Diabetes‐induced changes in the 5‐hydroxytryptamine inhibitory receptors involved in the pressor effect elicited by sympathetic stimulation in the pithed rat

1 We investigated the effect of alloxan‐induced diabetes on the inhibitory mechanisms of 5‐hydroxytryptamine (5‐HT) in the pressor responses induced by stimulation of sympathetic vasopressor outflow in pithed rats, and analysed the type and/or subtype of 5‐HT receptors involved. 2 Diabetes was induced in male Wistar rats by a single s.c. injection of alloxan, then 4 weeks later, they were anaesthetized, pretreated with atropine and pithed. Electrical stimulation of the sympathetic outflow from the spinal cord (0.1, 0.5, 1 and 5 Hz) resulted in frequency‐dependent increases in blood pressure. 3 Intravenous infusions of 5‐HT (1–80  μ g kg −1  min −1 ) reduced the pressor effects obtained by electrical stimulation. The 5‐HT 1 receptor agonist 5‐carboxamidotryptamine, 5‐CT (5  μ g kg −1  min −1 ), caused an inhibition of the pressor response, whereas the selective 5‐HT 2 receptor agonist, α ‐methyl‐5‐HT (5  μ g kg −1  min −1 ) and the selective 5‐HT 3 receptor agonist, 1‐phenylbiguanide (40  μ g kg −1  min −1 ), did not modify the sympathetic pressor responses. 5‐HT had no effect on exogenous noradrenaline (NA)‐induced pressor responses. 4 The inhibition of electrically induced pressor responses by 5‐HT (10  μ g kg −1  min −1 ) was unable to be elicited after i.v. treatment with methiothepin (100  μ g kg −1 ) because of the marked inhibition produced by methiothepin alone. The 5‐HT‐induced inhibition was blocked after i.v. administration of WAY‐100,635 (100  μ g kg −1 ) and not affected by ritanserin (1 mg kg −1 ), MDL 72222 (2 mg kg −1 ). 5 The selective 5‐HT 1A receptor agonist, 8‐hydroxydipropylaminotretalin hydrobromide (8‐OH‐DPAT) (5–20  μ g kg −1  min −1 ) but neither the rodent 5‐HT 1B receptor agonist, CGS‐12066B (5  μ g kg −1  min −1 ), nor the selective nonrodent 5‐HT 1B and 5‐HT 1D receptor agonist, L‐694,247 (5 and 40  μ g kg −1  min −1 ), inhibited the electrically induced pressor response. The selective 5‐HT 1A receptor antagonist, WAY‐100,635 (100  μ g kg −1 ), blocked the inhibition induced by 8‐OH‐DPAT (10  μ g kg −1  min −1 ). 8‐OH‐DPAT had no effect on exogenous NA‐induced pressor responses. 6 Experimental diabetes produces changes in the inhibitory effect induced by 5‐HT on electrically induced sympathetic pressor responses, such that the inhibitory action induced by 5‐HT in diabetic pithed rats is mediated by prejunctional 5‐HT 1A receptors.British Journal of Pharmacology (2005) 145 , 593–601. doi: 10.1038/sj.bjp.0706216