The alpha 1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human alpha 1c subtype.
Molecular cloning studies have revealed the existence of three subtypes of alpha 1-adrenergic receptors. However, the link between any individual subtype and its functional role in the body has remained elusive. In an effort to bridge the gap between molecular biology and pathophysiology, we have chosen a model smooth muscle system, the human prostate, and investigated the role of alpha 1 subtypes in this tissue. To determine which alpha 1-adrenergic receptor subtype mediates the contractile response of the human prostate, we first studied the pharmacological properties of three cloned human alpha 1 subtypes (alpha 1a/d, alpha 1b, and alpha 1c). Prazosin, terazosin, doxazosin, alfuzosin, and abanoquil showed no selectivity for the human alpha 1 subtypes. WB-4101 and 5-methylurapidil showed a rank order of potency of alpha 1c > alpha 1a/d >> alpha 1b. Indoramin and (+)-niguldipine were selective for the alpha 1c-adrenergic receptor, with at least 10-fold lower affinity at either alpha 1a/d or alpha 1b subtypes. SK&F104856 was found to be 6-fold more potent at the alpha 1a/d receptor subtype than at alpha 1b- or alpha 1c-adrenergic receptors. We next determined the potency of these antagonists to inhibit the phenylephrine-induced contraction of human prostatic tissue in vitro. The potencies of indoramin, 5-methylurapidil, and SK&F104856 to inhibit the contractile response and to displace [3H]prazosin from the cloned human alpha 1c subtype were similar. Our data suggest that the alpha 1 receptor that mediates the contraction of human prostate smooth muscle has the pharmacological properties of the cloned human alpha 1c-adrenergic receptor. The findings of the present study suggest that selective alpha 1c-adrenergic receptor antagonists may be clinically more efficacious and better tolerated agents for the treatment of symptomatic benign prostatic hyperplasia.
Forray
C
C
Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652.
Bard
J A
JA
Wetzel
J M
JM
Chiu
G
G
Shapiro
E
E
Tang
R
R
Lepor
H
H
Hartig
P R
PR
Weinshank
R L
RL
Branchek
T A
TA
D000818:Animals; D016466:CHO Cells; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D006224:Cricetinae; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D011467:Prostate / Q000502:physiology*; D011942:Receptors, Adrenergic, alpha / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins
D011942:Receptors, Adrenergic, alpha; D011994:Recombinant Proteins; D010656:Phenylephrine; C051731:chlorethylclonidine; D003000:Clonidine