1 This study was designed to examine further the attenuated contractile responses to 5-hydroxytryptamine (5-HT) previously observed in aortae from diabetic rats. 2 Cumulative concentration-response curves to 5-HT, and the 5-HT receptor agonists, at-methyl 5-HT (a-Me-5-HT, 5-HT21lc agonist), (± )-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 5-HT21IC agonist) and 5-carboxamidotryptamine (5-CT, 5-HTIA/1B/1D agonist), were examined in endotheliumintact and -denuded aortae from 2-week streptozotocin (STZ)-diabetic and control rats. 3 In endothelium-intact and -denuded aortae from diabetic rats, maximum responses to 5-HT and a-Me-5-HT were significantly reduced compared to those of aortae from control rats. Responses to these agonists were inhibited by the 5-HT21lc receptor antagonist, ketanserin (0.1 jAM). 4 The attenuated responses to 5-HT of aortae from diabetic rats were normalized by chronic insulin treatment of the rats (5 units day-', s.c.), but not by altering the glucose concentration of the bathing fluid. 5 The nitric oxide synthase inhibitor N-nitro-L-arginine (NOLA, 0.1 mM) significantly potentiated responses to both 5-HT and a-Me-5-HT in endothelium-intact aortae. However, the difference between maximum responses of aortae from diabetic and control rats was still evident in the presence of NOLA.6 Endothelium-intact rings, in the presence of ketanserin (0.1 tiM) and preconstricted with the thromboxane A2-mimetic, U46619 (0.1-0.3jIM), from control and diabetic rats, did not relax to cumulative additions of 5-HT (1 nM-30 jM). 7 Contractile responses to DOI were obtained only in endothelium-denuded aortae, and in endothelium-intact aortae in the presence of NOLA, from control rats. 8 Contractile responses to 5-CT were obtained only in endothelium-denuded aortae from both control and diabetic rats, and in endothelium-intact aortae in the presence of NOLA, from control rats. 9 [3H]-ketanserin binding studies showed that there was no significant change in the affinity or density of [3H]-ketanserin for binding sites in membrane preparations of aortae from control and diabetic rats.10 These results suggest that 5-HT contracts aortae from rats via 5-HT2,,c receptor activation.However, the simultaneous release of EDRF from endothelial cells in response to 5-HT does not appear to be receptor-mediated. The attenuated contractile responses observed to 5-HT in aortae from 2-week diabetic rats do not appear to be mediated by changes in either endothelial cell function or an alteration in 5-HT receptor affinity or density.

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1 We have previously reported maximum responses to 5-hydroxytryptamine (5-HT) are diminished in endothelium-intact and -denuded aortae from rats with streptozotocin-induced diabetes of 2-weeks duration.2 In the present study, the thromboxane A2/prostaglandin H2 (TP) receptor antagonist GR32191B(1 gM) significantly reduced maximum responses to 5-HT in endothelium-intact aortae from both control and diabetic rats. In the presence of GR32191B, maximum responses to 5-HT, in endotheliumintact aortae from diabetic rats, were still significantly reduced compared to those obtained in aortae from controls.3 GR32191B (1 gM) had no significant effect on maximum responses to 5-HT in endotheliumdenuded aortae from either control or diabetic rats.4 Interaction between 5-HT (0.1 gtM-0.1 mM) and threshold concentrations of endothelin-l (ET-1) or the thromboxane (Tx)A2-mimetic, U46619, were examined in endothelium-intact and -denuded aortae from control and 2-week streptozotocin-diabetic rats.5 Maximum responses to 5-HT in the presence of a threshold concentration of ET-1 (3 nM), in endothelium-intact aortae from diabetic rats, were not significantly different from those of control rats.6 Maximum responses to 5-HT in the combined presence of ET-1 (3 nM) and GR32191B (1 rM), in endothelium-intact aortae from diabetic rats, were significantly reduced compared to those obtained in aortae from controls. 7 Maximum responses to 5-HT in the presence of ET-1 (3 nM) in endothelium-denuded aortae from diabetic rats were significantly reduced compared to those from controls. 8 Maximum responses to 5-HT in the presence of a threshold concentration of U46619 (20 or 30 nM), in endothelium-intact aortae from diabetic rats, were not significantly different from responses of controls. 9 Maximum responses to 5-HT in the presence of a threshold (5-20 nM) concentration of U46619, in endothelium-denuded aortae from diabetic rats, were not significantly different from responses of controls. 10 The results of the present study indicate that endothelial-derived TxA2 contributes to the contractile response to 5-HT in aortae from control and diabetic rats. Endothelial-derived TxA2 also appears to play a role in the potentiation of 5-HT responses by ET-1 in aortae from diabetic rats.

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