Selective resistance to vasoactive effects of insulin in muscle resistance arteries of obese Zucker (fa/fa) rats.
Obesity is related to insulin resistance and hypertension, but the underlying mechanisms are unclear. Insulin exerts both vasodilator and vasoconstrictor effects on muscle resistance arteries, which may be differentially impaired in obesity.


OBJECTIVE
To investigate whether vasodilator and vasoconstrictor effects of insulin are impaired in muscle resistance arteries of obese rats and the roles of Akt and endothelial NO synthase (eNOS).


RESULTS
Effects of insulin were studied in resistance arteries isolated from cremaster muscles of lean and obese Zucker rats. In arteries of lean rats, insulin increased activity of both NO and endothelin (ET-1), resulting in a neutral effect under basal conditions. In arteries of obese rats, insulin induced endothelin-mediated vasoconstriction (-15 +/- 5% at 1 nM, P < 0.05 vs. lean). Insulin induced vasodilatation during endothelin receptor blockade in arteries of lean rats (20 +/- 5% at 1 nM) but not in those of obese rats. Inhibition of NO synthesis increased vascular tone (by 12 +/- 2%) and shifted insulin-mediated vasoreactivity to vasoconstriction (-25 +/- 1% at 1 nM) in lean rats but had no effect in arteries of obese rats, indicating reduced NO activity. Protein analysis of resistance arteries revealed that insulin-mediated activation of Akt was preserved in obese rats, whereas expression of eNOS was markedly decreased.


CONCLUSIONS
Vasodilator but not vasoconstrictor effects of insulin are impaired in muscle resistance arteries of obese rats, and this selective impairment is associated with decreased protein levels of eNOS. These findings provide a new mechanism linking obesity to insulin resistance and hypertension.
Eringa
Etto C
EC
Laboratory for Physiology, Institute for Cardiovascular Research ICaR-VU VU University Medical Center, 1081 BT, Amsterdam, The Netherlands. e.eringa@vumc.nl
Stehouwer
Coen D A
CD
Roos
Marjon H
MH
Westerhof
Nico
N
Sipkema
Pieter
P
D000818:Animals; D015153:Blotting, Western; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D009765:Obesity / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D009842:Oligopeptides / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D017466:Receptors, Endothelin / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007328:Insulin; D009842:Oligopeptides; D017466:Receptors, Endothelin; C076213:PD 142893; D019335:Nitroarginine; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt