5‐Hydroxytryptamine Antagonistic Effects of ICI 169,369, ICI 170,809 and Methysergide in Human Temporal and Cerebral Arteries

Abstract

ICI 169,369 and ICI 170,809 are two chemically novel 5-HT antagonists that have high affinity for the 5-HT2 binding site in rat cortex (Ki 1.79 x 10(-8)M and 6.6 x 10(-10)M, respectively). In human temporal artery preparations ICI 169,369 was shown to cause a progressive rightward shift of the 5-HT-response curve over the range 10(-7)-10(-5)M, while ICI 170,809 in these concentrations shifted the curve to the same degree (no dose dependency). In human cerebral vessels no effect was observed until a high concentration (10(-5)M) was used for either compounds. The mixed 5-HT1/5-HT2 antagonist, methysergide, induced a non parallel rightward shift of the 5-HT-induced concentration-effect curve with a depression of the maximum achievable response in both the temporal and cerebral artery. The mode of effect of ICI 169,369 and ICI 170,809 to block the 5-HT-induced contractions in human temporal vessels resembles that of the pure 5-HT2 antagonist ketanserin, thus suggesting that the two ICI compounds are mainly 5-HT2 antagonists. In high concentrations both ICI 169,369 and ICI 170,809 have vasorelaxant properties, explaining the reduction in maximum 5-HT-induced contraction seen at high antagonist concentrations.