Effect of Neocuproine, a Copper(I) Chelator, on Rat Bladder Function

Abstract

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 M 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 M) significantly increased the second, more sustained contraction, whereas 200 M 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 M) elicited a marked increase in basal tone of the strips. This effect was less prominent after the second application of 200 M NC or with NC-Cu treatment or in the presence of suramin. In anesthetized rats, during continuous infusion cystometry, intravesical infusion of 50 M 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.

Neocuproine, a Copper (I) Chelator, Potentiates Purinergic Component of Vas Deferens Contractions Elicited by Electrical Field Stimulation

“…This result supports the data obtained from experiments conducted in the presence of suramin that neocuproine enhances purinergic mechanisms and when purinergic receptors are desensitized, the neocuproine facilitatory effect is failed [12,14,15,22,23] . Findings supporting our results have been obtained from our previous study on rat bladder [9] . In this study, neocuproine enhanced the nonadrenergic-noncholinergic contractions of rat bladder detrusor smooth muscle to EFS and suramin or the prolonged exposure to ATP could prevent this facilitation effect.…”

“…These studies suggest that copper is a physiological modulator of these receptors. Also, the present results support our previous fi ndings in rat bladder [9] . In the present study, we may suggest that a copper-sensitive mechanism may play a role in the modulation of purinergic neurotransmission in rat vas deferens.…”

“…In a series of experiments, we used prazosin (0.3 mol/l) + suramin (100 mol/l) to isolate both purinergic and adrenergic components of the contraction elicited by EFS. In the presence of prazosin (0.3 mol/l) or suramin (100 mol/l), after the control responses to EFS were recorded for approximately 30 min, neocuproine (200 mol/l) [9] was applied twice to the same tissue consecutively at intervals ranging from 30 to 35 min. In our preliminary studies, we tried different concentrations of neocuproine in the range from 10 to 300 mol/l and determined that suitable concentration was 200 mol/l to obtain reproducible potentiating effects on the nerveevoked contractions of rat vas deferens.…”

“…It was suggested that copper ions can alter the function of P2X4 purinergic receptors expressed in Xenopus oocytes [7,8] , raising the possibility that other types of P2X receptors such as those expressed in the vas deferens may also be sensitive to copper ions. Also, in our previous study, we reported that copper (I)-sensitive mechanisms tonically inhibit purinergic transmission in rat bladder [9] .…”

Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neurons

“…For example, Neocuproine, a membrane permeable Cu (I) chelator, has been frequently used as a protective agent against oxidative stress caused by Cu (Calderaro et al, 1993 ). Moreover, Neocuproine can inhibit the relaxation of electrically stimulated mouse corpus cavernosum (Göçmen et al, 2000 ) and the facilitation of bladder contraction induced by purinergic nerve stimulation (Göçmen et al, 2005 ).…”