Vol. 297, Issue 1, 88-95, April 2001

Characterization of the Serotonin Receptor Mediating Contraction in the Mouse Thoracic Aorta and Signal Pathway Coupling

C. M. McKune and S. W. Watts

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan

The purpose of this study was to characterize pharmacologically the 5-HT receptor(s) mediating contraction in the mouse aorta and the pathways these receptors are coupled with to mediate contraction. We hypothesized that a 5-HT_2A receptor, as in the rat, mediates contraction by activating L-type calcium channels, phospholipase C (PLC), and tyrosine kinase(s). Endothelium-denuded aortic strips were placed in a tissue bath for measurement of isometric contractile force. 5-HT, the 5-HT_2A receptor agonist -methyl-5-HT, and partial 5-HT_2A receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (±-DOI) caused the most potent and efficacious contraction. The 5-HT_1E/1F receptor agonist BRL 54443 also induced contraction (log EC₅₀ = 6.52); however, the 5-HT_2A receptor antagonist ketanserin antagonized this contraction. Our hypothesis was further supported by the finding that antagonists with affinity for the 5-HT_2A receptor, ketanserin, 1-(1-naphthyl)piperazine, spiperone, and LY53857, reduced 5-HT-induced contraction. A correlation of 0.927 was found between literature-derived compound binding affinities for the agonists and antagonists at the 5-HT_2A receptor of the rat and the data generated in our experiments (log EC₅₀ and pK_B values). The L-type calcium channel blockers nifedipine and nitrendipine, PLC inhibitor 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate, and tyrosine kinase inhibitors genistein and PD 098,059 all shifted and/or reduced maximum contraction to 5-HT. We conclude that contraction to 5-HT in the mouse aorta is mediated primarily by a 5-HT_2A receptor and is coupled to L-type calcium channels, PLC, and tyrosine kinases.