Alfuzosin, a selective alpha 1-adrenoceptor antagonist in the lower urinary tract.
1. Phenylephrine-induced contractions of rabbit isolated trigone and urethra were antagonized in a competitive manner by alfuzosin (pA2 7.44 and 7.30, respectively) and prazosin. 2. The characteristics of [3H]-prazosin binding to human prostatic adenoma tissue were evaluated. [3H]-prazosin was potently displaced by alpha 1-adrenoceptor specific agents including alfuzosin, its (+)- and (-)-enantiomers and prazosin (IC50 0.035, 0.023, 0.019 and 0.004 microM, respectively), but only weakly by alpha 2-adrenoceptor selective agents, for example, yohimbine (IC50 = 6.0 microM). 3. In the pithed rat, alfuzosin (0.03-0.3 mg kg-1, i.v.) markedly inhibited pressor responses produced by the alpha 1-selective agonist, cirazoline but inhibited only slightly responses to the alpha 2-selective agonist, UK 14,304. Alfuzosin (1 mg kg-1, i.v.) had minimal effects against responses mediated by stimulation of prejunctional alpha 2-receptors (UK 14,304-induced inhibition of sympathetic tachycardia). 4. In the anaesthetized cat, alfuzosin (0.001-1 mg kg-1, i.v.) and prazosin (0.001-0.3 mg kg-1, i.v.) produced dose-related inhibition of the increases in urethral pressure caused by stimulation of sympathetic hypogastric nerves. Prazosin was approximately 5 fold more potent than alfuzosin. When phenylephrine was employed to induce urethral and vascular alpha 1-mediated tone simultaneously, prazosin inhibited both stimuli with similar potency whereas alfusozin was 3-5 fold more potent against elevated urethral pressure. This functional uroselectivity of alfuzosin was more evident by the intraduodenal route, since doses of 0.03 and 0.1 mg kg-1 alfuzosin inhibited urethral pressure with minimal effects on arterial blood pressure. 5. Alfuzosin is a potent selective alpha1-adrenoceptor antagonist in tissues of the lower urinary tract including the human prostate. This provides a pharmacological basis for its use in the treatment of benign prostatic hypertrophy.
Lefèvre-Borg
F
F
Department of Biology, Synthélabo Recherche, Bagneux, France.
O'Connor
S E
SE
Schoemaker
H
H
Hicks
P E
PE
Lechaire
J
J
Gautier
E
E
Pierre
F
F
Pimoule
C
C
Manoury
P
P
Langer
S Z
SZ
D000232:Adenofibroma / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002415:Cats; D003655:Decerebrate State / Q000503:physiopathology; D004558:Electric Stimulation; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011224:Prazosin / Q000493:pharmacokinetics / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013564:Sympathetic Nervous System / Q000502:physiology; D014407:Tumor Cells, Cultured; D014521:Urethra / Q000187:drug effects; D014551:Urinary Tract / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D011799:Quinazolines; D010656:Phenylephrine; C047638:alfuzosin; D011224:Prazosin