Depressed contractile responses to neurokinin A in idiopathic but not neurogenic overactive human detrusor muscle.
OBJECTIVE
The role of tachykinins such as neurokinin A in regulating bladder function is unclear, but NK2 receptors seem to mediate contraction in the human bladder and it has been suggested that these peptides may have a role in the pathophysiology of bladder dysfunction. The present study investigates neurokinin receptor-mediated contractility of detrusor muscle in the idiopathic overactive and neurogenic overactive bladder and investigates the neurokinin receptor subtypes involved.


METHODS
Human bladder was obtained from patients undergoing cystectomy (normal) or clam cystoplasty (idiopathic overactive) and from patients with spinal injuries (neurogenic overactive). Strips of isolated detrusor muscle were mounted in physiological Krebs-bicarbonate solution and cumulative concentration-response curves to 1 nM to 300 microM neurokinin A (NKA) were obtained in the absence and presence of neurokinin receptor antagonists, either the NK2 receptor-selective antagonist SR 48968 or the NK3 receptor-selective antagonist SB 223412.


RESULTS
NKA evoked concentration-dependent contraction of normal, idiopathic, and neurogenic overactive detrusor strips. In idiopathic overactive detrusor muscle, NKA-induced contraction was significantly reduced relative to normal detrusor (0.031 +/- 0.005 mg/g, n = 11 versus 0.193 +/- 0.039 mg/g, n = 7). Sensitivity to the peptide was also significantly (p < 0.01) reduced in idiopathic overactive detrusor, with mean pEC50 values (concentration producing 50% maximal response) of 6.62+/-0.16 (n = 11) compared to 7.47+/-0.19 (n = 7) in normal detrusor. In contrast, NKA-induced responses of neurogenic overactive detrusor were similar to those in normal detrusor, with a mean maximum contraction of 0.199 +/- 0.036 mg/g (n = 10) and mean pEC50 value of 7.85+/-0.16 (n = 10). NKA curves in all groups were shifted to the right by the NK2 receptor-selective antagonist SR 48968 with high affinity, pK(B) values being similar in normal, idiopathic, and neurogenic overactive detrusor (8.85 + 0.08, n = 14; 8.97 +/- 0.13, n = 12; 8.73 +/- 0.12, n = 8, respectively). In contrast the NK3 receptor-selective antagonist SB 223412 had a minimal effect on NKA responses and affinity values were low (pK(B) 5.81 +/- 0.11, n = 12 in normal; 5.75 +/- 0.08, n = 12 in idiopathic overactive, and 5.77 +/- 0.13, n = 11 in neurogenic overactive).


CONCLUSIONS
These data indicate that NKA-induced responses are impaired in detrusor muscle from idiopathic overactive human bladder, but not in detrusor muscle from neurogenic overactive bladder. The NK2 receptor subtype appears to mediate NKA responses in the normal, idiopathic overactive, and neurogenic overactive detrusor. This is important evidence suggesting a difference between the bladder pathophysiology observed in idiopathic versus neurogenic overactive detrusor.
Sellers
Donna J
DJ
Biomedical Research Centre, Sheffield Hallam University, Sheffield S1 1WB, UK. d.j.sellers@shu.ac.uk
Chapple
Christopher R
CR
W Hay
Douglas P
DP
Chess-Williams
Russell
R
D001549:Benzamides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects*
D001549:Benzamides; D010880:Piperidines; D011804:Quinolines; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; C106716:SB 223412; C073839:SR 48968; D015288:Neurokinin A