1 The pharmacological pro®le was studied of MEN 11420, or cyclo{[Asn(b-D-GlcNAc)-Asp-Trp-PheDap-Leu]cyclo(2b-5b)}, a glycosylated derivative of the potent, selective, conformationally-constrained tachykinin NK 2 receptor antagonist MEN 10627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2b-5b)). and ion channels. 4 In the rabbit isolated pulmonary artery and rat urinary bladder MEN 11420 potently and competitively antagonized tachykinin NK 2 receptor-mediated contractions (pK B =8.6+0.07, n=10, and 9.0+0.04, n=12; Schild plot slope=71.06 (95% c.l.=71.3; 70.8) and 71.17 (95% c.l.=71.3; 71.0), respectively). MEN 11420 produced an insurmountable antagonism at NK 2 receptors in the hamster trachea and mouse urinary bladder. However, in both preparations, the eect of MEN 11420 was reverted by washout and an apparent pK B of 10.2+0.14, n= 9, and 9.8+0.15, n=9, was calculated in the hamster trachea and mouse urinary bladder, respectively. 5 MEN 11420 showed low anity (pK B 56) at guinea-pig and rat tachykinin NK 1 (guinea-pig ileum and rat urinary bladder) and NK 3 (guinea-pig ileum and rat portal vein) receptors. On the whole, the anities (potency and selectivity) showed by MEN 11420 for dierent tachykinin receptors, measured either in binding or in functional bioassays, were similar to those shown by the parent compound, MEN 10627. ) and intraduodenal (100 ± 300 nmol kg 71 ) administration of MEN 11420. MEN 11420 was more potent (about 10 fold) and longer lasting than its parent compound MEN 10627, possibly due to a greater metabolic stability. 7 A dose of MEN 11420 (100 nmol kg 71 , i.v.), that produced potent and long lasting inhibition of the contraction of the rat urinary bladder induced by challenge with the NK 2 selective receptor agonist [bAla 8 ]neurokinin A(4 ± 10) (10 ± 300 nmol kg 71 ), was without eect on the responses produced by the NK 1 receptor selective agonist [Sar 9 ]substance P sulphone (1 ± 10 nmol kg 71 ). 8 These ®ndings indicate that MEN 11420 is a potent and selective tachykinin NK 2 receptor antagonist. The introduction of a sugar moiety did not produce major changes in the anity pro®le of this antagonist as compared to MEN 10627, but markedly improved its in vivo potency and duration of action. With these characteristics, MEN 11420 is a suitable candidate for studying the pathophysiological signi®cance of tachykinin NK 2 receptors in humans.
In conclusion, the findings of the present study indicate that nebivolol increases NO also by decreasing its oxidative inactivation.
1 Prostanoids, generated from cyclooxygenase (COX) isoenzymes, play a role in the physiological function of the lower urinary tract and are important mediators of in¯ammatory hyperalgesia. The present work evaluates the e ects of the COX-1/COX-2 inhibitor dexketoprofen as well as of a selective COX-2 inhibitor, NS-398, on urodynamic function following endotoxin (LPS) or cyclophosphamide (CYP)-induced in¯ammation of the urinary bladder. 2 The application of arachidonic acid (330 mg rat 71 ) onto the serosal surface of the urinary bladder in control rats elicited bladder contractions which could be blocked in a dose-dependent manner by dexketoprofen (0.1 ± 3 mg kg 71 , i.v.) but not by NS-398 (0.2 ± 6 mg kg 71 , i.v.). 3 Dexketoprofen (3 mg kg 71 , i.v.) decreased the micturition frequency and increased the pressure threshold for triggering the micturition either when administered within 15 min or 3 h following surgery in control animals. NS-398 (6 mg kg 71 , i.v.) decreased the micturition frequency and increased the pressure threshold when administered 3 h but not 15 min following surgery. 4 Administration of LPS (2 mg kg 71 , i.v., 90 ± 120 min) increased both the micturition frequency and the pressure threshold for triggering the micturition re¯ex. Changes in urodynamic parameters induced by LPS were prevented by doses of either dexketoprofen (1 mg kg 71 , i.v.) or NS-398 (2 mg kg 71 , i.v.) which were ine ective in control animals. 5 Pretreatment with CYP (150 mg kg 71 , i.p., 48 h) increased the micturition frequency, pressure threshold, and the minimal intravesical pressure but decreased the mean amplitude of micturition contractions. In CYP-treated rats, dexketoprofen (1 mg kg 71 , i.v.) or NS-398 (2 mg kg 71 , i.v.) blocked the CYP-induced urodynamic changes with exception of the micturition contraction amplitude. 6 These results indicate that COX-1 may be involved in modulating the threshold for activating the micturition re¯ex in the normal rats and also demonstrates that inhibition of COX-2 prevents or reverses the urodynamic changes associated with bladder in¯ammation induced either by surgery, LPS or CYP treatments.
Substance P (SP) and neurokinin A (NKA) are synthesized by enteric cholinergic motorneurons that project to the longitudinal and circular muscle of the mammalian intestine. Thus, acetylcholine, SP, and NKA are the excitatory neuromuscular transmitters in the intestine. Tachykinin NK1 and NK2 receptors are expressed by smooth muscle cells in most regions of the intestine: the corelease of SP and NKA from nerves thus realizes paradigms of tachykininergic cotransmission. Examples have been found in which a cooperative model can be applied to account for the action of SP-NKA acting at NK1 and NK2 receptors (e.g., circular muscle of guinea-pig duodenum), as well as examples in which the message produced by activation of the two receptors diverges sharply in producing responses that have a markedly different time course and use different effector systems (e.g., circular muscle of guinea-pig colon). NK3 receptors are expressed on both excitatory and inhibitory motor neurons: indirect contractions (via release of acetylcholine and tachykinins) and relaxations (via release of nitric oxide) can be evoked in the gut by selective stimulation of NK3 receptors. Although a role of NK3 receptors in certain enteric reflexes has been evidenced, the importance of this system in mediating hexamethonium-resistant enteric transmission appears less important than previously speculated.
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