PhD Scientific Days 2022

Pharmaceutical Sciences I.

Evidence on the Indirect Action of Phenylephrine on α1-receptors of Smooth Muscle: Transporter-mediated Release of Noradrenaline from Neuron Terminals alongside with Direct Activation

Text of the abstract

Introduction: Phenylephrine (PE) is regarded as a canonical α1-adrenoceptor-selective agonist. However, in preclinical experiments and clinical studies, several unexpected effects of PE were observed, which are not easily explained by its actions on α1-adrenoceptors, instead, these effects seemed to be mediated by α2- and β-adrenoceptors.
Aims: Herein we aimed to examine the contribution of noradrenaline (NA) released from presynaptic nerve terminals in response to PE to the effect of PE on postsynaptic α1-adrenoceptor.
Methods: Isolated mouse vas deferentia were obtained from male NMRI or CD1 mice for experiments attended to measure smooth muscle isometric contractions or [3H]noradrenaline ([3H]NA) release, respectively. The smooth muscle contractions and [3H]NA release were examined following electrical field stimulation, PE or NA administration under various experimental conditions. The release experiments were designed to assess the effects of PE at the presynaptic terminal, whereas smooth muscle isometric contractions in response to stimulation were used to assess the postsynaptical effect of PE.
Results: PE significantly enhanced the release of [3H]NA in a [Ca2+]-independent manner. In these experiments, the selective or non-selective NA transporter inhibitors nisoxetine or cocaine, respectively inhibited the PE-induced [3H]NA release. Prazosin failed to affect the release of [3H]NA evoked by PE administration. On the other hand, PE-evoked smooth muscle contractions were inhibited by prazosin administration indicating the α1-adrenoceptor-mediated effect. When the function of the NA transporter was inhibited, PE-induced contractions were largely attenuated. The contractions in response to NA administration were not affected by nisoxetine. Similar effect of nisoxetine was observed in organs pre-treated with reserpine, however PE alone still induced α1-adrenoceptor-mediated contractions in a significantly higher magnitude than in control experiments
Conclusions: Herein for the first time we have demonstrated that the effect of PE on smooth muscle is largely dependent on transporter-mediated cytosolic NA release from presynaptic nerve terminals. Thus, this mechanism of action on NA release may be responsible for the side effects observed with PE in preclinical experiments and during surgery.
Funding: EFOP-3.6.3-VEKOP-16-2017-00009