Noradrenaline contractions of human prostate mediated by alpha 1A-(alpha 1c-) adrenoceptor subtype

1. The subtype of alpha 1-adrenoceptor mediating contractions of human prostate to noradrenaline was characterized by use of a range of competitive and non-competitive antagonists. 2. Contractions of the prostate to either noradrenaline (pD2 5.5), phenylephrine (pD2 5.1) or methoxamine (pD2 4.4) were unaltered by the presence of neuronal and extraneuronal uptake blockers. Noradrenaline was about 3 and 10 times more potent than phenylephrine and methoxamine respectively. Phenylephrine and methoxamine were partial agonists. 3. Pretreatment with the alkylating agent, chlorethylclonidine (10(-4M) shifted the noradrenaline concentration-contraction curve about 3 fold to the right and depressed the maximum response by 31%. This shift is 100 fold less than that previously shown to be produced by chlorethylclonidine under the same conditions on alpha 1B-adrenoceptor-mediated contractions. 4. Cumulative concentration-contraction curves for noradrenaline were competitively antagonized by WB 4101 (pA2 9.0), 5-methyl-urapidil (pA2 8.6), phentolamine (pA2 7.6), benoxathian (pA2 8.5), spiperone (pA2 7.3), indoramin (pA2 8.2) and BMY 7378 (pA2 6.6). These values correlated best with published pKi values for their displacement of [3H]-prazosin binding on membranes expressing cloned alpha 1c-adrenoceptors and poorly with values from cloned alpha 1b- and alpha 1d-adrenoceptors. 5. The good correlation between the functional data on the prostate and the binding data on the expressed alpha 1c-subtype clone for the affinities of the competitive antagonists suggests that they are the same subtype. As the expressed alpha 1c-adrenoceptor clone corresponds to the alpha 1A-adrenoceptor expressed in tissues, contraction of the human prostate to noradrenaline is therefore mediated by an alpha 1A-adrenoceptor.