title: Pharmacological characterization of tachykinin NK2 receptors on isolated human urinary bladder, prostatic urethra and prostate.
abstract: The contractile effect of two highly potent, selective and peptidase-resistant neurokinin (NK) 1 and NK2 receptor agonists, namely delta-Aminovaleryl-[L-Pro9, N-MeLeu10]substance P-(7-11) (GR 73632) and [Lys3, Gly8-R-gamma-lactam-Leu9]NKA-(3-10) (GR 64349), respectively, was investigated on smooth muscle strips dissected from specimens of human detrusor, prostatic urethra and prostate. Furthermore, the potencies of two peptidic NK2 receptor antagonists, GR 87389 L 659,837, in antagonizing GR 64349-induced contractions were compared in these three tissues. In human detrusor muscle the rank order of agonist potency was: [beta Ala8 (NKA-(4-10)] > GR 64349 >> NKA-(4-10) >> SP = GR 73632 >> SP-methylester. The NK2 receptor antagonist, GR 87389, antagonized GR 64349-induced contractions in a competitive manner, whereas L 659,837 was a noncompetitive antagonist. In the prostatic urethra the rank order of agonist potency was GR 64349 > NKA-(4-10) > SP > GR 73632, whereas in the prostate it was: GR 64349 >> [beta Ala8 (NKA-(4-10)] > NKA-(4-10) > SP; GR 73632 was ineffective up to 30 microM. In the prostatic urethra and in the prostate GR 87389 was a noncompetitive antagonist with a potency similar to that exhibited in the detrusor. On the contrary, L 659,837 appeared to be a competitive antagonist in the prostate and in the prostatic urethra, having approximately the similar potency in these two tissues. The selective NK3 agonist senktide was ineffective up to 30 microM in all three tissues. These results are discussed in the view of the proposed NK2 receptor subtypes and considering possible therapeutic implications in the treatment of urinary bladder disorders.
authors.affiliation: Department of Pharmacology, Glaxo Research Laboratories, Verona, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Palea
authors.forename: M
authors.initials: M
authors.lastname: Corsi
authors.forename: W
authors.initials: W
authors.lastname: Artibani
authors.forename: E
authors.initials: E
authors.lastname: Ostardo
authors.forename: C
authors.initials: C
authors.lastname: Pietra
mesh_terms: D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology; D010803:Physalaemin / Q000031:analogs & derivatives / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects* / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000187:drug effects* / Q000502:physiology; D013373:Substance P / Q000494:pharmacology; D014521:Urethra / Q000187:drug effects* / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
chemical_list: D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; C073362:L 659837; C079014:GR 82334; D010803:Physalaemin; D013373:Substance P