Phenylephrine Precontraction Increases the Sensitivity of Rabbit Femoral Artery to Serotonin by Enabling 5-HT1-Like Receptors

We used selective receptor antagonists to identify the receptors mediating the isometric contractile response to serotonin in control and phenylephrine (PHE)-precontracted rabbit femoral artery rings. Serotonin, in the absence of PHE, elicited monophasic concentration-response curves (CRCs) early, but biphasic CRCs late in the course of the study. In the monophasic curves, the threshold and maximal concentrations were 10 and 1,000 μM, respectively. In biphasic CRCs, the threshold and maximal concentrations of the first phase were 0.03 and 3 μM, respectively. The respective values for the second phase were 10 and 1,000 μM. Prazosin, 0.1 μM, a selective α1-adrenoceptor antagonist, inhibited the monophasic curves, but only the second phase of the biphasic curves. Ritanserin, 0.01 μM, a selective 5-HT2A-receptor antagonist, shifted the first phase of the biphasic serotonin CRCs to the right but had little effect on the second phase. PHE increased the sensitivity of rabbit femoral artery response to serotonin. This amplified response to serotonin was antagonized by 0.01 μM GR 127935T, a selective 5-HT1B-receptor antagonist. The selective 5-HT1 agonist, sumatriptan, had no effect in control femoral arteries, but caused a concentration-dependent contraction after PHE precontraction. These results suggest that 5-HT1-like receptors are normally inactive or "silent" in the absence of PHE. However, in the presence of PHE, these receptors become enabled and mediate the amplified response to serotonin. The evidence also suggests that, in the absence of PHE, α1-adrenoceptors mediated the contractile response to serotonin in the monophasic CRCs. In the biphasic curves observed late in the study, the first phase was mediated by 5-HT2A receptors, and the second, by the α1-adrenergic receptors.