Abstract
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 α-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-HT1E/1F receptor agonist BRL 54443 also induced contraction (−log EC50 = 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 EC50 and pKB values). The L-type calcium channel blockers nifedipine and nitrendipine, PLC inhibitor 2-nitro-4-carboxyphenylN,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.
Footnotes
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Send reprint requests to: Carolyn McKune/Dr. Stephanie W. Watts, Department of Pharmacology and Toxicology, B445 Life Sciences Bldg., Michigan State University, East Lansing, MI 48824-1317. E-mail:wattss{at}msu.edu
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The American Heart Association (Michigan Affiliate), as well as the College of Veterinary Medicine at Michigan State University, and National Institutes of Health HL 58489 generously funded part of this project.
- Abbreviations:
- 5-HT
- 5-hydroxytryptamine
- α-methyl-5-HT
- α-methyl serotonin maleate
- PLC
- phospholipase C
- PE
- phenylephrine
- m-CPP
- 1-(3-chlorophenyl)piperazine
- 5-CT
- 5-carboxamidotryptamine maleate
- dipropyl-5-CT
- N,N-dipropyl-5-carboxamidotryptamine maleate
- PAPP
- p-aminophenylethyl-m-trifluoromethylphenyl piperazine
- 8-OH-DPAT
- (±)-8-hydroxy-2-(di-N-propylamino)tetralin hydrobromide
- DOI
- (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride
- 2-Me-5-HT
- 2-methyl-5-hydroxytryptamine maleate
- m-CPBG
- 1-(m-chlorophenyl)-biguanide hydrochloride
- MAO
- monoamine oxidase
- DMSO
- dimethyl sulfoxide
- 1-NP
- 1-(1-naphthyl)piperazine hydrochloride
- ICS 205-930
- 3-tropanyl-indole-3-carboxylate hydrochloride
- NCDC
- 2-nitro-4-carboxyphenylN,N-diphenylcarbamate
- MAPKK
- mitogen-activated protein kinase kinase
- E
- efficacy
- Received July 21, 2000.
- Accepted December 7, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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