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 mu M), 252% (NE 1 mu M), and 129% (NE 3 mu M) of control. Insulin (1 mU/mL) had no effect on NE (10 and 100 mu M) 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 mu M). 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 mu M) or the TK inhibitor genistein (10 mu M). Ca-45(2+) influx due to NE (3 mu M) did not change in the presence of insulin (1 mU/mL) or PMA (0.1 mu M) despite a higher contractile response, so that wall force per unit of Ca-45(2+) influx was increased by insulin (1 mU/mL) and PMA (0.1 mu M). Calphostin C (0.1 mu M) and genistein (10 mu M) both prevented the increase in wall force per unit of Ca-45(2+) influx due to insulin (1 mU/mL). Our study shows that insulin potentiates NE-induced tone through a TK- and PKC-dependent mechanism.