Impaired endothelium-derived hyperpolarization-type relaxation in superior mesenteric arteries isolated from female Otsuka Long-Evans Tokushima Fatty rats

Eur J Pharmacol. 2017 Jul 15:807:151-158. doi: 10.1016/j.ejphar.2017.03.062. Epub 2017 Apr 19.

Abstract

Endothelium-derived hyperpolarization (EDH) is an important signaling mechanism of endothelium-dependent vasorelaxation, and little attention has been paid to the EDH-type responses in female metabolic syndrome such as that observed with type-2 diabetes. We previously reported that EDH-type relaxation was impaired in superior mesenteric arteries from male Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type-2 diabetes, however, the response was unclear in female OLETF rat. Thus, the aim of this study was to examine if EDH-type relaxation was altered in superior mesenteric arteries isolated from female OLETF rats compared to age-matched, control female Long-Evans Tokushima Otsuka (LETO) rats at age 50-59 weeks. We investigated concentration-relaxation curves for acetylcholine (at age 50-53 weeks), NS309 (an activator of small- and intermediate-conductance calcium-activated potassium channels) (at age 50-53 weeks), and GSK1016790A (an agonist of transient receptor potential vanilloid type 4, TRPV4) (at age 58 or 59 weeks) in the presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine and the cyclooxygenase inhibitor indomethacin to investigate EDH-type responses in the superior mesenteric artery. Obesity, mild hyperglycemia, hyperinsulinemia, and hyperlipidemia (i.e., increased total cholesterol, triglyceride, and non-esterified fatty acids) were more frequent in OLETF rats than in age-matched LETO rats at age 50-53 weeks. Acetylcholine-, NS309-, and GSK1016790A-induced relaxations in arteries from OLETF rats were all significantly reduced compared to those in LETO rats. These results indicated that EDH-type relaxations were impaired in female OLETF rats. This novel experimental model may provide new insights into vascular dysfunction in metabolic syndrome in females.

Keywords: Acetylcholine chloride (PubChem CID: 6060); Apamin (PubChem CID: 16218850): GSK1016790A (PubChem CID: 23630211); Endothelium-derived hyperpolarization; Female; HC-067047 (PubChem CID: 2742550); Indomethacin (PubChem CID: 3715); L-NNA (PubChem CID: 440005); NS309 (PubChem CID: 11637204); Phenylephrine (PubChem CID: 5284443); Relaxation; TRAM-34 (PubChem CID: 656734); TRPV4; Type-2 diabetes.

MeSH terms

  • Animals
  • Cyclooxygenase Inhibitors / pharmacology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Female
  • Indoles / pharmacology
  • Intermediate-Conductance Calcium-Activated Potassium Channels / metabolism
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Mesenteric Artery, Superior / drug effects
  • Mesenteric Artery, Superior / metabolism
  • Mesenteric Artery, Superior / physiology*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Oximes / pharmacology
  • Rats
  • Rats, Inbred OLETF
  • Small-Conductance Calcium-Activated Potassium Channels / metabolism
  • Sulfonamides / pharmacology
  • Vasodilation* / drug effects

Substances

  • 6,7-dichloro-1H-indole-2,3-dione 3-oxime
  • Cyclooxygenase Inhibitors
  • Indoles
  • Intermediate-Conductance Calcium-Activated Potassium Channels
  • N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide
  • Oximes
  • Small-Conductance Calcium-Activated Potassium Channels
  • Sulfonamides
  • Nitric Oxide Synthase
  • Leucine