Different mechanisms involved in liraglutide and glucagon-like peptide-1 vasodilatation in rat mesenteric small arteries.
Animals
Dose-Response Relationship, Drug
Glucagon-Like Peptide 1
/ pharmacology
Glucagon-Like Peptide-1 Receptor
/ agonists
Liraglutide
/ pharmacology
Male
Mesenteric Arteries
/ drug effects
Myocytes, Smooth Muscle
/ drug effects
Rats
Rats, Wistar
Structure-Activity Relationship
Superoxides
/ analysis
Vasodilation
/ drug effects
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
07
02
2018
revised:
23
10
2018
accepted:
24
10
2018
pubmed:
8
11
2018
medline:
25
2
2020
entrez:
8
11
2018
Statut:
ppublish
Résumé
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates insulin biosynthesis and secretion in a glucose-dependent manner and has been reported to induce vasodilatation. Here, we examined the possible vasorelaxant effect of GLP-1 and its underlying mechanisms. Rat mesenteric arteries (diameter ≈ 200-400 μm) and human s.c. arteries were mounted in microvascular myographs for isometric tension recordings. The effect of GLP-1 on vascular responses was examined under normoglycaemic conditions and at high glucose concentrations. In rat mesenteric arteries and human s.c. arteries without branches, physiological concentrations (1-100 nM) of GLP-1(7-36) and liraglutide failed to cause relaxation or affect contractions evoked by electrical field stimulation. In contrast to GLP-1(7-36), liraglutide induced relaxations antagonized by the GLP-1 receptor antagonist, exendin-(9-39), in branched mesenteric arteries. In contrast to liraglutide, GLP-1 leftward shifted the concentration relaxation curves for bradykinin in s.c. arteries from patients with peripheral arterial disease, an effect resistant to exendin-(9-39). Under normoglycaemic conditions, neither GLP-1 nor liraglutide affected ACh relaxation in rat mesenteric arteries. In arteries exposed to 40 mM glucose, GLP-1, in contrast to liraglutide, potentiated ACh-induced relaxation by a mechanism that was not antagonized by exendin-(9-39). GLP-1 decreased superoxide levels measured with dihydroethidium in rat mesenteric arteries exposed to 40 mM glucose. GLP-1 receptors are involved in the liraglutide-induced relaxation of branched arteries, under normoglycaemic conditions, while GLP-1 inhibition of vascular superoxide levels contributes to GLP-1 receptor-independent potentiation of endothelium-dependent vasodilatation in hyperglycaemia.
Sections du résumé
BACKGROUND AND PURPOSE
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates insulin biosynthesis and secretion in a glucose-dependent manner and has been reported to induce vasodilatation. Here, we examined the possible vasorelaxant effect of GLP-1 and its underlying mechanisms.
EXPERIMENTAL APPROACH
Rat mesenteric arteries (diameter ≈ 200-400 μm) and human s.c. arteries were mounted in microvascular myographs for isometric tension recordings. The effect of GLP-1 on vascular responses was examined under normoglycaemic conditions and at high glucose concentrations.
KEY RESULTS
In rat mesenteric arteries and human s.c. arteries without branches, physiological concentrations (1-100 nM) of GLP-1(7-36) and liraglutide failed to cause relaxation or affect contractions evoked by electrical field stimulation. In contrast to GLP-1(7-36), liraglutide induced relaxations antagonized by the GLP-1 receptor antagonist, exendin-(9-39), in branched mesenteric arteries. In contrast to liraglutide, GLP-1 leftward shifted the concentration relaxation curves for bradykinin in s.c. arteries from patients with peripheral arterial disease, an effect resistant to exendin-(9-39). Under normoglycaemic conditions, neither GLP-1 nor liraglutide affected ACh relaxation in rat mesenteric arteries. In arteries exposed to 40 mM glucose, GLP-1, in contrast to liraglutide, potentiated ACh-induced relaxation by a mechanism that was not antagonized by exendin-(9-39). GLP-1 decreased superoxide levels measured with dihydroethidium in rat mesenteric arteries exposed to 40 mM glucose.
CONCLUSIONS AND IMPLICATIONS
GLP-1 receptors are involved in the liraglutide-induced relaxation of branched arteries, under normoglycaemic conditions, while GLP-1 inhibition of vascular superoxide levels contributes to GLP-1 receptor-independent potentiation of endothelium-dependent vasodilatation in hyperglycaemia.
