Role of prostanoids in the contraction induced by a tachykinin NK2 receptor agonist in the hamster urinary bladder.
In isolated strips of the hamster urinary bladder the selective tachykinin NK2 receptor agonist [betaAla8]NKA(4-10) induced a concentration-dependent (1 nM-10 microM) contraction (EC50 104 nM) associated with significant release of prostaglandin E2 (PGE2, 50+/-17 pg/mg tissue). In mucosa-free bladder strips [betaAla8]NKA(4-10) was as potent as in the presence of mucosa (EC50 46 nM), although the evoked PGE2 release was significantly less than in controls (6+/-1.7 pg/mg tissue). Dexketoprofen (10 microM) produced a significant but limited rightward shift of the concentration/response curve to [betaAla8]NKA(4-10) both in the presence and absence of the mucosal layer: the EC50 for [betaAla8]NKA(4-10) was increased five- and threefold, respectively. The evoked PGE2 release was abolished in both cases. The selective tachykinin NK2 receptor antagonist, nepadutant (10 nM-1 microM) produced a concentration-dependent and even inhibition of both contraction and PGE2 release induced by [betaAla8]NKA(4-10). The L-type calcium channel blocker, nifedipine (1 microM) and the non-selective cationic channel blocker SKF 96365 (30 microM) both inhibited the contractile response to [betaAla8]NKA(4-10) (89+/-2 and 83+/-2% inhibition, respectively). The evoked PGE2 release was not affected by nifedipine but was almost abolished by SKF 96365. Arachidonic acid (100 microM) induced a contractile response (5.9+/-0.7 mN) associated with a large production of PGE2 (383+/-78 pg/mg tissue). The contractile response to arachidonic acid was inhibited by both nifedipine (1 microM) and SKF 96365 (30 microM) (83+/-5 and 79+/-3% inhibition, respectively). The PGE2 production induced by arachidonic acid was markedly inhibited by SKF 96365 only (about 94% inhibition). Exogenous PGE2 contracted hamster bladder strips in the presence of dexketoprofen (EC50 1 microM) and strongly potentiated the contractile response to a submaximal concentration of [betaAla8]NKA(4-10). In anaesthetized hamsters the administration of [betaAla8]NKA(4-10) (10 nmol/kg, i.v.) produced a contractile response of the urinary bladder (13+/-0.4 mmHg) that was inhibited partly by dexketoprofen (25+/-3 and 35+/-4% inhibition for 0.2 and 2 mg/kg, i.v. dexketoprofen, respectively). We conclude that activation of tachykinin NK2 receptors determines prostanoid synthesis/release in the hamster urinary bladder and that this effect is largely ascribable to structures present in the bladder mucosa. Prostanoids generated following NK2 receptor activation amplify the direct contractile effect of NK2 receptor agonists. This latter response is largely due to activation of L-type calcium channels (nifedipine-sensitive) although this source of calcium apparently is not essential for activation of prostanoid synthesis.
Tramontana
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Pharmacology Department, Menarini Ricerche, Florence, Italy.
Catalioto
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Lecci
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Maggi
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D000818:Animals; D006224:Cricetinae; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007660:Ketoprofen / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008647:Mesocricetus; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology*; D018041:Receptors, Neurokinin-2 / Q000819:agonists*; D013237:Stereoisomerism; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D010446:Peptide Fragments; D011453:Prostaglandins; D018041:Receptors, Neurokinin-2; C064218:neurokinin A (4-10), beta-Ala(8)-; D015288:Neurokinin A; D007660:Ketoprofen; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D009543:Nifedipine; D015232:Dinoprostone