ADRENERGIC RECEPTORS IN HEART MUSCLE: RELATIONS AMONG FACTORS INFLUENCING THE SENSITIVITY OF THE CAT PAPILLARY MUSCLE TO CATECHOLAMINES

¹ Department of Pharmacology, Harvard Medical School, Boston, Massachusetts; Department of Pharmacology, Mayo Graduate School of Medicine, Rochester, Minnesota

The sensitizing effects of U-0521, a catechol-O-methyltransferase (COMT) inhibitor, and of phenoxybenzamine on the responses of isolated cat papillary muscles to norepinephrine and isoproterenol have been studied. Field stimulation and tyramine were used for releasing endogenous norepinephrine. U-0521 potsntiated the effects of (-)-isoproterenol and tyramine but not those of (-)-norepinephrine or of field stimulation. In several situations in which neuronal uptake or reuptake of norepinephrine was inhibited (in the presence of cocaine or tyramine) or was relatively ineffective (newborn kittens), U-0521 sensitized the muscles to exogenous and endogenously released norepinephrine. However, in the presence of (±)-propranolol (2 x 10^-8 M), higher concentrations of norepinephrine were required to obtain a given effect, and although cocaine still sensitized the muscles to norepinephrine, no potentiation of norepinephrineby U-0521 was detected. These results indicate that: 1) neuronal uptake of norepinephrine appears to predominate in limiting the concentration of norepinephrine at the beta receptors so that the action of COMT is concealed; and 2) in the absence of neuronal uptake, inhibition of COMT apparently results in a significant increase of norepinephrine concentration at the beta receptors only if the concentration of norepinephrine in the bath is relatively low. Phenoxybensamine potentiated isoproterenol, norepinephrine and the effect of field stimulation. In the presence of phenoxybensamine, U-0521 did not sanitize the muscles to the effects of isoproterenol, norepinephrine or field stimulation. The increase in supersensitivity to isoproterenol induced by either phenoxybensamine or U-0521 was reduced to about one-third when 31-times higher concentrations of isoproterenol were used in the presence of propranolol. These observations are consistent with the view that phenoxybenzamine prevents the access of isoproterenol and exogenous and endogenously released norepinephrine to the metabolizing COMT. In the presence of 10^-6 M (±)-propranolol, phenoxybenzamine potentiated isoproterenol but irreversibly antagonized norepinephrine; sensitization to norepinephrine by phenoxybenzamine may be underestimated because of this antagonism.