In vivo evidence for the involvement of tachykinin NK3 receptors in the hexamethonium-resistant inhibitory transmission in the rat colon.
In urethane-anaesthetized rats, moderate colonic distention (0.5 ml) induced reflex rhythmic contractions (5 mm Hg amplitude and 1.1 cycles/min frequency). Senktide (1-10 nmol/kg, i.v.), a tachykinin NK3 receptor selective agonist, transiently suppressed distension-induced contractions. SR 142,801 (1-10 mumol/kg i.v.), a non-peptide tachykinin NK3 receptor antagonist, had no effect on distension-induced contractions but prevented the inhibitory effect of senktide. Infusion of N-omega-nitro-1-arginine methyl esther hydrochloride (L-NAME, 20 mumol/ml/h, i.v) increased the amplitude of colonic contractions and decreased the inhibitory effect of senktide. Hexamethonium (15 mumol/ml/h, i.v.) or atropine (1 mumol/ml/h, i.v.) inhibited the distension-induced contractions. In hexamethonium- or atropine-treated rats, senktide (10 nmol/kg) transiently and selectively enhanced the amplitude of contractions. Also SR 142,801 (10 mumol/kg), but not its inactive enantiomer SR 142,806, increased both amplitude and frequency of contractions. During continuous infusion of L-NAME and hexamethonium or atropine both frequency and amplitude of distension-induced colonic contractions were higher than when in hexamethonium or atropine only. Senktide (10 nmol/kg) had no effect and SR 142,801 (10 mumol/kg) produced a slight enhancement of colonic contractions. Infusion of sodium nitroprusside (3 mumol/ml/h, i.v.) decreased amplitude and frequency of distension-induced contractions. SR 142,801 had no effect in the presence of the nitric oxide (NO) donor. We conclude that tachykinins acting through NK3 receptors exert at least four different actions on colonic motility activated by distension: 1) a hexamethonium-resistant, NO-dependent, suppressant effect on contractions; 2) a hexamethonium-sensitive, NO-independent inhibitory effect on the amplitude of contractions; 3) a hexamethonium-resistant, NO-independent inhibitory effect on the amplitude of contractions and 4) a hexamethonium resistant and L-NAME-sensitive excitatory effect on amplitude of contractions. The prevalent inhibitory effect evoked in normal conditions along with the excitatory activity induced by SR 142,801 on hexamethonium-resistant colonic motility indicates that tachykinins, acting through neuronal NK3 receptors, activate NO-dependent and NO-independent inhibitory neurotransmission in the rat colon.
Lecci
A
A
Pharmacology Research Department A. Menarini Pharmaceuticals, Florence, Italy.
Giuliani
S
S
Tramontana
M
M
Meini
S
S
De Giorgio
R
R
Maggi
C A
CA
D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000737:chemistry / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006145:Guanethidine / Q000494:pharmacology; D018738:Hexamethonium / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D015288:Neurokinin A / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D018039:Receptors, Tachykinin / Q000187:drug effects / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives* / Q000494:pharmacology
D018663:Adrenergic Agents; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; C054724:senktide; D013373:Substance P; D018738:Hexamethonium; D015288:Neurokinin A; C091554:SR 142801; D019331:NG-Nitroarginine Methyl Ester; D006145:Guanethidine