Pharmacological analysis of the interaction between Bay K 8644 and 5‐HT in rabbit aorta

Abstract

Bay K 8644 potentiated and augmented 5‐hydroxytryptamine (5‐HT)‐induced contractions in the rabbit, isolated aorta preparation, as manifested in leftward shift and increase in the asymptote of 5‐HT E/[A] (effect vs concentration) curves. The operational model of agonism (Black & Leff, 1983) was used to analyse this interaction and the concomitant effects of irreversible receptor alkylation by phenoxybenzamine. The competitive effects of spiperone in the presence and absence of Bay K 8644 were also examined. From these analyses it is concluded that Bay K 8644 elicits its potentiating effects by increasing the efficacy of 5‐HT at the 5‐HT2 receptor with no alteration in affinity. This is consistent with the known effect of Bay K 8644 of causing an increase in the functional concentration of plasmalemmal calcium channels coupled to the 5‐HT2 receptors in this preparation. The positively co‐operative shape of the 5‐HT E/[A] curves obtained in the aorta and the quantitative nature of their potentiation by Bay K 8644 indicated that the coupling of 5‐HT2 receptor occupancy to intracellular calcium concentration is linear and that the co‐operativity resides in the subsequent relation between intracellular calcium and pharmacological effect. Bay K 8644 may serve as a probe for differentiating between the types of calcium channels that transduce 5‐HT receptor‐mediated effects in different systems. Such information would be useful in the classification of agonist interactions with 5‐HT receptors. 1986 British Pharmacological Society