Insulin increases cyclic nucleotide content in human vascular smooth muscle cells: a mechanism potentially involved in insulin-induced modulation of vascular tone |
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Authors: | Prof M Trovati P Massucco L Mattiello F Cavalot E Mularoni A Hahn G Anfossi |
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Institution: | (1) Diabetes Unit, Department of Clinical and Biological Sciences of the University of Turin, San Luigi Gonzaga Hospital, I-10043 Orbassano, Torino, Italy;(2) Research Department, Basel University, Basel, Switzerland |
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Abstract: | Summary It has been suggested that insulin exerts a vasodilating effect, but the mechanisms involved are not completely understood. Since cyclic nucleotides mediate the vasodilation induced by endogenous substances, such as prostacyclin and nitric oxide, we aimed to investigate the influence of insulin (concentration range 240–960 pmol/l) on both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content in human vascular smooth muscle cells. Insulin dose-dependently increased both nucleotides (cAMP: from 0.7±0.1 to 2.6±0.4 pmol/106 cells, p=0.0001; cGMP: from 1.3±0.2 to 3.4±0.7 pmol/106 cells, p=0.033). This increase is receptor-mediated, since it was blunted when cells were preincubated with the tyrosine kinase inhibitor genistein. The effect of insulin remained significant (p=0.0001) when preincubation with the phosphodiesterase inhibitor theophylline prevented cyclic nucleotide catabolism. The increase of cGMP was blunted when the cells were preincubated with the guanylate cyclase inhibitor methylene blue, and with the nitric oxide-synthase inhibitor NG-monomethyl-l-arginine. At all the concentrations tested, insulin potentiated the increase of cAMP induced by the stable prostacyclin analogue Iloprost (p=0.0001), whereas only at 1920 pmol/l did it potentiate the cGMP increase induced by glyceryltrinitrate (p=0.05). This study demonstrates that the vasodilating effects exerted by insulin may at least in part be attributable to an increase of both cGMP and cAMP via a receptor-mediated activation of adenylate and guanylate cyclases in human vascular smooth muscle cells and that the insulin effect on cGMP is mediated by nitric oxide.Abbreviations cAMP
cyclic adenosine monophosphate
- cGMP
cyclic guanosine monophosphate
- PDE
phosphodiesterases
- NO
nitric oxide
- hVSMC
human vascular smooth muscle cells
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l-NMMA
NG-monomethyl-l-arginine
- GTN
glyceryltrinitrate
- BSA
bovine serum albumin
- NIDDM
non-insulin-dependent diabetes mellitus
- MEM
minimal essential medium
- RIA
radioimmunoassay |
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Keywords: | Insulin arterial hypertension vasodilation vascular smooth muscle cells cyclic adenosine monophosphate cyclic guanosine monophosphate nitric oxide |
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