Insulin potentiates norepinephrine-induced vascular tone by activation of protein kinase C and tyrosine kinase.
Insulin might play a role in the hypertension occurring in insulin-resistant diabetes. In addition, insulin has recently been shown to potentiate norepinephrine (NE) induced vascular tone. We used ring segments of the rabbit facial artery mounted in a myograph to test the hypothesis that potentiation of NE-induced tone by insulin may be related to activation of protein kinase C (PKC) and tyrosine kinase (TK). NE-induced contractions in the presence of insulin (1 mU/mL) were 200% (NE 0.1 and 0.3 microM), 252% (NE 1 microM), and 129% (NE 3 microM) of control. Insulin (1 mU/mL) had no effect on NE (10 and 100 microM) induced contractions. The potentiation by insulin of NE-induced tone was not altered by endothelium removal and could be mimicked by phorbol-12-myristate-13-acetate (PMA, 0.1 microM). Histamine-induced contractions were not altered by insulin (1 mU/mL). Insulin potentiation of NE-induced tone was suppressed by pretreatment of the rabbit facial artery with the PKC inhibitor calphostin C (0.1 microM) or the TK inhibitor genistein (10 microM). 45Ca2+ influx due to NE (3 microM) did not change in the presence of insulin (1 mU/mL) or PMA (0.1 microM) despite a higher contractile response, so that wall force per unit of 45Ca2+ influx was increased by insulin (1 mU/mL) and PMA (0.1 microM). Calphostin C (0.1 microM) and genistein (10 microM) both prevented the increase in wall force per unit of 45Ca2+ influx due to insulin (1 mU/mL). Our study shows that insulin potentiates NE-induced tone through a TK- and PKC-dependent mechanism.
Henrion
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Institut national de la santé et de la recherche médicale U 141, Hôpital Lariboisière, Paris, France.
Laher
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D000818:Animals; D002118:Calcium / Q000378:metabolism; D004357:Drug Synergism; D019833:Genistein; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology*; D011083:Polycyclic Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011817:Rabbits; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D007328:Insulin; D007529:Isoflavones; D009281:Naphthalenes; D011083:Polycyclic Compounds; D006632:Histamine; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; C058819:calphostin C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D009638:Norepinephrine