The antidiuretic action of a number of vasopressin analogues has been measured in the rat and man in water diuresis. These analogues had the following categories of structural alteration: a) substitution of -CH2CH2-(dicarba) and -SCH2-(6-monocarba) for the natural -SS- bridge between residues 1 and 6, b) changes in the nature of the C-terminal tripeptide produced by substitution of D-arginine and L-Nalpha-methylarginine for L-arginine in sequence position 8 and L-leucine for proline in position 7, and c) combinations of a and b. In addition, a highly active analogue which results when valine is substituted for glutamine in position 4 was tested. Trained, unanesthetized rats and normal human volunteers were complemented by a volunteer patient with posttraumatic diabetes insipidus (DI) in the total group of experimental subjects. The only change in the C-terminal tripeptide which was associated with a high antidiuretic action was D-Arg substitution. The meArg and Leu analogues showed low to very little activity and no signs of antidiuretic antagonist action. All of the carba analogues showed both high potency and prolongation of antidiuretic action in the following order (for both potency and duration): monocarba + 8-D-Arg greater than 4-Val + 8-D-Arg greater than 8-D-Arg alone, all in deamino form. None of the 8-D-Arg analogues had any side effects on the cardiovascular system, gut, uterus, bladder, etc. The prolongation was such that even with a DI patient refractory to the action of lysine-vasopressin and relatively resistant to deamino-[8-D-Arg]-vasopressin, water turnover could be reduced from untreated levels of 20 to 30 liters/day to less than 2 liters/day with only a single administration of deamino-6-carba-[8-D-Arg]-vasopressin as nose drops. The significance of these structural alterations in the vasopressin molecule for interaction with both antidiuretic and smooth muscle receptors was discussed.

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PMgUe, Ci%XhOdOveki8Abafrad. Crude Van Dyke protein prepared from frozen bovine posterior pituitary glands WBB treated with formic acid to reletme small bound and &orbed peptides. Gel filtration, continuous free-flow eledrophoreais and descending paper electrophoresis were need to separate the amall ptides into successively purer fractions which were a m a x f o r preaeor, uterotonk, natriuretic and mehnocyte stimdating acthitien under double blind conditions. The higheat peak of natriuretio activity was ~eeociated with ody 8 small premor and no uterotonic activities, and the name fractions contained a ninhydrin-positive spot on paper electrophoresis, the mobility stimulating hormone (MSH) and A(;TH-( 1-13-amide)-tridecapeptide (1-13 ACI'H-amide) but differed fmm v wpreaein and oxytocin. Material from this spot had an amino Of Which a t pH 5.6 W8d Simik that Of 8lph8-mel8mCyte acid composition which comsponded with the first 13 residues of ACI'H. Qoantitativs biosMsy of the fins1 fraction in the frog demonstrated a melanotropic sctivity which, however, wan lower than would have been expected for p m alpha-MSH.The natriuretic activity of the isolated fraction wan far higher than the potency of separately adminiatemd peptidee which might be present ' ' e-vampreasin, alpha-MSH or 1-13 mixture of alpha-biSH and 1-13 A m , and that alpha-MSH may be an scetylsted end-product of ACI!H cleavage in the pituitary.Key wor&: A(;TH fragments, alpha-MSH, natriuretic peptiden, natriuretic hormone. ACTH. It is s n g g 2 3 -that the isolated fraction represents aThere is an extensive literature over the past decade concerning the appearance of a natriuretic activity in blood plesma and urine during natriuretic states in many mammalian species, induced by such stimuli as: saline, dextran or blood infusion, carotid occlusion, etc. The physiological evidence has been reviewed

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The effects of decreased dietary sodium content during pregnancy and lactation on the activity of adrenal glands of the offspring were investigated. Low salt diet (0.3% of NaCl) increased the aldosterone production in newborn rats, on day 7 and on day 15 decreased the production of 18-hydroxydeoxycorticosterone only; on day 20 only the aldosterone production was increased. Based on the measurements of sodium and potassium concentrations in milk and urine of the offspring, the lasting effects of intrauterine conditions on newborn adrenal gland regulation and the adrenocortical regulatory system activity during the suckling period are discussed. This is done on the basis of literary evidence on amounts of the sodium and potassium required for body mass growth and the observation on the probable shortage of potassium supply in maternal milk towards the end of the suckling period.

dbstrad. Because 8) D mixture of alpha-melanotropin (MSH) and cortimtropin (l-l3)-tridecapeptide (1-13 ACTH) haa apparently been isolated from natriuretic fractions of posterior pituitary which also contained inine-vaeopreaein, fraction waa greater than that of any of the above three peptidee (eynthetic) given separately, possible interaction was etudied with model eubstancea in the chloraloeed cat preparation. It waa found that with both alpha-MSH and lysine-vasopressin, extracted samples were more natriuretic than eynthetic samples despite an equivalence of presaor activities. When combined with and b) the natriuretic activity of the h a t e d Y nrginine-vesopreaein in one injectate, synthetic alpha-MSH, 1 4 ACTH, 1-13 ACTH-amide and 1-18 ACTH all showed potentiation of natriuretic activities with no effect on p r m r nctivity. Thia effect wm not ahown by synthetic 4-10 ACTH and 5-18 ACTH, or by estracted alpha-MSH. It was concluded thnt the 1-4 sequence Ser-Tyr-Ser-Met, regardless of whether the N-terminal ie free or blocked, can potentiate the natriuretic action of vasopressin.

Dedicated 10 the 1l1f!lIwry of Dr Karel BhiIUl.Solid phase methodology all bcnzhydryluminc resin was used for the synthesis of three analogues of vasopressin with non-ceded amino ucid.1 -uminocyclopropunc-l-carbcxylic acid, in position 9. Two analogues oflysine-vuscprcssin ([Lysll, Acc'[vusopressln (I) and Glyr[Lysll. Acc''[vnsopressin (11) and one analogue of arginine-vasopressin ([Arg N, Acc'[vasoprcssln (111) have been synthesized. The dubious value of tile biological activity of [LysN, D-AlalJlvusopressin was reevaluated and [Lys'', L-Alu'Jlvusoprcssin wus also synthesized and tested for the comparlscu. Differences in solution conformation of these two unulogucs were studied by 11-1 and DC NMR spectroscopy. Biological activities of all analogues were either significantly lowered or almost completely eliminated. Analogues 1-111 were found to be completely inactive in analgesia and the eNS activities tested (active and passive avoidance).During the years of structure-activity studies, the extent of attention devoted to different positions in the peptide chain of vasopressin varied. As far as the position 9 is concerned, even though some analogues modified in this position