Izzo A A, Mascolo N, Capasso F
Department of Experimental Pharmacology, University of Naples Federico II, Italy.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Jun;357(6):677-81. doi: 10.1007/pl00005224.
The effect of selective phosphodiesterase (PDE) inhibitors was studied on neural transmission within the enteric nervous system employing a two-compartment bath (containing the oral and the anal end of a segment of guinea-pig ileum, respectively). Ascending excitatory enteric nerve pathways were activated by electrical field stimulation (10 Hz for 2 s, 45 mA, 0.5 pulse duration) in the anal compartment and the resulting contraction of the intestinal circular muscle in the oral compartment was recorded. The partitioned bath enables PDE inhibitors and other drugs to be applied to enteric nerve pathways (in the anal compartment) without interfering with the recording of the smooth muscle contraction in the oral compartment. The PDE 4 inhibitors rolipram (0.01-10 microM) and Ro-20-1724 (0.01-10 microM) significantly (P<0.01) inhibited (10-91% and 9-83%, respectively) the nerve-mediated contractions. When both rolipram and Ro-20-1724 were tested after phentolamine (1 microM) or yohimbine (0.1 microM), they were significantly (P<0.01) less effective. By contrast prazosin (1 microM) was ineffective. Vinpocetine (50 microM), milrinone (30 microM) and zaprinast (100 microM), which inhibit PDE 1, 3 and 5, respectively, did not modify the nerve-mediated contractions. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-Br-cyclic AMP) or N6,2'-O-dibutyryladenosine 3',5' cyclic monophosphate (dibutyryl cyclic AMP), two analogues of cyclic AMP, at lower concentrations (0.1-1 microM) significantly (P<0.01) inhibited (15-73% and 5-49%, respectively) the nerve-mediated contractions, while at higher concentrations (10-100 microM) they caused a significant (P<0.01) potentiating (48-68% and 77-78%, respectively) effect. These results indicate that inhibition of PDE 4 (but not PDE 1, PDE 3 or PDE 5) produces a depression of neural transmission within the enteric nervous system, possibly by releasing noradrenaline acting at alpha2-adrenoceptors on enteric neurons.
采用双隔室浴槽（分别包含一段豚鼠回肠的口腔端和肛门端）研究了选择性磷酸二酯酶（PDE）抑制剂对肠神经系统内神经传递的影响。在肛门隔室通过电场刺激（10 Hz，持续2 s，45 mA，0.5脉冲持续时间）激活上行兴奋性肠神经通路，并记录口腔隔室中肠环行肌的收缩情况。分隔的浴槽可使PDE抑制剂和其他药物作用于肠神经通路（在肛门隔室），而不会干扰口腔隔室中平滑肌收缩的记录。PDE 4抑制剂咯利普兰（0.01 - 10 μM）和Ro - 20 - 1724（0.01 - 10 μM）显著（P<0.01）抑制（分别为10 - 91%和9 - 83%）神经介导的收缩。当在酚妥拉明（1 μM）或育亨宾（0.1 μM）之后测试咯利普兰和Ro - 20 - 1724时，它们的效果显著（P<0.01）降低。相比之下，哌唑嗪（1 μM）无效。分别抑制PDE 1、3和5的长春西汀（50 μM）、米力农（30 μM）和扎普司特（100 μM）并未改变神经介导的收缩。环磷酸腺苷（cAMP）的两种类似物8 - 溴环磷酸腺苷（8 - Br - cAMP）或N6,2'-O - 二丁酰环磷酸腺苷（二丁酰环磷酸腺苷），在较低浓度（0.1 - 1 μM）时显著（P<0.01）抑制（分别为15 - 73%和5 - 49%）神经介导的收缩，而在较高浓度（10 - 100 μM）时它们产生显著（P<0.01）的增强作用（分别为48 - 68%和77 - 78%）。这些结果表明，抑制PDE 4（而非PDE 1、PDE 3或PDE 5）可能通过释放作用于肠神经元α2 - 肾上腺素能受体的去甲肾上腺素，导致肠神经系统内神经传递的抑制。
