Mechanism of action of isoprenaline, isoxuprine, terbutaline and orciprenaline on gravid human isolated myometrium. Influence of the neuronal uptake process.

The present report analyzes the relative potencies and the mechanism of action of isoprenaline (Iso), isoxsuprine (Isox), terbutaline (Terb) and orciprenaline (Orc) on gravid isolated human myometrium in either spontaneous or in K+-induced contractions. Spontaneous activity was observed in 80% of the strips studied and the rate of contractions was 3.22 +/- 0.21 per 15 min. Dose-dependent inhibition of spontaneous contractions was observed with all the agonists. Preincubation with cocaine, 10(-5) M, shifted the inhibitory dose-response curves of Iso and Orc to the left, 16.6- and 23.3-fold respectively. The rank order of relative potencies was: Iso much greater than Isox greater than Terb greater than Orc in the absence and Iso much greater than Isox greater than Orc greater than Terb in the presence of cocaine. In the strips stimulated with K+, 80 mM, Isox, Terb and Orc produced only 20-30% inhibition while Iso was without effect. The incubation with propranolol (10(-8) -10(-4) M) did not modify the inhibitory response produced by Isox, Terb and Orc, but produced a parallel shift to the right of the Iso dose-response curve. Dose-ratio experiments yielded a straight line, and a Schild plot showed a pA2 value of 8.5 +/- 0.26 (slope = 2.76 +/- 0.47). The results with Iso confirm the existence of beta-adrenoreceptors in gravid human myometrium. On the other hand, in view of the low potency of Isox, Terb and Orc, and also the inability of propranolol to block their responses, it is suggested that the relaxant effects of these drugs are not mediated by beta-adrenoreceptors.