In experiments on isolated rat uteri the relation was studied between the mechanical effects of catecholamines and the level of adenosine 3′,5′-monophosphate (cAMP). Adrenaline (1–100 ng/ml) caused relaxation of isolated rat uteri and a highly significant increase in the tissue cAMP concentration; both relaxation and cAMP increase were blocked by propranolol or butoxamine but unaffected by phenoxybenzamine. The rise in cAMP level was maintained in a Ca-free solution when the muscle could not contract. The stimulation of α-receptors of propranolol-pretreated uteri induced contractions but it caused no change in the cAMP concentration. cAMP level, increased by a previous application of isoproterenol, remained unchanged when the uterus contracted after application of oxytocin, propranolol, or propranolol with adrenaline. cAMP levels remained elevated after previous adrenaline whether oxytocin dose–effect curves were still shifted to the right or were shifted back by subsequent propranolol. Adrenaline decreased significantly the ATP concentration in the uterus. The effect persisted with a propranolol blockade but was reversed to an increase by pretreatment with phenoxybenzamine or in a Ca-free solution. We conclude that the level of cAMP in the uterus is controlled by mechanisms related to β-receptors but that α-receptor mechanisms do not affect cAMP levels. Also the level of cAMP is not the primary determinant of uterine motility.

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Theophylline, diazoxide, and papaverine in low concentrations relaxed the uterus with minimal or no elevation of cyclic AMP (cAMP) levels. In higher concentrations, theophylline relaxed the uterus and increased its cAMP levels, but imidazole reversed the increase in cAMP without causing recontraction. Imidazole and NaF caused uterine contractures but did not detectably decrease cAMP levels until several minutes after the onset of contractures. The uterine relaxations produced by theophylline and/or dibutyryl cAMP in amounts which increased uterine cAMP were not reversed by propranolol. These results eliminate the possibility that propranolol interfered with a relaxant action of cAMP. Along with previous data, these results also show that uterine contractile activity was not determined primarily by the general levels of cAMP and that phosphodiesterase activity in the uterus was insufficient to rapidly affect these cAMP levels. Also, substances like theophylline, diazoxide, and papaverine, postulated to inhibit phosphodiesterase activity, did not bring about their relaxant effects by this mechanism.

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An antagonist to neurohypophvsial hormones quiescent uterus by the intravenous infusion of oxytocin was interrupted by intravenous injections of the analogue. 5. The response of the isolated strip of rat mammary gland to the analogue depended on whether or not magnesium was present in the bath solution. In the presence oe.this ion, the analogue generally caused an increase in tension; in its absence, it acted as a pure antagonist. As on the isolated uterus, oxytocin and vasopressin were equally inhibited, and the analogue caused a parallel displacement of the log dose-response curve for oxytocin. With 0 9 mm Ca and 1I0 mm Mg, the mean pA2 value (2 min contact) was 6-28 +0-08 (S.E.) 6. In the lactating rat, the analogue inhibited the milk-ejection response to oxytocin and vasopressin but not that to acetylcholine, bradykinin or 5-hydroxytryptamine. A milk-ejection response to the analogue itself was seen occasionally with retrograde arterial but not with intravenous injections. 7. The analogue inhibited the avian depressor response to oxytocin and the rat pressor response to vasopressin. 8. On all assay preparations, the degree of inhibition caused by the analogue was dependent on the dose, and the inhibition could be surmounted by increasing the dose of agonist. Recovery usually occurred within 15 min. These features, together with the parallel displacement of the dose-response curve for oxytocin on the isolated uterus and mammary strip, and the equal inhibition of the responses to oxytocin and vasopressin, suggest that carbamoyl-methyloxytocin acts as a specific competitive inhibitor of the neurohypophysial hormones. 9. The structure-activity relationships of analogues of oxytocin having substituents in the terminal amino and phenolic hydroxyl groups, and some practical applications of the carbamoyl-methyl analogue, are discussed.