Contractile 5‐HT1 receptors in human isolated pial arterioles: correlation with 5‐HT1D binding sites

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Abstract
1 The 5-hydroxytryptamine (5-HT) receptor responsible for inducing vasoconstriction in human isolated pial arterioles has been pharmacologically characterized. 2 Of several 5-HT agonists tested, 5-carboxamidotryptamine (5-CT) was the most potent and the rank order of agonist potency can be summarized as: 5-CT > 5-HT > RU 24969 = α-methyl-5-HT = methysergide ≫ MDL 72832 = 2-methyl-5-HT ≫ 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydro-naphthalene (8-OH-DPAT). With few exceptions, the maximal contractile responses of these agonists were comparable to that induced by 5-HT. 3 A correlation analysis performed between the agonists vascular potency (pD2 values) and their affinities (pKD values) published at various subtypes of 5-HT binding sites showed a positive significant correlation with rat cortical 5-HT1B (r = 0.86; P < 0.01) and human caudate 5-HT1D (r = 0.98; P < 0.005) subtypes. 4 Selective antagonists at 5-HT2 (ketanserin, mianserin, MDL 11939) and 5-HT3 (MDL 72222) sites were totally devoid of inhibitory activity on the 5-HT-induced contraction, an observation which agreed with the agonist data and further excluded activation of these receptors. In contrast, the 5-HT1-like/5-HT2 antagonist methiothepin and the non-selective 5-HT1D compound metergoline inhibited with high affinity the contraction induced by 5-HT with respective pA2 values of 8.55 ± 0.16 and 6.88 ± 0.05. This contractile response was, however, insensitive to 5-HT1B (propranolol) and 5-HT1C (mesulergine, mianserin) antagonists. 5 It is concluded that a 5-HT1-like receptor, which shares strong similarities with the 5-HT1D binding sites identified in human caudate membranes, is mediating the vasocontractile action of 5-HT in human pial arterioles.