5-hydroxytryptamine-induced potentiation of endothelin-1-and norepinephrine-induced contraction is mitogen-activated protein kinase pathway dependent

5-Hydroxytryptamine (5-HT)-induced arterial contraction depends on activati on of the tyrosine kinase-dependent extracellular signal-regulated mitogen- activated protein kinase (Erk MAPK) pathway. The importance of 5-HT in the control of peripheral resistance has been questioned because circulating fr ee levels of 5-HT are low (in the nanomolar range). We tested the hypothesi s that physiologically relevant concentrations of 5-HT potentiate arterial contraction in response to agonists proved to have importance in blood pres sure maintenance (norepinephrine [NE] and endothelin-1 [ET-1]) in a tyrosin e kinase- and an Erk MAPK-dependent manner. Strips of endothelium-denuded r at tail artery were used for the measurement of isometric force. The genera l tyrosine kinase inhibitor genistein (5 mu mol/L) and the inhibitor of MAP K/Erk kinase activation PD098059 (10 mu mol/L) shifted concentration-respon se curves to 5-HT (1x10(-9) to 3x10(-4) mol/L) rightward but did not shift concentration-response curves to NE or ET-1. In separate experiments, 5-HT (10 nmol/L) potentiated contraction in response to NE (20 nmol/L) by approx imate to 200% to 300% and to ET-1 (0.3 and 1 nmol/L) by 640% and 180%, resp ectively. Genistein and PD098059 significantly (66% to 100%) reduced 5-HT-i nduced potentiation of both NE (20 nmol/L)- and ET-1 (0.3 and 1 nmol/L)-ind uced contraction. Thus, these data support the ability of low physiological concentrations of 5-HT to amplify arterial responses to hormones with bona fide effects on blood pressure in the novel manner of depending on a tyros ine kinase/Erk MAPK pathway. Although these findings were generated in larg e arteries, we speculate that they may be applicable to vascular functionin g in the; deoxycorticosterone acetate salt model of hypertension in which a ll 3 hormones, 5-HT, NE, and ET-1, have been implicated as causal factors.