Yang X P, Chiba S
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan.
Eur J Pharmacol. 1999 Sep 3;380(1):5-11. doi: 10.1016/s0014-2999(99)00529-4.
The aim of this study was both to investigate the effects of progressive inhibition of adrenergic neurons by increasing concentrations of guanethidine (0.1-10 microM) on the double-peaked vasoconstrictor responses to electrical periarterial nerve stimulation in the isolated and perfused canine splenic artery, and to clarify whether release of noradrenaline is presynaptically separate from release of adenosine 5'-triphosphate (ATP). Double-peaked vasoconstrictions (biphases of vasoconstrictions) were consistently observed under the conditions of 30-s trains of pulses at 1-10 Hz frequencies. Guanethidine, at a lower concentration (0.1 microM) did not modify the first (1st) phase vasoconstriction at low frequencies (1-2 Hz), but markedly inhibited the second (2nd) responses. On the other hand, it slightly but significantly inhibited the double-peaked vasoconstrictor responses at high frequencies (6-10 Hz). Furthermore, a 10-fold increase of concentration of guanethidine (1 microM) almost completely inhibited the 2nd phase responses at any frequencies used but did not completely inhibit the 1st phase response. A further increased concentration of guanethidine (10 microM) failed to enhance the 1 microM guanethidine-induced inhibition. The 1 microM guanethidine-resistant 1st phase responses at any frequencies used (1-10 Hz) were sensitive to tetrodotoxin (30 nM). Treatment with 0.1 microM prazosin did not modify the 1st phase response at any frequencies used in the 1 microM guanethidine-treated preparation. The responses remaining after 1 microM guanethidine and 0.1 microM prazosin were completely suppressed by a subsequent application of 1 microM alpha,beta-methylene ATP at any frequencies used. The results indicated that guanethidine, an adrenergic neuron blocker, may exert a dominant inhibitory effect on adrenergic rather than on purinergic components of sympathetic nerve co-transmission, indicating that guanethidine-sensitive mechanisms may mainly contribute to determine noradrenaline secretion from neurosecretory vesicles rather than ATP secretion.
本研究的目的是，一方面研究通过增加胍乙啶浓度（0.1 - 10微摩尔）逐步抑制肾上腺素能神经元，对离体灌注犬脾动脉中动脉周围神经电刺激引起的双峰血管收缩反应的影响，另一方面阐明去甲肾上腺素的释放是否在突触前与5'-三磷酸腺苷（ATP）的释放相分离。在1 - 10赫兹频率下施加30秒脉冲串的条件下，始终观察到双峰血管收缩（血管收缩的双相性）。较低浓度（0.1微摩尔）的胍乙啶在低频（1 - 2赫兹）时不改变第一（第1）相血管收缩，但显著抑制第二（第2）相反应。另一方面，它在高频（6 - 10赫兹）时轻微但显著地抑制双峰血管收缩反应。此外，胍乙啶浓度增加10倍（1微摩尔）几乎完全抑制了所使用的任何频率下的第2相反应，但未完全抑制第1相反应。胍乙啶浓度进一步增加（10微摩尔）未能增强1微摩尔胍乙啶引起的抑制作用。在所使用的任何频率（1 - 10赫兹）下，1微摩尔胍乙啶抗性的第1相反应对河豚毒素（30纳摩尔）敏感。在1微摩尔胍乙啶处理的制剂中，用0.1微摩尔哌唑嗪处理在任何所使用的频率下均未改变第1相反应。在1微摩尔胍乙啶和0.1微摩尔哌唑嗪处理后剩余的反应，在任何所使用的频率下随后应用1微摩尔α,β-亚甲基ATP可完全抑制。结果表明，肾上腺素能神经元阻滞剂胍乙啶可能对交感神经共同传递的肾上腺素能成分而非嘌呤能成分发挥主要抑制作用，这表明胍乙啶敏感机制可能主要有助于决定神经分泌囊泡中去甲肾上腺素的分泌而非ATP的分泌。
