The present study has identified a receptor for 5-hydroxytryptamine (5-HT) which functions to inhibit the stimulus-induced release of [3H] noradrenaline following sympathetic periarterial nerve stimulation to the isolated perfused rat kidney. In addition to 5-HT (IC30 = 4.5 X 10(-8) mol/l), both 5-carboxamidotryptamine (IC30 = 8 X 10(-9) mol/l) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl) indole (RU-24969, IC30 = 2.5 X 10(-7) mol/l) acted as agonists whereas 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was inactive. The inhibitory effect of 5-HT on the electrically-evoked release of tritium was antagonized in a concentration-dependent manner by methiothepin (IC50 = 4 X 10(-9) mol/l), metergoline (IC50 = 4 X 10(-8) mol/l) and methysergide (IC50 = 1.3 X 10(-7) mol/l) but not by cyproheptadine, ketanserin, mesulergine, (-)-propranolol, (+/-)-pindolol, (+/-)-cyanopindolol, metoclopramide or phentolamine. It is concluded that the receptor to 5-HT conforms to general criteria defining 5-HT1-like receptors but at the present time the receptor site cannot be fitted to the designated 5-HT1A, 5-HT1B or 5-HT1C subtypes.

The subtype of alpha-adrenoreceptor mediating contraction in rat isolated thoracic aorta was classified pharmacologically using preferential agonists and antagonists, and by utilizing mixed agonist and antagonist interactions. Noradrenaline was 8 to 10-times more potent at contracting the aorta than phenylephrine and both agonists were about 1000 and 10,000-fold respectively more potent than azepexole (a preferential alpha 2-agonist). Prazosin (a preferential alpha 1-antagonist) inhibited the dose-response curves to noradrenaline and phenylephrine 100 and 1000-times respectively more effectively than either phentolamine or rauwolscine (a preferential alpha 2-antagonist). Furthermore, prazosin (5 x 10(-9) M) completely abolished contractions elicited by a single concentration of azepexole (3 x 10(-4) M). In mixed antagonist studies, rauwolscine (5 x 10(-7) M) failed to shift the dose-response curves to noradrenaline and phenylephrine obtained in the presence of prazosin (5 x 10(-9) M). In mixed agonist experiments, azepexole (3 x 10(-4) M) acted as a partial antagonist toward phenylephrine-induced contractions. The results suggest that the alpha-adrenoreceptor of the rat thoracic aorta is predominantly, if not exclusively, of the alpha 1-subtype.

Kynuramines are endogenously occurring diamines derived from tryptophan. In the present study, we have compared the pharmacological actions of 5-hydroxykynuramine (5-OH-K) with kynuramine and 5-hydroxytryptamine (5-HT) on vascular resistance changes and responsiveness to adrenergic stimuli in the isolated perfused rat kidney. 5-OH-K was found to mimic the actions of 5-HT in that it produced vasoconstriction, potentiation of alpha 1-adrenoceptor-mediated responses to norepinephrine (NE) and periarterial nerve stimulation, and displaced specific [3H]spiroperidol binding from rat cortical membranes. With regard to all parameters measured, 5-OH-K was about 15-times less active than 5-HT. Vascular responses to 5-OH-K and 5-HT were inhibited noncompetitively by ketanserin and cyproheptadine. Unlike 5-OH-K, kynuramine, failed to evoke vasoconstriction and inhibited vascular responses to NE via alpha 1-adrenoceptors. Thus, kynuramine lacks serotonin receptor agonist activity but possesses alpha 1-adrenoceptor blocking properties. In contrast, 5-OH-K potentiates NE and acts as a serotonin agonist. The present results raise the possibility that kynuramine and 5-OH-K might act as endogenous modulators of serotonergic and adrenergic mechanisms in the renal vascular bed.

Kynuramines occur endogenously in brain and peripheral tissues as metabolites of indoleamino acids and indolamines but little is known regarding their possible physiological and/or pharmacological activity. The present study has investigated the effects of kynuramine and 5-hydroxykynuramine on the cardiovascular system of pithed rats and attempted to correlate effects seen on adrenergic and serotonergic receptors with ligand binding experiments done in vitro using rat brain membranes. Kynuramine was found to release cardiac catecholamines and to act as a weak partial agonist on vascular alpha-adrenoceptors. Hydroxylation in the 5-position (5-hydroxykynuramine) did not alter cardiac potency but increased pressor activity 100-fold. Vasopressor responses to 5-hydroxykynuramine were mediated via a dual agonistic action on both postsynaptic alpha 2-adrenoceptors and vascular serotonin2 receptors. These findings were supported by ligand binding studies, in which both kynuramine and 5-hydroxykynuramine showed affinity for cortical [3H]spiroperidol and [3H]clonidine binding sites. Overall, the results show that kynuramines can exert peripheral (and possibly central) actions which may prove to be of physiological and/or pharmacological significance.

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