Activation of the micturition reflex by NK2 receptor stimulation in the anaesthetized guinea-pig.
1. The mechanisms underlying stimulation of bladder contractions and bronchoconstriction by the selective NK2 receptor agonist, [beta-Ala8]NKA(4-10), were examined in the anaesthetized guinea-pig. 2. Atropine, alpha,beta-methylene-ATP and ganglion blocking agents were used to examine the contribution of reflex arc activation and/or potentiation of efferent mechanisms to the NK2 receptor-mediated responses seen in these two tissues. 3. [beta-Ala8]NKA(4-10)-induced bronchoconstriction was immediate, dose-dependent and was unaffected by pretreatment with ganglion blockers (hexamethonium or chlorisondamine), blockade of muscarinic receptors by atropine, or desensitization of P2 purinoceptors by alpha,beta-methylene-ATP. 4. At does of 5 micrograms kg-1 and above, [beta-Ala8]NKA(4-10) induced bladder contractions that appeared to be of an 'all-or-nothing' nature. These contractions occurred after a delay of 10 to 30 s and were often biphasic, comprised of an initial rapid component followed by a slower tonic component. 5. Pretreatment of the animals with either atropine or the desensitizing purinoceptor agonist alpha,beta-methylene-ATP, resulted in partial inhibition of bladder contractile responses to [beta-Ala8]NKA(4-10). The combination of atropine and alpha,beta-methylene-ATP pretreatment resulted in additive inhibition leading to complete blockade of the response. 6. The bladder responses to [beta-Ala8]NKA(4-10) (5 micrograms kg-1) were inhibited by pretreatment with the ganglion blockers, hexamethonium and chlorisondamine, indicating a preganglionic mechanism of action. 7. These findings demonstrate the indirect nature of the bladder contractions induced by activation of NK2 receptors in the anaesthetized guinea-pig. Contractions occur secondary to the release of endogenous cholinergic and NANC transmitters by activation of neuronal NK2 receptors located at apreganglionic site, possibly on capsaicin-sensitive sensory afferent nerves, where NK2 sites have been demonstrated autoradiographically. In contrast, [beta-Ala8]NKA(4- 10)-induced bronchoconstriction in the anaesthetized guinea-pig is a direct smooth muscle contractile response that is unaffected by ganglionblockade or blockade of muscarinic receptors.
Bushfield
M
M
Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent.
Metcalfe
M
M
Naylor
A M
AM
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005730:Ganglionic Blockers / Q000494:pharmacology; D006168:Guinea Pigs; D010880:Piperidines / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000819:agonists* / Q000187:drug effects*; D012018:Reflex / Q000187:drug effects*; D001743:Urinary Bladder / Q000187:drug effects; D014554:Urination / Q000187:drug effects*
D001549:Benzamides; D005730:Ganglionic Blockers; D010880:Piperidines; D018041:Receptors, Neurokinin-2; C073839:SR 48968; D001285:Atropine