Abstract
The proerectile properties of three novel α1-adrenoceptor (α1-ADR) antagonists with different profiles of selectivity for the α1-ADR subtypes have been evaluated in anesthetized rats and dogs on intracavernous (IC) injection, in comparison with prazosin and phentolamine. In rats, the tested compounds decreased blood pressure (BP) and increased IC pressure (ICP), as well as the ratio ICP/BP. Rec 15/2841 (α1a- plus α1L-ADR-selective antagonist) and Rec 15/2615 (α1b-ADR selective) were the most potent compounds. The ICP/BP ratios calculated after injection of Rec 15/3039 (α1d-ADR selective) were not markedly different from those observed after vehicle injection. Prazosin and phentolamine proved poorly active, their main effect being hypotension. Approximate ED25 values (dose of compound in micrograms inducing 25% increase of ICP/BP ratio) were Rec 15/2615 (22 μg/kg) >= Rec 15/2841 (29 μg/kg) > prazosin (136 μg/kg) > phentolamine (1298 μg/kg) > Rec 15/3039 (9600 μg/kg). Submaximal stimulation of the cavernous nerve elicited an ICP rise whose amplitude was not altered by Rec compounds. In contrast, prazosin and phentolamine decreased this ICP rise. All compounds but 15/3039 induced significant increase of the ICP/BP ratio in dogs. Rec 15/2615 proved to be the most interesting compound, inducing significant increases of ICP/BP at doses practically devoid of effects on BP. The rank order of potency in dog in increasing the ICP/BP ratio was similar to that observed in rats. Only at the highest doses tested, all compounds, except Rec 15/3039, decreased the ICP rise elicited by submaximal stimulation of the cavernous nerve. Our data demonstrate that the α1b- and α1L-ADR subtypes are functionally relevant for the erectile function in these models, and that α1b- and/or α1L-ADR subtypes selective antagonists could represent a real advantage in erectile dysfunction therapy.
Footnotes
-
Send reprint requests to: Giorgio Sironi, Pharmaceutical R&D Division, RECORDATI S.p.A., Via Civitali 1, 20148 Milano, Italy. E-mail: sironi.g{at}recordati.it
-
↵1 Current address: Laboratoire de Neurobiologie des Fonctions Végétatives, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas, Cedex, France.
-
↵2 Current address: Service d'Urologie, C.H.U. de Bicêtre, Assitance Publique-Hôpitaux de Paris 78 rue du Général Leclerc 94270 Le Kremlin-Bicêtre, France.
- Abbreviations:
- IC
- intracavernous
- NA
- noradrenaline
- ADR
- adrenoceptor
- CC
- corpus cavernosum
- ICP
- intracavernous pressure
- BP
- blood pressure
- CN
- cavernous nerve
- PN
- pelvic nerve
- CEC
- chloroethylclonidine
- SBP
- systolic blood pressure
- DBP
- diastolic blood pressure
- PGE1
- prostaglandin E1
- Received June 17, 1999.
- Accepted November 9, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|