Effects of Catecholamine Metabolites on Beta-Adrenoceptor-Mediated Relaxation of Smooth Muscle: Evaluation in Mouse and Guinea-Pig Trachea and Rat Aorta

The β-adrenoceptor (β-AR)-mediated pharmacological effects of Catecholamine (CA) metabolites are not well known. We examined the effects of seven CA metabolites on smooth muscle relaxation in mouse and guinea pig (GP) tracheas and rat thoracic aorta. Among them, metadrenaline (MA) significantly relaxed GP trachea (β₂-AR dominant), even in the presence of clorgiline, a monoamine oxidase-A inhibitor. In mouse trachea (β₁-AR dominant), normetadrenaline (NMA) and MA (10^-4 M each) apparently did not affect isoprenaline (ISO)-induced relaxation, but significantly inhibited it in the presence of clorgiline. ISO-induced relaxation was also unaffected by 3,4-dihydroxyphenylglycol (DHPG) (10^-4 M), but significant suppression was observed with the addition of 3,5-dinitrocatechol, a catechol-O-methyltransferase inhibitor. In GP trachea, NMA, MA, 3,4-dihydroxymandelic acid (DOMA), and DHPG (10^-4 M each) significantly augmented ISO-induced relaxation. However, in the presence of clorgiline plus 3,5-dinitrocatechol, both NMA and MA (10^-4 M) significantly suppressed ISO-induced relaxation. DHPG (10^-4 M) also significantly suppressed ISO-induced relaxation in the presence of 3,5-dinitrocatechol. In rat thoracic aorta, DHPG (10^-4 M) significantly suppressed relaxation induced by CGP-12177 A (a β₃-AR partial agonist) in the presence of 3,5-dinitrocatechol plus propranolol. Our findings indicate that 1) MA may possess β₂-AR agonistic action; 2) NMA and MA augment β₂-AR-mediated tracheal relaxation in the absence of CA metabolic inhibitors, though themselves possessing β₁-, β₂-AR antagonistic action (β₂ > β₁); 3) DHPG exhibits β₁-, β₂-, β₃-AR antagonistic action, and this is particularly marked for β₃-AR. Our observations may help explain some of the pathologies associated with pheochromocytoma, which is characterized by increased CA metabolite levels.