title: 5-Hydroxytryptamine-induced potentiation of endothelin-1- and norepinephrine-induced contraction is mitogen-activated protein kinase pathway dependent.
abstract: 5-Hydroxytryptamine (5-HT)-induced arterial contraction depends on activation 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 free levels of 5-HT are low (in the nanomolar range). We tested the hypothesis that physiologically relevant concentrations of 5-HT potentiate arterial contraction in response to agonists proved to have importance in blood pressure maintenance (norepinephrine [NE] and endothelin-1 [ET-1]) in a tyrosine kinase- and an Erk MAPK-dependent manner. Strips of endothelium-denuded rat tail artery were used for the measurement of isometric force. The general tyrosine kinase inhibitor genistein (5 micromol/L) and the inhibitor of MAPK/Erk kinase activation PD098059 (10 micromol/L) shifted concentration-response 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 approximately 200% to 300% and to ET-1 (0.3 and 1 nmol/L) by 640% and 180%, respectively. Genistein and PD098059 significantly (66% to 100%) reduced 5-HT-induced potentiation of both NE (20 nmol/L)- and ET-1 (0.3 and 1 nmol/L)-induced 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 tyrosine kinase/Erk MAPK pathway. Although these findings were generated in large arteries, we speculate that they may be applicable to vascular functioning in the deoxycorticosterone acetate salt model of hypertension in which all 3 hormones, 5-HT, NE, and ET-1, have been implicated as causal factors.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824-1317, USA. watts@pilot.msu.edu
authors.forename: S W
authors.initials: SW
authors.lastname: Watts
mesh_terms: D000818:Animals; D001158:Arteries / Q000201:enzymology; D002070:Butadienes / Q000494:pharmacology; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D012701:Serotonin / Q000494:pharmacology*; D013623:Tail / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000378:metabolism*
chemical_list: D002070:Butadienes; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016166:Free Radical Scavengers; D009570:Nitriles; C113580:U 0126; D014662:Vasoconstrictor Agents; D012701:Serotonin; D019833:Genistein; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D009638:Norepinephrine