Identifiants
pubmed: 30403290
doi: 10.1111/bph.14534
pmc: PMC6329621
doi:
Substances chimiques
Glucagon-Like Peptide-1 Receptor
0
Superoxides
11062-77-4
Liraglutide
839I73S42A
Glucagon-Like Peptide 1
89750-14-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
386-399Informations de copyright
© 2018 The British Pharmacological Society.
Références
J Pharmacol Exp Ther. 2006 Feb;316(2):852-9
pubmed: 16221740
Br J Pharmacol. 2007 Jan;150(1):80-7
pubmed: 17128286
J Clin Endocrinol Metab. 2012 Jul;97(7):E1165-9
pubmed: 22544917
Horm Metab Res. 2004 Nov-Dec;36(11-12):747-54
pubmed: 15655703
Br J Pharmacol. 2006 Jul;148(5):703-13
pubmed: 16715120
Nucleic Acids Res. 2018 Jan 4;46(D1):D1091-D1106
pubmed: 29149325
Endocrinology. 2013 Jan;154(1):4-8
pubmed: 23267050
N Engl J Med. 2016 Jul 28;375(4):311-22
pubmed: 27295427
J Diabetes Complications. 2014 May-Jun;28(3):399-405
pubmed: 24561125
Regul Pept. 2005 Feb 15;125(1-3):173-7
pubmed: 15582729
Br J Pharmacol. 2019 Feb;176(3):386-399
pubmed: 30403290
Diabetes. 2014 Apr;63(4):1224-33
pubmed: 24296712
Circ Res. 2014 May 23;114(11):1788-803
pubmed: 24855202
Int J Cardiol. 2015 Jan 15;178:292-6
pubmed: 25465309
Clin Sci (Lond). 1998 Dec;95(6):719-24
pubmed: 9831697
Br J Pharmacol. 2017 Jun;174(12):1620-1632
pubmed: 27435156
Diabetes. 2015 Jul;64(7):2624-35
pubmed: 25720388
Eur J Intern Med. 2014 Jun;25(5):407-14
pubmed: 24694879
Arch Biochem Biophys. 2008 Oct 15;478(2):136-42
pubmed: 18708025
Cell Metab. 2016 Jul 12;24(1):15-30
pubmed: 27345422
Br J Pharmacol. 2015 Jul;172(14):3461-71
pubmed: 26114403
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Diabetes Care. 1999 Jul;22(7):1137-43
pubmed: 10388979
JAMA. 2015 Aug 18;314(7):687-99
pubmed: 26284720
Br J Clin Pharmacol. 2016 Apr;81(4):613-20
pubmed: 26609792
Br J Pharmacol. 2017 Dec;174 Suppl 1:S272-S359
pubmed: 29055034
Am J Physiol Endocrinol Metab. 2004 Dec;287(6):E1209-15
pubmed: 15353407
J Clin Invest. 1991 May;87(5):1643-8
pubmed: 2022734
Br J Pharmacol. 2010 Aug;160(7):1577-9
pubmed: 20649561
Diab Vasc Dis Res. 2014 Nov;11(6):419-30
pubmed: 25212693
J Pediatr. 2017 Feb;181:146-153.e3
pubmed: 27979579
Hypertension. 2015 Feb;65(2):306-12
pubmed: 25452475
Vascul Pharmacol. 2006 Dec;45(6):374-82
pubmed: 16837248
Diabetes Care. 2010 May;33(5):1028-30
pubmed: 20200309
Endocrinology. 2013 Jan;154(1):127-39
pubmed: 23183176
Circ Res. 1977 Jul;41(1):19-26
pubmed: 862138
J Clin Pharmacol. 2006 Jun;46(6):635-41
pubmed: 16707410
Circulation. 2008 May 6;117(18):2340-50
pubmed: 18427132
Br J Pharmacol. 2008 Mar;153(6):1185-94
pubmed: 18193068
Br J Pharmacol. 2017 Dec;174 Suppl 1:S17-S129
pubmed: 29055040
Pharmacol Res. 2015 Apr;94:26-33
pubmed: 25697548
Am J Physiol Heart Circ Physiol. 2016 Nov 1;311(5):H1214-H1224
pubmed: 27638877
Endocrinology. 2014 Apr;155(4):1280-90
pubmed: 24467746
Am J Physiol Heart Circ Physiol. 2006 Jan;290(1):H181-91
pubmed: 16143648
Br J Pharmacol. 2015 Jul;172(13):3189-93
pubmed: 25964986
J Cardiovasc Pharmacol. 2014 Sep;64(3):277-84
pubmed: 24887687
Circ Heart Fail. 2010 Jul;3(4):512-21
pubmed: 20466848