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. 1993 Sep;110(1):77–86. doi: 10.1111/j.1476-5381.1993.tb13774.x

Effects of LY274614, a competitive NMDA receptor antagonist, on the micturition reflex in the urethane-anaesthetized rat.

M Yoshiyama 1, J R Roppolo 1, K B Thor 1, W C de Groat 1
PMCID: PMC2175996  PMID: 8106110

Abstract

1. The effects of 3 competitive N-methyl-D-aspartate (NMDA) receptor antagonists, LY274614, LY233536 and LY235723, on the micturition reflex and external urethral sphincter EMG activity, were examined either under isovolumetric conditions or during continuous filling cystometry in urethane-anaesthetized (1.2 g kg-1, s.c.) rats. 2. Intravenous administration of LY274614 (3-30 mg kg-1) inhibited in a dose-dependent fashion both bladder and sphincter activity in the intact rats. In addition, the volume threshold for inducing micturition was increased and voided volume was decreased. 3. Intrathecal administration of LY274614 (0.06-30 micrograms) similarly inhibited bladder and sphincter activity during cystometry in intact rats. 4. In chronic spinal cord (T6-T8) transected rats LY274614 (0.1-30 mg kg-1, i.v.) did not alter bladder activity under isovolumetric conditions but decreased the amplitude of micturition contractions and sphincter EMG activity during cystometry at a dose of 10-30 mg kg-1. 5. The inhibitory effects of i.v. administration of LY274614, on bladder and sphincter activity induced by infusion of chemical irritant (0.1% acetic acid) or saline, were similar; except that a slightly larger dose was needed to inhibit sphincter activity during acetic acid infusion. 6. Peak amplitude of micturition contractions recovered to 50% of control 3 h following i.v. (30 mg kg-1) or i.t. (6 micrograms) administration of LY274614. 7. Two other chemically related NMDA antagonists, LY233536 and LY235723 produced similar but less potent effects than LY274614 when given i.v. 8. These data indicate that glutamatergic transmitter mechanisms at the level of the spinal cord are important in modulating bladder activity in the intact animal, but that these mechanisms do not contribute to bladder reflexes in the chronic spinal rat. These mechanisms may, however, contribute to sphincter activity in both intact or chronic spinal rats.

