AuthorKillam, Anne Louise.
AdvisorNelson, David L.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractDetermination of the physiologic roles of serotonin (5-HT) has long been hampered by the lack of compounds specific for certain of the 5-HT receptor subtypes. The objective of this dissertation was to characterize vascular serotonin receptors in certain arteries and to develop functional assays for the putative 5-HT₁(A) and 5-HT₂ receptors in vascular tissue to test novel compounds. Although 5-HT₁(A) receptor involvement in the 5-HT contraction of the canine basilar artery was previously reported, the 8-OH-DPAT (5-HT₁(A) specific agonist) EC₅₀ values in the canine, rabbit, guinea pig, and bovine basilar arteries studies were not consistent with the presence of 5-HT₁(A) receptors. Studies examining the 5-HT₂ selective antagonist ketanserin, several novel aryltryptamines with a range of affinities, and enantiomers of spiroxatrine, in the 5-HT-contracted rat aorta showed a good correlation between the aorta affinities and the affinities of these compounds at the [³H] ketanserin binding site (defined as 5-HT₂) in the rat frontal cortex. Comparison of the affinities of several known and novel compounds in the rat aorta and the rabbit femoral artery to the [³H] ketanserin site affinities in the frontal cortices of both species showed that the rabbit femoral artery 5-HT₂-like receptor was similar but not identical to either the rat aorta or the CNS sites from either species. The rabbit aorta and the rat femoral artery were then examined to determine if the 5-HT₂ receptor heterogeneity was species or vascular bed specific. The results from all four vascular tissues showed that no two tissues had identical responses to the compounds studied. The rat aorta appeared unique in the lack of agonist activity of RU24969 and the non-competitive antagonism of 5-HT by methysergide, but correlated to the CNS site for the affinities of all compounds. The major finding of the dissertation was the definitive evidence for vascular 5-HT₂ receptor heterogeneity; this subtype was previously thought to be homogeneous. Development of more selective compounds for 5-HT receptor subtypes may lead to greater understanding of the physiological roles of serotonin.
Degree ProgramPharmacology & Toxicology