Normetadrenaline and metadrenaline induce rat thoracic aorta/prostate contraction via α_1D/1A-adrenoceptor stimulation

Certain catecholamine metabolites exert significant pharmacological effects. Herein, we evaluated the pharmacological activities of catecholamine metabolites in the rat thoracic aorta, prostate, and spleen to determine whether these metabolites affect the contractile functions of smooth muscle tissue via direct action on α-adrenoceptors and α-adrenoceptor subtypes. Among the catecholamine metabolites examined, normetadrenaline and metadrenaline (10^-4 M each) produced relatively strong contractions in the rat thoracic aorta. Maximum aortic contractions induced by normetadrenaline (≈70% of phenylephrine (3 × 10^-7 M)-induced contractions) and metadrenaline (≈45%) were significantly smaller than those induced by phenylephrine (≈95%). Normetadrenaline and metadrenaline (10^-4 M each) inhibited phenylephrine (3 × 10^-7 M)-induced aortic contractions, which were not affected by propranolol (10^-6 M), by 5-20%. Normetadrenaline- and metadrenaline (3 × 10^-5 M each)-induced aortic contractions were strongly inhibited by prazosin (10^-8 M; an α₁-adrenoceptor antagonist) and BMY 7378 (10^-8-10^-7 M; a selective α_1D-adrenoceptor antagonist). Metadrenaline (3 × 10^-5 M)-induced aortic contractions were also significantly inhibited by silodosin (10^-9 M; a selective α_1A-adrenoceptor antagonist). Normetadrenaline and metadrenaline (3 × 10^-5 M each) caused silodosin (10^-9 M)-sensitive prostate contractions but did not cause a prominent spleen contraction. Maximum prostate contractions induced by metadrenaline (≈100% of phenylephrine (3 × 10^-5 M)-induced contractions) were nearly identical to those induced by phenylephrine (≈100%) but were significantly larger than those induced by normetadrenaline (≈80%). These findings suggest that normetadrenaline and metadrenaline act as a partial α_1D/α_1A-adrenoceptor agonist and partial α_1D-adrenoceptor/full α_1A-adrenoceptor agonist, respectively, functioning as adrenaline system stabilizers in α_1D/α_1A-adrenoceptor-abundant smooth muscle tissues.