Potentiation by endothelin-1 of 5-hydroxytryptamine responses in aortae from streptozotocin-diabetic rats: a role for thromboxane A2.
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 microM) 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 endothelium-intact aortae from diabetic rats, were still significantly reduced compared to those obtained in aortae from controls. 3. GR32191B (1 microM) had no significant effect on maximum responses to 5-HT in endothelium-denuded aortae from either control or diabetic rats. 4. Interaction between 5-HT (0.1 microM-0.1 mM) and threshold concentrations of endothelin-1 (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 microM), 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.
James
G M
GM
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Hodgson
W C
WC
D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004357:Drug Synergism; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D001713:Biphenyl Compounds; D016232:Endothelins; D006538:Heptanoic Acids; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D012701:Serotonin; D013928:Thromboxane A2; C060013:vapiprost