

ODQ1H-1,2,4oxadiazolo4,3-aquinoxalin-1-one

PKAProtein kinase A

PKGProtein kinase G

PPGDL-Propargylglycine

ROSReactive oxygen species

sGCSoluble guanyly cyclase

SODSuperoxide dismutase

TEATetraethylammonium chloride.

Electronic supplementary materialThe online version of this article doi:10.1186-1475-2840-13-69 contains supplementary material, which is available to authorized users.

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Autor: Eszter Sélley - Szilárd Kun - István András Szijártó - Boglárka Laczy - Tibor Kovács - Ferenc Fülöp - István Wi

Fuente: https://link.springer.com/article/10.1186/1475-2840-13-69







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