Mutual-effect amplification of contractile responses elicited by simultaneous activation of alpha-1 adrenergic and 5-hydroxytryptamine2 receptors in isolated rat aorta

5-Hydroxytryptamine (5-HT), and the selective alpha-1 agonists phenylephrine (PE) and oxymetazoline (OXY), were used to study the effects of simultaneous coactivation of the 5-HT2 and alpha-1 adrenergic receptors, respectively, on the contractile responses of isolated rat aortic rings. Dissociation constants (KA) were determined for each of the agonists at their respective receptor subtypes. The KA values for PE and OXY at the alpha-1 receptor were 316 nM and 1.82 microM, respectively, while the KA for 5-HT at the 5-HT2 receptor was 478 nM. Concentration-response curves for each agonist were analyzed by the Black and Leff operational model of pharmacological agonism to determine efficacy (tau) and slope factor values. The estimated tau for PE (16.02) was much greater than the tau for either OXY (4.15) or 5-HT (2.95), which had similar efficacies. Using a previously described drug concentration paradigm, a mutual-effect amplification of the 5-HT-induced contractile response was observed with mixtures of 5-HT and PE, whereas mixtures of OXY and 5-HT elicited a mutual-effect amplification of the observed response to OXY alone. In both cases, the theoretical concentration-response curve constructed using the Poch and Holzmann method of equiactive substitution demonstrated that mutual-effect amplification was largely the result of simple additivity of agonist effects. In addition, estimates of tau and slope factor determined from the Black and Leff equation were substituted into the Leff model of mutual-effect amplification and used to accurately predict the location of the concentration-response curves elicited by mixtures of 5-HT and PE, as well as mixtures of OXY and 5-HT. This represents the first time a mathematical model has been used to accurately predict the outcome of coactivation of the alpha-1 and 5-HT2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)