Pharmacological Properties of Propiverine Contribute to Improving Lower Urinary Tract Dysfunctions in Rats with Spinal Cord Injuries

Abstract

Patients with spinal cord injury (SCI) usually develop lower urinary tract dysfunctions, including detrusor overactivity which is also known to be a risk factor for upper urinary tract dysfunction. Antimuscarinic agents, such as propiverine, have been used clinically for the treatment of detrusor overactivity. Also, propiverine has been known to possess antagonistic activity against L-type Ca channels and transient receptor potential vanilloid subtype 1 (TRPV1), in addition to activity against muscarinic receptors. These mechanisms of action may contribute to improving detrusor overactivity in SCI. We therefore investigated the effects of antagonists of these mechanisms on non-voiding contraction (NVC) in SCI rats that are similar to clinical cases of detrusor overactivity, and considered whether these action mechanisms contribute to the incidence of NVC in SCI. Cystometry was performed in rats 4 weeks after spinal transection. Urinary functions were evaluated before and after intravenous administration of propiverine and specific antagonists for muscarinic receptors (atropine), L-type Ca channels (verapamil), and TRPV1 (capsazepine). Propiverine markedly decreased the amplitude pressure of NVC in SCI rats, which was partially inhibited by atropine. Verapamil also suppressed the amplitude pressure of NVC to the same degree as propiverine. NVC disappeared almost completely after C-fiber desensitization, although capsazepine exerted no evident effects. These findings suggest that muscarinic receptors, L-type Ca channels, and C-fiber afferent nerves contribute to the incidence of detrusor overactivity in SCI, and a drug that has multiple antagonistic effects, such as propiverine, is very effective for the treatment of lower urinary tract dysfunctions in SCI.

Injecting RNA interference lentiviruses targeting the muscarinic 3 receptor gene into the bladder wall inhibits neurogenic detrusor overactivity in rats with spinal cord injury

“…Previous studies suggested that the NVC in SCI rats are mediated predominantly by C‐fiber afferents in urothelial and suburothelial layers while A δ‐fiber afferents are involved in voiding reflexes in normal rats . In addition, mounting evidence indicates that M 3 receptor may play an important role in the NDO after SCI, resulting from those results that activation of muscarinic receptor could enhance NDO through increasing C‐fiber afferents mediated activity in SCI rats and muscarinic receptor antagonists participated in the desensitization of C‐fiber afferents . For example, Iijima et al found that systemic administration of M 3 receptor selective antimuscarinic agent suppressed the activity of bladder afferent C fibers in rats during bladder filling .…”

“…17 In addition, mounting evidence indicates that M 3 receptor may play an important role in the NDO after SCI, resulting from those results that activation of muscarinic receptor could enhance NDO through increasing C-fiber afferents mediated activity in SCI rats and muscarinic receptor antagonists participated in the desensitization of C-fiber afferents. [17][18][19][20] For example, Iijima et al found that systemic administration of M 3 receptor selective antimuscarinic agent suppressed the activity of bladder afferent C fibers in rats during bladder filling. 21 In addition to the direct muscarinic control of bladder afferent pathways, another possible mechanism by which downregulating M 3 receptor expression decreases NVC might be related to ATP.…”

“…In addition, studies reported that the M 3 receptor may play an important role in the NDO after SCI, though there was no significant difference in M 3 receptor protein expression between SCI rats and normal control . For example, activation of muscarinic receptor could enhance NDO through increasing C‐fiber afferents mediated activity in SCI rats and muscarinic receptor antagonists were implicated in the desensitization of C‐fiber afferents, whereas it is hard to reach the detrusor layer and modulate detrusor muscle activity by intravesical administration . Unsurprisingly, M 3 receptor selective antimuscarinic agent was also found to be able to suppress the activity of bladder afferent C fibers in rats .…”

“…16,17 For example, activation of muscarinic receptor could enhance NDO through increasing C-fiber afferents mediated activity in SCI rats and muscarinic receptor antagonists were implicated in the desensitization of C-fiber afferents, whereas it is hard to reach the detrusor layer and modulate detrusor muscle activity by intravesical administration. [17][18][19][20] Unsurprisingly, M 3 receptor selective antimuscarinic agent was also found to be able to suppress the activity of bladder afferent C fibers in rats. 21 Furthermore, in SCI rats, pre-synaptic M 3 receptor was found to be involved in the facilitated release of Ach, whereas it was mediated via pre-synaptic M 1 receptor in normal rats.…”

Intestinal, urinary and uterine antispasmodic effects of isoespintanol, metabolite from Oxandra xylopioides leaves

“…Moreover, there are medicines with anticholinergic and calcium antagonist properties to synergistically reduce the anormal contractions of bladder due to inestability or hiperactivity of detrusor (Sugaya et al 2012). To this therapeutic group belong oxybutinine and propiverine, which have strong anticholinergic activity but weak effect as calcium channels blocker (Hamada et al, 1997;Sakakibara et al 2016). Other…”