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-resistant neurokinin (NK) 1 and NK2 receptor agonists, namely delta-Aminovaleryl-[L-Pro(9), N-MeLeu(10)]substance P-(7-11) (GR 73632) and [Lys(3), Gly(8)-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 and 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 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 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 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 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 mu M in all three tissues. These results are discussed in the view of the proposed NK3 receptor subtypes and considering possible therapeutic implications in the treatment of urinary bladder disorders.