Hernández M, Barahona M V, Recio P, Benedito S, Martínez A C, Rivera L, García-Sacristán A, Prieto D, Orensanz L M
Departamento de Fisiología, Fisiología Animal, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
Br J Pharmacol. 2006 Sep;149(1):100-9. doi: 10.1038/sj.bjp.0706832. Epub 2006 Jul 17.
As pituitary adenylate cyclase-activating polypeptide 38 (PACAP 38)- and vasoactive intestinal peptide (VIP) are widely distributed in the urinary tract, the current study investigated the receptors and mechanisms involved in relaxations induced by these peptides in the pig bladder neck.
Urothelium-denuded strips were suspended in organ baths for isometric force recordings and the relaxations to VIP and PACAP analogues were investigated.
VIP, PACAP 38, PACAP 27 and [Ala(11,22,28)]-VIP produced similar relaxations. Inhibition of neuronal voltage-gated Ca(2+) channels reduced relaxations to PACAP 38 and increased those induced by VIP. Blockade of capsaicin-sensitive primary afferents (CSPA), nitric oxide (NO)-synthase or guanylate cyclase reduced the PACAP 38 relaxations but failed to modify the VIP responses. Inhibition of VIP/PACAP receptors and of voltage-gated K(+) channels reduced PACAP 38 and VIP relaxations, which were not modified by the K(+) channel blockers iberiotoxin, charybdotoxin, apamin or glibenclamide. The phosphodiesterase 4 inhibitor rolipram and the adenylate cyclase activator forskolin produced potent relaxations. Blockade of protein kinase A (PKA) reduced PACAP 38- and VIP-induced relaxations.
PACAP 38 and VIP relax the pig urinary bladder neck through muscle VPAC(2) receptors linked to the cAMP-PKA pathway and involve activation of voltage-gated K(+) channels. Facilitatory PAC(1) receptors located at CSPA and coupled to NO release, and inhibitory VPAC receptors at motor endings are also involved in the relaxations to PACAP 38 and VIP, respectively. VIP/PACAP receptor antagonists could be useful in the therapy of urinary incontinence produced by intrinsic sphincter deficiency.
由于垂体腺苷酸环化酶激活多肽38（PACAP 38）和血管活性肠肽（VIP）在尿路中广泛分布，本研究调查了这些肽在猪膀胱颈诱导舒张所涉及的受体和机制。
将去除尿路上皮的条带悬挂在器官浴槽中进行等长张力记录，并研究对VIP和PACAP类似物的舒张反应。
VIP、PACAP 38、PACAP 27和[Ala(11,22,28)]-VIP产生相似的舒张作用。抑制神经元电压门控钙通道可减少对PACAP 38的舒张反应，并增强由VIP诱导的舒张反应。阻断辣椒素敏感的初级传入神经（CSPA）、一氧化氮（NO）合酶或鸟苷酸环化酶可减少PACAP 38的舒张反应，但未能改变VIP的反应。抑制VIP/PACAP受体和电压门控钾通道可减少PACAP 38和VIP的舒张反应，而钾通道阻滞剂iberiotoxin、charybdotoxin、apamin或格列本脲对此无影响。磷酸二酯酶4抑制剂咯利普兰和腺苷酸环化酶激活剂福斯可林产生强效舒张作用。阻断蛋白激酶A（PKA）可减少PACAP 38和VIP诱导的舒张反应。
PACAP 38和VIP通过与cAMP-PKA途径相关的肌肉VPAC(2)受体使猪膀胱颈舒张，并涉及电压门控钾通道的激活。位于CSPA且与NO释放相关的促进性PAC(1)受体以及运动终末的抑制性VPAC受体也分别参与了对PACAP 38和VIP的舒张反应。VIP/PACAP受体拮抗剂可能对治疗内在括约肌缺陷导致的尿失禁有用。
