5-HT Antagonism on Cerebral and Common Carotid Arteries by the 5-HT Uptake Inhibitors Femoxetine and Paroxetine

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Abstract
The 5-hydroxytryptamine (5-HT) antagonism of methysergide was compared with that of the phenylpiperidine 5-HT uptake inhibitors, paroxetine and femoxetine, using 2 different models; the isolated cat middle cerebral artery and the common carotid artery of pithed rat perfused with the rat''s own blood (autoperfusion). The extracorporeal circulation consisted of .apprx. 1.5 ml blood, which was temperature regulated to 36-38.degree. C at the inlet to the carotid vessel by an automatic thermistor coupled heating system. In these experiments systemic blood pressure responses and perfusion pressure responses to 5-HT were recorded simultaneously. The 5-HT induced contractile response of the middle cerebral artery was reduced in a non-competitive way by both uptake inhibitors at concentrations above 0.3 .mu.M which is .apprx. 100 times the concentration needed for methysergide. In autoperfusion experiments inhibition was seen only at 5 mg/kg of both drugs. Methysergide 0.001 mg/kg totally abolished all 5-HT responses. The uptake inhibitors can be described as weak 5-HT antagonists.