Characterization of the serotonin receptor mediating contraction in the mouse thoracic aorta and signal pathway coupling.
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-HT2A 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-HT2A receptor agonist alpha-methyl-5-HT, and partial 5-HT2A 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 EC(50) = 6.52); however, the 5-HT2A receptor antagonist ketanserin antagonized this contraction. Our hypothesis was further supported by the finding that antagonists with affinity for the 5-HT2A 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-HT2A receptor of the rat and the data generated in our experiments (-log EC(50) 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-HT2A receptor and is coupled to L-type calcium channels, PLC, and tyrosine kinases.
Michigan State University, Department of Pharmacology and Toxicology, B445 Life Sciences Building, East Lansing, MI 48824-1317, USA.
C M
CM
McKune
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Watts
D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000502:physiology; D019833:Genistein / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D010738:Type C Phospholipases / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
D020746:Calcium Channels, L-Type; D008996:Monoamine Oxidase Inhibitors; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D010738:Type C Phospholipases; D009543:Nifedipine