Angiotensin inhibition stimulates PPARgamma and the release of visfatin.
BACKGROUND
Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) exhibit beneficial antidiabetic effects in patients with type 2 diabetes independent of their blood pressure-lowering effects. Some antidiabetic properties of ARB and ACE-I might by exerted by activation of peroxisome proliferator-activated receptor gamma (PPARgamma). However, it is not clear whether this action is drug specific.


METHODS
The binding affinity of telmisartan, valsartan, lisinopril, rosiglitazone and angiotensin II to PPARgamma was assessed in a cell-free assay system. PPARgamma signalling was studied in isolated skeletal muscle cells using Western blot analysis of phosphorylated protein kinase B (pAKT) and phosphorylated insulin like growth factor-1 receptor (pILGF-1R). Further, the ability of the drugs under study to stimulate the release of the adipocytokine visfatin was investigated in isolated human adipocytes, skeletal muscle cells, and umbilical vein endothelial cells (HUVEC).


RESULTS
The binding affinity to PPARgamma was highest for telmisartan with a half-maximal effective concentration of 463 nM, followed by lisinopril (2.9 microM) and valsartan (6.2 microM). In skeletal muscle cells phosphorylation of ILGF-1R was 2-fold increased after incubation with telmisartan or valsartan and 1.7-fold with lisinopril. pAKT expression was enhanced after incubation with telmisartan, valsartan and with lisinopril. The release of visfatin from adipocytes was 1.6-fold increased after treatment with lisinopril and about 2.0-fold increased with telmisartan and valsartan. Similar results were obtained in skeletal muscle cells and HUVEC.


CONCLUSIONS
Our data confirm agonism of telmisartan, valsartan and lisinopril on PPARgamma. Pharmacokinetic differences may explain different potencies of PPARgamma stimulation by drugs acting on the renin-angiotensin system in clinical settings.
Storka
A
A
Department of Clinical Pharmacology, Medical University of Vienna, Austria.
Vojtassakova
E
E
Mueller
M
M
Kapiotis
S
S
Haider
D G
DG
Jungbauer
A
A
Wolzt
M
M
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000804:Angiotensin II; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001562:Benzimidazoles / Q000378:metabolism; D001565:Benzoates / Q000378:metabolism; D015153:Blotting, Western; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D017706:Lisinopril / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism; D000077154:Rosiglitazone; D000077333:Telmisartan; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000068756:Valsartan
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D013777:Tetrazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000804:Angiotensin II; D000068756:Valsartan; D017706:Lisinopril; D054409:Nicotinamide Phosphoribosyltransferase; D017526:Receptor, IGF Type 1; D014633:Valine; D000077333:Telmisartan