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Selected References

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  1. Amador M., Dani J. A. MK-801 inhibition of nicotinic acetylcholine receptor channels. Synapse. 1991 Mar;7(3):207–215. doi: 10.1002/syn.890070305. [DOI] [PubMed] [Google Scholar]
  2. Birder L. A., de Groat W. C. The effect of glutamate antagonists on c-fos expression induced in spinal neurons by irritation of the lower urinary tract. Brain Res. 1992 May 15;580(1-2):115–120. doi: 10.1016/0006-8993(92)90934-2. [DOI] [PubMed] [Google Scholar]
  3. FELDBERG W., FLEISCHHAUER K. Penetration of bromophenol blue from the perfused cerebral ventricles into the brain tissue. J Physiol. 1960 Feb;150:451–462. doi: 10.1113/jphysiol.1960.sp006397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Foster A. C., Fagg G. E. Neurobiology. Taking apart NMDA receptors. Nature. 1987 Oct 1;329(6138):395–396. doi: 10.1038/329395a0. [DOI] [PubMed] [Google Scholar]
  5. Fuller R. W., Hemrick-Luecke S. K., Ornstein P. L. Protection against amphetamine-induced neurotoxicity toward striatal dopamine neurons in rodents by LY274614, an excitatory amino acid antagonist. Neuropharmacology. 1992 Oct;31(10):1027–1032. doi: 10.1016/0028-3908(92)90104-w. [DOI] [PubMed] [Google Scholar]
  6. Jansen K. L., Faull R. L., Dragunow M., Waldvogel H. Autoradiographic localisation of NMDA, quisqualate and kainic acid receptors in human spinal cord. Neurosci Lett. 1990 Jan 1;108(1-2):53–57. doi: 10.1016/0304-3940(90)90705-e. [DOI] [PubMed] [Google Scholar]
  7. Kruse M. N., Noto H., Roppolo J. R., de Groat W. C. Pontine control of the urinary bladder and external urethral sphincter in the rat. Brain Res. 1990 Nov 5;532(1-2):182–190. doi: 10.1016/0006-8993(90)91758-9. [DOI] [PubMed] [Google Scholar]
  8. Lumb B. M., Morrison J. F. An excitatory influence of dorsolateral pontine structures on urinary bladder motility in the rat. Brain Res. 1987 Dec 1;435(1-2):363–366. doi: 10.1016/0006-8993(87)91626-x. [DOI] [PubMed] [Google Scholar]
  9. Maggi C. A., Giuliani S., Giachetti A., Meli A. The effect of MK-801 on the micturition reflex in anesthetized rats. Eur J Pharmacol. 1990 May 31;181(1-2):105–109. doi: 10.1016/0014-2999(90)90250-a. [DOI] [PubMed] [Google Scholar]
  10. Maggi C. A., Santicioli P., Meli A. The nonstop transvesical cystometrogram in urethane-anesthetized rats: a simple procedure for quantitative studies on the various phases of urinary bladder voiding cycle. J Pharmacol Methods. 1986 Apr;15(2):157–167. doi: 10.1016/0160-5402(86)90064-1. [DOI] [PubMed] [Google Scholar]
  11. Mallory B. S., Roppolo J. R., de Groat W. C. Pharmacological modulation of the pontine micturition center. Brain Res. 1991 Apr 19;546(2):310–320. doi: 10.1016/0006-8993(91)91495-m. [DOI] [PubMed] [Google Scholar]
  12. Mallory B., Steers W. D., De Groat W. C. Electrophysiological study of micturition reflexes in rats. Am J Physiol. 1989 Aug;257(2 Pt 2):R410–R421. doi: 10.1152/ajpregu.1989.257.2.R410. [DOI] [PubMed] [Google Scholar]
  13. Monaghan D. T., Cotman C. W. Distribution of N-methyl-D-aspartate-sensitive L-[3H]glutamate-binding sites in rat brain. J Neurosci. 1985 Nov;5(11):2909–2919. doi: 10.1523/JNEUROSCI.05-11-02909.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Nishizawa O., Fukuda T., Matsuzaki A., Moriya I., Harada T., Tsuchida S. Role of the sympathetic nerve in bladder and urethral sphincter function during the micturition cycle in the dog evaluated by pressure flow EMG study. J Urol. 1985 Dec;134(6):1259–1261. doi: 10.1016/s0022-5347(17)47707-x. [DOI] [PubMed] [Google Scholar]
  15. Ornstein P. L., Schoepp D. D., Arnold M. B., Augenstein N. K., Lodge D., Millar J. D., Chambers J., Campbell J., Paschal J. W., Zimmerman D. M. 6-substituted decahydroisoquinoline-3-carboxylic acids as potent and selective conformationally constrained NMDA receptor antagonists. J Med Chem. 1992 Sep 18;35(19):3547–3560. doi: 10.1021/jm00097a012. [DOI] [PubMed] [Google Scholar]
  16. Ornstein P. L., Schoepp D. D., Arnold M. B., Jones N. D., Deeter J. B., Lodge D., Leander J. D. NMDA antagonist activity of (+/-)-(2SR,4RS)-4-(1H-tetrazol-5-ylmethyl)piperidine-2-carboxylic acid resides with the (-)-2R,4S-isomer. J Med Chem. 1992 Aug 21;35(17):3111–3115. doi: 10.1021/jm00095a004. [DOI] [PubMed] [Google Scholar]
  17. Rasmussen K. Afferent effects on locus coeruleus in opiate withdrawal. Prog Brain Res. 1991;88:207–216. doi: 10.1016/s0079-6123(08)63810-8. [DOI] [PubMed] [Google Scholar]
  18. Rasmussen K., Fuller R. W., Stockton M. E., Perry K. W., Swinford R. M., Ornstein P. L. NMDA receptor antagonists suppress behaviors but not norepinephrine turnover or locus coeruleus unit activity induced by opiate withdrawal. Eur J Pharmacol. 1991 May 2;197(1):9–16. doi: 10.1016/0014-2999(91)90358-w. [DOI] [PubMed] [Google Scholar]
  19. Schoepp D. D., Ornstein P. L., Leander J. D., Lodge D., Salhoff C. R., Zeman S., Zimmerman D. M. Pharmacological characterization of LY233053: a structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action. J Pharmacol Exp Ther. 1990 Dec;255(3):1301–1308. [PubMed] [Google Scholar]
  20. Schoepp D. D., Ornstein P. L., Salhoff C. R., Leander J. D. Neuroprotectant effects of LY274614, a structurally novel systemically active competitive NMDA receptor antagonist. J Neural Transm Gen Sect. 1991;85(2):131–143. doi: 10.1007/BF01244705. [DOI] [PubMed] [Google Scholar]
  21. Shaw P. J., Ince P. G., Johnson M., Perry E. K., Candy J. The quantitative autoradiographic distribution of [3H]MK-801 binding sites in the normal human spinal cord. Brain Res. 1991 Jan 18;539(1):164–168. doi: 10.1016/0006-8993(91)90701-v. [DOI] [PubMed] [Google Scholar]
  22. Sillén U. Central neurotransmitter mechanisms involved in the control of urinary bladder function. An experimental study in the rat. Scand J Urol Nephrol Suppl. 1980;58:1–45. [PubMed] [Google Scholar]
  23. Willette R. N., Morrison S., Sapru H. N., Reis D. J. Stimulation of opiate receptors in the dorsal pontine tegmentum inhibits reflex contraction of the urinary bladder. J Pharmacol Exp Ther. 1988 Jan;244(1):403–409. [PubMed] [Google Scholar]
  24. Wong E. H., Kemp J. A., Priestley T., Knight A. R., Woodruff G. N., Iversen L. L. The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104–7108. doi: 10.1073/pnas.83.18.7104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Yaksh T. L., Rudy T. A. Chronic catheterization of the spinal subarachnoid space. Physiol Behav. 1976 Dec;17(6):1031–1036. doi: 10.1016/0031-9384(76)90029-9. [DOI] [PubMed] [Google Scholar]
  26. Yoshiyama M., Roppolo J. R., Rihmland J., Blastos B., de Groat W. C. The effects of MK-801, an NMDA receptor antagonist, on the micturition reflex in the rat. Neurosci Lett. 1991 May 27;126(2):141–144. doi: 10.1016/0304-3940(91)90539-6. [DOI] [PubMed] [Google Scholar]
  27. Yoshiyama M., Roppolo J. R., de Groat W. C. Effects of MK-801 on the micturition reflex in the rat--possible sites of action. J Pharmacol Exp Ther. 1993 May;265(2):844–850. [PubMed] [Google Scholar]

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