The stereoselective O-methylation of isoprenaline in the isolated rabbit thoracic aorta

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Abstract
1. This investigation examined the stereoselective nature of the steroid-sensitive extraneuronal O-methylation process for the isomers of isoprenaline in the rabbit aorta. 2. The rate of O-methylation of (-)- and (+)-isoprenaline was linear with substrate concentration in the range 0.24 to 4.7 μmol·l−1. There was marked preference for the O-methylation of (-)-isoprenaline rather than (+)-isoprenaline at low (−1) substrate concentrations. In contrast, at concentrations equal to or greater than 9.4 μmol·l−1 the rates of O-methylation of (-)- and (+)-isoprenaline were similar. 3. Phenoxybenzamine (30 μmol·l−1) inhibited but did not abolish the O-methylation of both (-)- and (+)-isoprenaline when the isomers were present in a concentration range of 0.24 μmol·l−1 to 9.4 μmol·l−1. Phenoxybenzamine did not significantly influence the O-methylation of either (-)- or (+)-isoprenaline when the isomers were present at a concentration of 24 μmol·l−1. 4. Deoxycorticosterone acetate (DOCA) produced an equipotent and marked inhibition of the O-methylation of both (-)- and (+)-isoprenaline at a low (0.24 μmol·l−1) substrate concentration. When higher substrate concentrations were used, there was a significantly greater resistance to the inhibition of O-methylation of (-)-isoprenaline than was the case for (+)-isoprenaline. At a concentration of 9.4 μmol·l−1, the steroid failed to inhibit the O-methylation of (-)-isoprenaline but was effective in inhibiting the O-methylation of (+)-isoprenaline. 5. The selective inhibitory influence of DOCA on the O-methylation of (+)-isoprenaline was unaltered in cocainetreated tissues and in tissues incubated with propranolol. The latter observations suggest that neuronal uptake mechanisms and beta adrenoceptor mediated processes were not involved in the selective actions of DOCA upon the (+)-isomer of isoprenaline. 6. It is concluded that the phenoxybenzamine- and steroid-sensitive extraneuronal O-methylation of isoprenaline is stereoselective. Moreover the resistance of O-methylation to phenoxybenzamine and DOCA particularly at high substrate concentration is due to non-stereoselective diffusional entry of isoprenaline to a site or sites of O-methylation.

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