CHARACTERIZATION OF PREJUNCTIONAL 5-HT RECEPTORS MEDIATING INHIBITIONOF SYMPATHETIC VASOPRESSOR RESPONSES IN THE PITHED RAT

1 It has recently been shown that continuous infusions of 5-hydroxytry ptamine (5-HT) are able to inhibit, in a dose-dependent manner, the pr esser responses induced by preganglionic (T-7-T-9) sympathetic stimula tion in pithed rats pretreated with desipramine (50 mu g kg(-1), i.v.) . This inhibitory effect, besides being significantly more pronounced at lower frequencies of stimulation (0.03-1 Hz) and devoid of tachyphy laxis, is reversible after interrupting the infusions of 5-HT (up to 5 .6 mu g kg(-1) min(-1)). In the present study we have characterized th e pharmacological profile of the receptors mediating the above inhibit ory effect of 5-HT. 2 The inhibition induced by 5.6 mu g kg(-1) min(-1 ) of 5-HT on sympathetically-induced presser responses was not blocked after i.v. treatment with physiological saline (I ml kg(-1)), ritanse rin (0.1 mg kg(-1)), MDL 72222 (0.15 mg kg(-1)) or tropisetron (3 mg k g(-1)), which did not modify the sympathetically-induced presser respo nses per se, but was significantly antagonized by the 5-HT1-like and 5 -HT2 receptor antagonist, methysergide (0.3 mg kg(-1)), which also pro duced a slight attenuation of the presser responses to 0.03 and 0.1 Hz per se. 3 Unexpectedly and contrasting with methysergide, the 5-HT1-l ike and 5-HT2 receptor antagonists, methiothepin (0.01, 0.03 and 0.1 m g kg(-1)) and metergoline (1 and 3 mg kg(-1)), apparently failed to bl ock the above 5-HT-induced inhibition. Nevertheless, it is noteworthy that these antagonists also blocked the electrically-induced presser r esponses per se, presumably by blockade of vascular alpha(1)-adrenocep tors and, indeed, this property might have masked their potential anta gonism at the inhibitory 5-HT1-like receptors. 4 Consistent with the a bove findings, 5-carboxamidotryptamine (5-CT, a potent 5-HT1-like rece ptor agonist), metergoline and methysergide mimicked the inhibitory ac tion of 5-HT with the following rank order of agonist potency: 5CT muc h greater than 5-HT>metergoline greater than or equal to methysergide. 5 Taken together, the above results suggest that the inhibitory actio n of 5-HT on the electrically-induced presser responses is primarily m ediated by an action on inhibitory prejunctional 5-HT1-like receptors leading to a decrease in the sympathetic nerve discharge. Interestingl y, 5-HT-induced excitatory mechanisms could be made manifest once the inhibitory action of 5-HT had been antagonized.