Evidence that phenylephrine is not direct-acting α1-agonist on smooth muscle and its effects are due to transporter-mediated release of noradrenaline

Background and Purpose: Phenylephrine is regarded as a canonical α1-adrenoceptor selective agonist that acts directly on the receptor. However, in preclinical experiments and clinical trials, several unexpected effects of phenylephrine has been observed that could not be easily explained by acting on α1- but instead seemed to be mediated by α2- and β-adrenoceptors. In our earlier study we have observed that phenylephrine is able to release noradrenaline. In this study we compared its effects on NA release and α1-mediated smooth muscle contractions. Experimental Approach: The isolated vas deferens is one of the most useful ex vivo preparations for studying sympathetic neurochemical transmission. Smooth muscle isometric contractions and the release of [3H]noradrenaline were measured in response to phenylephrine administration. Key Results: Phenylephrine in a concentration between 0.3 and 30 µM significantly enhanced the resting release of [3H]noradrenaline in a [Ca2+]-independent manner. While the release of NA evoked by phenylephrine was not reduced by prazosin, both the initial and secondary tonic phases of phenylephrine-evoked contractions were subjected to α1-adrenoceptor-mediated inhibition. When NA transporter was attenuated by nisoxetine, both noradrenaline release and contractions in response to phenylephrine were inhibited. Conclusions and Implications: Phenylephrine, as a substrate of noradrenaline transporter reverses its function and results in an increase of resting, nonvesicular release of noradrenaline. The fact that its α1-mediated contractile effects on smooth muscle were attenuated by the inhibition of transporter activity indicates that its action on smooth muscle is indirect due to NA being released from the cytoplasm of the sympathetic nerve terminals.