Abstract
This study was performed to characterize the β-adrenoceptor population in rabbit isolated corpus cavernosum (RbCC) by using nonselective and selective β-adrenoceptor agonists and antagonists in functional assays. Metaproterenol, ritodrine, fenoterol, and 8-hydroxy-5-[(1R)-1-hydroxy-2-[N-[(1R)-2-(ρ-methoxyphenyl)-1-methylethyl]amino]ethyl]carbostyril (TA 2005) (3–100 nmol each) dose dependently relaxed the RbCC preparations. These relaxations were markedly reduced by Nω-nitro-l-arginine methyl ester (l-NAME; 10 μM) and 1H-[1,2,4]-oxadiazolo-[4,3,-a]quinoxalin-1-one (ODQ) (10 μM), whereas the adenylyl cyclase inhibitor SQ 22,536 [9-(2-tetrahydrofuryl) adenine] (10 μM) had no effect. In contrast, neither l-NAME nor ODQ affected the isoproterenol-induced RbCC relaxations, but SQ 22,536 abolished this response. Sildenafil (1 μM) significantly potentiated the relaxations induced by β2-agonists without affecting the isoproterenol-evoked relaxations. Rolipram (10 μM) enhanced the relaxations elicited by isoproterenol but had no effect on those induced by the selective β2 agonists. Propranolol and (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride (ICI 118,551) determined a rightward shift in the concentration-response curves to isoproterenol in a noncompetitive manner with a reduction of maximum response at the highest antagonist concentration, with the slope values significantly different from unity. Propranolol and ICI 118,551 had no effect on the relaxations elicited by fenoterol, TA 2005, metaproterenol, and ritodrine. Atenolol and 1-[2-((3-carbamoyl-4-hydroxy)phenoxy) ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]-2-propanol methanesulfonate (CGP 20712A) (0.1–10 μM) failed to affect the relaxations induced by all tested β-adrenoceptor agonists. Our study revealed the existence of two atypical β-adrenoceptors in the rabbit erectile tissue. Isoproterenol relaxes the rabbit cavernosal tissue by activating atypical β-adrenoceptors coupled to adenylyl cyclase pathway, whereas the selective β2-adrenoceptor agonists relax the RbCC tissue through another atypical β-adrenoceptor subtype coupled to nitric oxide release from the sinusoidal endothelium.
Footnotes
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ABBREVIATIONS: RbCC, rabbit corpus cavernosum; TA 2005, 8-hydroxy-5-[(1R)-1-hydroxy-2-[N-[(1R)-2-(ρ-methoxy-phenyl)-1-methylethyl]amino]ethyl]carbostyril; BRL 37344, (±)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid; l-NAME, Nω-nitro-l-arginine methyl ester; ODQ, 1H-[1,2,4]-oxadiazolo-[4,3,-a]quinoxalin-1-one; SQ 22,536, 9-(2-tetrahydrofuryl) adenine; CGP 20712A (1-[2-((3-carbamoyl-4-hydroxy)phenoxy)ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]-2-propanol methanesulfonate); ICI 118,551, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride; GTN, glyceryl trinitrate; NO, nitric oxide; ACh, acetylcholine; TTX, tetrodotoxin; PDE, phosphodiesterase.
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C.E.T. is supported by Fundação de Amparo à Pesquisa do Estado de São Paulo.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.062026.
- Received October 23, 2003.
- Accepted January 23, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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