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Four structural analogues of oxytocin were investigated with regard to their oxytocic, milkejecting, pressor and diuretic/antidiuretic effects. In three of them the isoleucyl group of oxytocin was replaced by a phenylalanyl, leucyl, or valyl residue; in the fourth the asparaginyl group was replaced by a glutaminyl residue. Synthetic oxytocin and the international standard pituitary (posterior lobe) powder were used for comparison. Although the analogues showed marked differences in their oxytocic effects, there was a fairly good agreement between the results obtained on the isolated rat uterus and the blood pressure of the chicken for each polypeptide. The milk-ejection pressure test gave much higher values throughout. The pressor and antidiuretic activities of the four analogues showed no obvious correlation with the values obtained in the other tests. The valyl and the leucyl analogues also had a diuretic effect. The phenylalanyl analogue was remarkable for the close correspondence between its oxytocic and antidiuretic effects: practically identical values were obtained for the potency, whether measured on the rat uterus in vitro, the blood pressure in the chicken, the cat uterus in situ or water diuresis in the rat. The leucyl analogue showed an oxytocic activity on the cat uterus in situ or the rabbit mammary gland roughly 7 to 9 times as high as that measured by means of the conventional bioassay methods, such as the blood pressure of the chicken or the rat uterus in vitro. The glutaminyl analogue, the weakest of the whole series, had only a modest effect on the mammary gland. The valyl analogue was the most interesting of the new polypeptides. Its oxytocic action on the cat uterus in situ and its milk-ejecting effect were greater than that of synthetic oxytocin, whereas its antidiuretic and pressor effects were less. In cats and rats, the uterine effect was stronger in situ than in vitro. There were also distinct species differences between cats, rabbits, and rats in their sensitivity to valyl-oxytocin.

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1. Six ergot alkaloids were tested for their effect on vascular resistance and for a-adrenergic blocking activity on the innervated perfused hind limib of the dog. The results were compared with those obtained earlier for three compounds of the ergotamine group. 2. Ergostine, dihydroergostine, 1-methylergostine and dihydroergocristine resembled ergotamine, dihydroergotamine and 1-methylergotamine in eliciting vasoconstriction at low vascular resistance and vasodilatation at high vascular resistance. The changeover occurred at the following " inversion points ": ergostine and dihydroergostine as with ergotamine and dihydroergotamine at about 4 R.U.; 1-methylergostine as with l-methylergotamine at aibout 2.3 R.U.; dihydroergocristineatabout 19R.U. [1 R.U.=1 resistanceunit=1 mmHg/ml. per min.] 3. 1-methyldihydroergocristine consistently elicited vasodilatation (for initial vascular resistances down to 1-3 R.U.) and 5'-methylergoalanine always caused vasoconstriction (for initial values up to 5.8 R.U.). 4. Ergostine and 5'-methylergoalanine had the most powerful vasoconstrictor effect, which was of the same order of magnitude as that of ergotamine. Dihydroergostine, like dihydroergotamine, was considerably less active. Both 1-methylergostine and 1-methylergotamine elicited only weak vasoconstriction. Moreover, when the initial vascular resistance exceeded the critical inversion value, they elicited only weak vasodilatation. Dihydroergocristine and I-methyldihydroergocristine had the least effect on vascular resistance. 5. The increase in vascular resistance by noradrenaline was inhibited in a dose-dependent manner by all the ergot alkaloids investigated. Ergostine, 5'-methylergoalanine and ergotamine had the greatest a-adrenergic blocking activity and 1-methylergostine, 1-methyldihydroergocristine and 1-methylergotamine the weakest. The activity of dihydroergostine, dihydroergocristine and dihydroergotamine fell between these two extremes. 6. No correlation was found between the qualitative effect of these ergot alkaloids on vascular resistance (inversion point) and (a) their quantitative effect on this parameter or (b) their a-adrenergic blocking activity. Determination of the inversion point thus provides additional pharmacological information on the vasoactive properties of the ergot alkaloids.