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Reversible inhibition of vasoconstriction by thiazolidinediones related to PI3K/Akt inhibition in vascular smooth muscle cells.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2013 Feb 15; Vol. 85 (4), pp. 551-9. Date of Electronic Publication: 2012 Nov 27. - Publication Year :
- 2013
-
Abstract
- Thiazolidinediones (also referred to as glitazones), agonists for Peroxisome Proliferator-Activated Receptor gamma (PPARĪ³), are used for treating type 2 diabetes mellitus, where they decrease insulin resistance and cardiovascular risk. Compounds bearing the thiazolidinedione structure have also been shown to inhibit phosphoinositide 3-kinase (PI3K). Here we tried to elucidate the poorly defined role of PI3K/Akt in the physiology of vascular smooth muscle cell contraction and tested the hypothesis that thiazolidinediones, by affecting the PI3K/Akt pathway, may influence vascular physiology. Isolated rat femoral arteries segments were mounted in a wire myograph and challenged with 100mM KCl or phenylephrine (PE), in the absence or presence of troglitazone, rosiglitazone, pioglitazone, LY294002 (PI3K inhibitor) and 10-DEBC (Akt inhibitor). All these compounds dose-dependently inhibited vasoconstriction to KCl or PE; their effect was reversible (after 60-120 min washout) and not affected by GW9662 (a PPARĪ³ antagonist) or by N(G)-nitro-L-arginine (LNNA, an inhibitor of NO biosynthesis). Analysis of phospho-Akt (ser 473) in lysates from rat arteries (by immunoblot) revealed that thiazolidinediones, LY294002 and 10-DEBC, at the same concentration and kinetics inhibiting vasoconstriction, produced a similar decrease of Akt phosphorylation. PI3K/Akt pathway therefore appears to be an important, fast acting, modulator of contraction of vascular smooth muscle. Thiazolidinediones decrease vasoconstriction of isolated vessels possibly by inhibiting PI3K/Akt pathway. Such an effect of glitazones, if occurring in vivo, may impact cardiovascular syndromes related to vasospasm in diabetic patients.<br /> (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Subjects :
- Anilides pharmacology
Animals
Chromans pharmacology
Dose-Response Relationship, Drug
Enzyme Inhibitors pharmacology
Femoral Artery
Male
Muscle, Smooth, Vascular physiology
Myocytes, Smooth Muscle physiology
Nitroarginine pharmacology
PPAR gamma antagonists & inhibitors
Phosphatidylinositol 3-Kinases genetics
Phosphatidylinositol 3-Kinases metabolism
Pioglitazone
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
Rats
Rats, Sprague-Dawley
Rosiglitazone
Troglitazone
Muscle, Smooth, Vascular cytology
Myocytes, Smooth Muscle drug effects
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Thiazolidinediones pharmacology
Vasoconstriction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 85
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23194750
- Full Text :
- https://doi.org/10.1016/j.bcp.2012.11.013