Göçmen Cemil, Giesselman Ben, de Groat William C
University of Cukurova, School of Medicine, Department of Pharmacology, Adana, TR-01330, Turkey.
J Pharmacol Exp Ther. 2005 Mar;312(3):1138-43. doi: 10.1124/jpet.104.076398. Epub 2004 Oct 22.
The effects of a specific copper(I)-chelator, neocuproine (NC), and a selective copper(II)-chelator, cuprizone, on nonadrenergic-noncholinergic transmitter mechanisms in the rat urinary bladder were studied by measuring nerve-evoked contractions of bladder strips and voiding function under urethane anesthesia. After blocking cholinergic and adrenergic transmission with atropine and guanethidine, electrical field stimulation induced bimodal contractions of bladder strips. An initial, transient contraction that was blocked by the purinergic antagonist, suramin, was significantly enhanced by NC (20 and 200 microM applied sequentially) but not affected by cuprizone. The facilitating effect, which was blocked by suramin and reversible after washout of the drug, did not occur following administration of neocuproine-copper(I) complex (NC-Cu). NC (20 microM) significantly increased the second, more sustained contraction, whereas 200 microM decreased this response. These effects of NC on the sustained contractions were not elicited by NC-Cu and not blocked by suramin. The nitric oxide synthase inhibitor, l-nitroarginine, did not alter the responses to NC. NC (20 microM) elicited a marked increase in basal tone of the strips. This effect was less prominent after the second application of 200 microMNC or with NC-Cu treatment or in the presence of suramin. In anesthetized rats, during continuous infusion cystometry, intravesical infusion of 50 microM NC but not NC-Cu or cuprizone significantly decreased the intercontraction interval (ICI) without changing contraction amplitude. The ICI returned to normal after washout of NC. Suramin blocked this effect. These results indicate that NC enhances bladder activity by facilitating purinergic excitatory responses and that copper(I)-sensitive mechanisms tonically inhibit purinergic transmission in the bladder.
通过在乌拉坦麻醉下测量膀胱条带的神经诱发收缩和排尿功能，研究了一种特定的铜（I）螯合剂新铜试剂（NC）和一种选择性铜（II）螯合剂铜克酮对大鼠膀胱非肾上腺素能-非胆碱能递质机制的影响。在用阿托品和胍乙啶阻断胆碱能和肾上腺素能传递后，电场刺激诱发了膀胱条带的双峰收缩。一种被嘌呤能拮抗剂苏拉明阻断的初始短暂收缩，在依次应用NC（20和200微摩尔）后显著增强，但不受铜克酮影响。这种促进作用被苏拉明阻断且在药物洗脱后可逆，而在给予新铜试剂-铜（I）络合物（NC-Cu）后未出现。NC（20微摩尔）显著增加了第二次更持久的收缩，而200微摩尔则降低了这种反应。NC对持续收缩的这些作用不是由NC-Cu引起的，也不被苏拉明阻断。一氧化氮合酶抑制剂L-硝基精氨酸未改变对NC的反应。NC（20微摩尔）使条带的基础张力显著增加。在第二次应用200微摩尔NC或进行NC-Cu处理或存在苏拉明的情况下，这种作用不太明显。在麻醉大鼠中，在连续灌注膀胱测压期间，膀胱内灌注50微摩尔NC而非NC-Cu或铜克酮显著缩短了收缩间期（ICI），而不改变收缩幅度。NC洗脱后，ICI恢复正常。苏拉明阻断了这种作用。这些结果表明，NC通过促进嘌呤能兴奋性反应增强膀胱活动，并且铜（I）敏感机制对膀胱中嘌呤能传递具有紧张性抑制作用。
