Characterization of 5-Hydroxytryptamine-Evoked Isometric Contractile Responses in Aortic Vascular Smooth Muscle in Thyropathological Rats
Edgington, Nicholas P.
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The problem, in the past, research on these sequellae of thyropathology has utilized a variety of animal models. Recently, vascular smooth muscle has increasingly been used as an effective bioassay to assess physiological function of hormones and ligands. While general effects of thyroid status are well documented, specific thyropathologic-induced changes in 5-hydroxytryptamine (serotonergic; 5-HT) receptor function mediating contraction/dilation in rat aorta have not been completely characterized. Procedure. Aortic rings from hyperthyroid (TRX),hypothyroid (PTU), and euthyroid control (CON) rats were mounted in climate controlled tissue baths and subjected to isometric contraction experiments. The endothelium was removed from some rings (denuded) while others were left intact. All rings were initially contracted with a single dose of 55 mM KCl and then relaxed to normal potassium while concomitantly measuring the time course of this relaxation. All rings were subsequently subjected to dose/response experiments with 5-HT, either in the presence or absence of ketanserin (5-HT2 antagonist) and ICS 205-930(5-UT3 antagonist). Flndings. 5-HT generated a nonsignificant trend toward increased contractile tension in TRX rats, but a significant reduction in contractile tension in rings from PTU rats. These differences were eliminated in the denuded preparations with PTU and control tensions increasing back to TRX levels. There were no differences in sensitivity to 5-HT in the intact preparations in the three thyroid groups, but an increased sensitivity was observed in the TRX denuded preparation. Ketanserin was found to completely antagonize the 5-HT2 receptor-mediated contraction. High concentrations of 5-HT in the presence of high concentrations of ICS 205-930, generated significantly attenuated contractile tension in rings from TRX rats. Conclusions. The elimination of a significant difference in the PTU and CON treatment groups in the denuded tissue as compared to the intact tissue, suggests an enhanced 5-HT-mediated release of endothelial derived relaxing factor (EDRP) in PTU rats and reduced release in TRX rats. An incre ase in sensitivity in the denuded tissues, but not in the intact tissues, suggests an enhanced responsiveness of a 5-HT receptor subtype subserving contraction. The significant effect of micromolar concentrations of ICS 205-930 suggests that an increased contractile response in the TRX group, in light of the apparent lack of 5-HT3 sites in this tissue, may be mediated, in part, by a novel serotonergic receptor mediating contraction. Alternatively, this effect may reflect activity of the ligand at 5-HT1 or 5-HT2 receptors differentially sensitized by thyropathology. These data suggest that thyropathological alterations in 5-HT1 or 5-HT2 receptor subtype-mediated responses occur in rat thoracic aorta.
viii, 48 leaves. Advisor: Donald B. Stratton