Activity of nonpeptide tachykinin antagonists on neurokinin a induced contractions in dog urinary bladder.

Abstract

PURPOSE:

There is abundant evidence indicating that tachykinin (TK) containing sensory nerves (C-fibers) play an important role in neural regulation of reflex micturition in mammals. Desensitization of urinary bladder C-fibers with resiniferatoxin ameliorates bladder hyperreflexia and incontinence and supports a similar role for C-fibers in man. TK-induced contraction of isolated human urinary bladder smooth muscle appears to be exclusively neurokinin NK2-receptor mediated. Dog urinary bladder contractility to a series of TK-receptor agonists also suggests a predominance of NK2-receptor activation by tachykinins and indicates the dog may provide a useful model for the development of pharmacotherapy for bladder hyperreflexia.

MATERIALS AND METHODS:

We evaluated the activity of the nonpeptide NK-receptor selective antagonists SR 48968 (NK2), SB 223412 (NK3) and CP 99994 (NK1) against neurokinin A (NKA)-induced contractions in isolated dog urinary bladder strips to determine the NK-receptor type which mediates contractile responses to NKA. The dual NK1 and NK2 antagonist MDL 103392 was also tested in this preparation.

RESULTS:

NKA-induced contractions (pD2 = 8.0) were dose dependently blocked by SR 48968 (pA2 = 8.2 +/- 0.2) while CP 99994 (1.0 microM) and SB 223412 (1.0 microM) were inactive. MDL 103392 was a weak functional antagonist (pKb = 6.1 +/- 0.1) of NKA.

CONCLUSIONS:

Relative activities of SR 48968, CP 99994 and SB 223412 confirm that the NK2-receptor is the mediator of NKA-induced contractions of dog urinary bladder smooth muscle.

• Authors: C A Rizzo, J A Hey
• Journal: The Journal of urology (J Urol) Vol. 163 Issue 6 Pg. 1971-4 (Jun 2000) ISSN: 0022-5347 [Print] United States
• PMID: 10799241 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Piperidines
• Quinolines
• Receptors, Neurokinin-2
• 3-(2-methoxybenzylamino)-2-phenylpiperidine
• SB 223412
• SR 48968
• Neurokinin A

Topics

• Animals
• Benzamides (pharmacology)
• Dogs
• Dose-Response Relationship, Drug
• Male
• Muscle Contraction (drug effects, physiology)
• Muscle, Smooth (drug effects, physiology)
• Neurokinin A (pharmacology)
• Piperidines (pharmacology)
• Quinolines (pharmacology)
• Receptors, Neurokinin-2 (antagonists & inhibitors)
• Stereoisomerism
• Urinary Bladder (physiology)