Tachykinin NK2 receptors in the hamster urinary bladder: in vitro and in vivo characterization.
We have characterized the contractile responses produced by stimulation of the tachykinin NK2 receptor in the hamster urinary bladder in vitro and in vivo. In isolated bladder strips, neurokinin A (NKA, pD2 7.40, Emax 71% of the response to 80 mM KCl) and the synthetic tachykinin NK2 receptor selective agonist [betaAla8]NKA(4-10) (pD2 7.48, Emax 77% of the response to KCl) both induced a concentration-dependent contraction, whereas the tachykinin NK1 and NK3 receptor selective agonists, [Sar9]substance P sulfone and senktide, respectively, produced a negligible contractile effect. The bicyclic peptide antagonists MEN 11420 and MEN 10627 behaved as competitive antagonists of the response to [betaAla8]NKA(4-10) with apparent pK(B) values of 9.3 and 9.7, respectively. Comparable apparent pK(B) values were estimated against NKA (pK(B) 9.2 and 9.4 for MEN 11420 and MEN 10627, respectively). Under isovolumetric recording of the intravesical pressure, the nicotinic receptor agonist DMPP (0.6 micromol/kg i.v.) produced a phasic contraction of the hamster bladder in vivo that was abolished by hexamethonium (110 micromol/kg i.v.) or by surgical ablation of pelvic ganglia. In vivo [betaAla8]NKA(4-10) (10 nmol/kg i.v.) induced a tonic-type sustained bladder contraction with superimposed high frequency and small amplitude (<12 mmHg) phasic contractions and, in about 70% of cases examined, a few high amplitude (>20 mmHg) phasic contractions. Hexamethonium abolished the high amplitude phasic contractions, indicating their reflex origin. In animals subjected to the ablation of pelvic ganglia, the urinary bladder response to [betaAla8]NKA(4-10) was comparable to that observed after administration of hexamethonium. Moreover, hexamethonium did not affect the contractile responses to [betaAla8]NKA(4-10) in ganglionectomized animals. MEN 10627 and MEN 11420 produced a dose-dependent and long-lasting inhibition of the contractile response to [betaAla8]NKA(4-10): the least effective doses of the two antagonists were 30 and 3 nmol/kg i.v. for MEN 10627 and MEN 11420, respectively. An almost complete and long-lasting inhibition of the response to the agonist was produced at doses of 10 and 100 nmol/kg i.v. of MEN 11420 and MEN 10627. In urethane-anaesthetized hamsters the non-stop intravesical infusion of saline (50 microl/min) produced repetitive micturition cycles which were abolished by hexamethonium (110 micromol/kg i.v.) or by surgical removal of the pelvic ganglia. MEN 11420 (100 nmol/kg) had no significant effect on the volume-evoked micturition reflex in anaesthetized hamsters. In conclusion, the hamster urinary bladder is a suitable preparation for studying the action of tachykinin NK2 receptor antagonists in vivo: in this species, the stimulation of tachykinin NK2 receptors induces bladder contractions. Blockade of tachykinin NK2 receptors does not appreciably modify the volume-evoked micturition reflex in this species.
Pharmacology Department, Menarini Ricerche, Florence, Italy.
M
M
Tramontana
R
R
Patacchini
A
A
Lecci
S
S
Giuliani
C A
CA
Maggi
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000494:pharmacology; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005730:Ganglionic Blockers / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D015288:Neurokinin A / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism; D014554:Urination / Q000187:drug effects
D000897:Anti-Ulcer Agents; D001993:Bronchodilator Agents; D005730:Ganglionic Blockers; C107754:MEN 11420; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; C110303:neurokinin A (4-10), Ala(5)-; C090951:MEN 10627; D018738:Hexamethonium; D015288:Neurokinin A