(Open access funding provided by Semmelweis University)
Szakterületek:
Gyógyszerészet, farmakogenomika, gyógyszerkutatás és tervezés, gyógyszeres kezelés
Phenylephrine (PE) is a canonical α1-adrenoceptor-selective agonist.
However, unexpected effects of PE have been observed in preclinical and clinical studies,
that cannot be easily explained by its actions on α1-adrenoceptors.
The probability of the involvement of α2- and β-adrenoceptors
in the effect of PE has been raised. In addition, our earlier study observed that
PE released noradrenaline (NA) in a [Ca2+]o-independent
manner. To elucidate this issue, we have investigated the effects of PE on [3H]NA
release and α1-mediated smooth muscle contractions in the mouse
vas deferens (MVD) as ex vivo preparation. The release experiments were designed to
assess the effects of PE at the presynaptic terminal, whereas smooth muscle isometric
contractions in response to electrical field stimulation were used to measure PE effect
postsynaptically. Our results show that PE at concentrations between 0.3 and 30 µM
significantly enhanced the resting release of [3H]NA in a [Ca2+]o-independent
manner. In addition, prazosin did not affect the release of NA evoked by PE. On the
contrary, PE-evoked smooth muscle contractions were inhibited by prazosin administration
indicating the α1-adrenoceptor-mediated effect. When the function
of the NA transporter (NAT) was attenuated with nisoxetine, PE failed to release NA
and the contractions were reduced by approximately 88%. The remaining part proved
to be prazosin-sensitive. The present work supports the substantial indirect effect
of PE which relays on the cytoplasmic release of NA, which might explain the reported
side effects for PE.
