Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4., Budapest, 1089, Hungary.
Institute of Experimental Medicine, Eötvös Lóránd Research Network, Szigony utca 43., Budapest, 1083, Hungary.
Neurochem Res. 2022 Nov;47(11):3272-3284. doi: 10.1007/s11064-022-03681-2. Epub 2022 Aug 9.
Phenylephrine (PE) is a canonical α-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 α-adrenoceptors. The probability of the involvement of α- and β-adrenoceptors in the effect of PE has been raised. In addition, our earlier study observed that PE released noradrenaline (NA) in a [Ca]-independent manner. To elucidate this issue, we have investigated the effects of PE on [H]NA release and α-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 [H]NA in a [Ca]-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 α-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.
苯肾上腺素（PE）是一种经典的α-肾上腺素受体选择性激动剂。然而，在临床前和临床研究中观察到了 PE 的意外作用，这些作用不能简单地用其对α-肾上腺素受体的作用来解释。人们提出了α-和β-肾上腺素受体参与 PE 作用的可能性。此外，我们之前的研究观察到，PE 以[Ca]非依赖性的方式释放去甲肾上腺素（NA）。为了阐明这个问题，我们研究了 PE 对离体小鼠输精管（MVD）中[H]NA 释放和α介导的平滑肌收缩的影响。释放实验旨在评估 PE 在突触前末端的作用，而平滑肌对电刺激的等长收缩则用于测量 PE 在后突触的作用。我们的结果表明，浓度在 0.3 到 30µM 之间的 PE 以[Ca]非依赖性的方式显著增强了[H]NA 的静息释放。此外，哌唑嗪并不影响 PE 诱发的 NA 释放。相反，PE 诱发的平滑肌收缩被哌唑嗪给药抑制，表明存在α-肾上腺素受体介导的作用。当用尼索西汀减弱 NA 转运体（NAT）的功能时，PE 无法释放 NA，收缩减少了约 88%。剩下的部分被证明对哌唑嗪敏感。本工作支持了 PE 的实质性间接作用，该作用依赖于 NA 的细胞质释放，这可能解释了报道的 PE 的副作用。
