PHARMACOLOGICAL CHARACTERIZATION OF TACHYKININ NK2 RECEPTORS ON ISOLATED HUMAN URINARY-BLADDER, PROSTATIC URETHRA AND PROSTATE

The contractile effect of two highly potent, selective and peptidase-r esistant neurokinin (NK) 1 and NK2 receptor agonists, namely delta-Ami novaleryl-[L-Pro(9), N-MeLeu(10)]substance P-(7-11) (GR 73632) and [Ly s(3), Gly(8)-R-gamma-lactam-Leu9]NKA-(3-10) (GR 64349), respectively, was investigated on smooth muscle strips dissected from specimens of h uman detrusor, prostatic urethra and prostate. Furthermore, the potenc ies of two peptidic NK2 receptor antagonists, GR 87389 and L 659,837, in antagonizing GR 64349-induced contractions were compared in these t hree tissues. In human detrusor muscle the rank order of agonist poten cy was: [beta Ala(8) (NKA-(4-10)] > GR 64349 much greater than NKA-(4- 10) much greater than SP = GR 73632 much greater than SP-methylester. The NK2 receptor antagonist, GR 87389, antagonized GR 64349-induced co ntractions in a competitive manner, whereas L 659,837 was a noncompeti tive antagonist. In the prostatic urethra the rank order of agonist po tency was GR 64349 > NKA-(4-10) > SP GR 73632, whereas in the prostate it was: GR 64349 much greater than [beta Ala(8) (NKA-(4-10)] > NKA-(4 -10) > SP; GR 73632 was ineffective up to 30 mu M. In the prostatic ur ethra and in the prostate GR 87389 was a noncompetitive antagonist wit h a potency similar to that exhibited in the detrusor. On the contrary , L 659,837 appeared to be a competitive antagonist in the prostate an d in the prostatic urethra, having approximately the similar potency i n these two tissues. The selective NK3 agonist senktide was ineffectiv e up to 30 mu M in all three tissues. These results are discussed in t he view of the proposed NK3 receptor subtypes and considering possible therapeutic implications in the treatment of urinary bladder disorder s.