Attenuated 5-hydroxytryptamine receptor-mediated responses in aortae from streptozotocin-induced diabetic rats.
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, alpha-methyl 5-HT (alpha-Me-5-HT, 5-HT2/1C agonist), (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane (DOI, 5-HT2/1C agonist) and 5-carboxamidotryptamine (5-CT, 5-HT1A/1B/1D agonist), were examined in endothelium-intact 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 alpha-Me-5-HT were significantly reduced compared to those of aortae from control rats. Responses to these agonists were inhibited by the 5-HT2/1C receptor antagonist, ketanserin (0.1 microM). 4. The attenuated responses to 5-HT of aortae from diabetic rats were normalized by chronic insulin treatment of the rats (5 units day-1, 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 alpha-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 microM) and preconstricted with the thromboxane A2-mimetic, U46619 (0.1-0.3 microM), from control and diabetic rats, did not relax to cumulative additions of 5-HT (1 nM-30 microM). 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-HT2/1c 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.
Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
G M
GM
James
W C
WC
Hodgson
E A
EA
Davis
J M
JM
Haynes
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000502:physiology; D007328:Insulin / Q000494:pharmacology; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D019335:Nitroarginine; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
D001786:Blood Glucose; D007328:Insulin; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D019335:Nitroarginine; D012701:Serotonin; C045918:2-methyl-5-HT; D001120:Arginine; D007650:Ketanserin