A mutation in the chicken resulting in total amelia is described. Genetic analysis indicates that the limbless condition is due to an autosomal recessive gene. In the limbless embryos the apical ectodermal ridge is lacking. However both the pectoral and pelvic girdles as well as the respiratory and excretory systems are normal. In the affected embryos usually the upper beak is shorter than the lower beak.

Grant No. GM-17574. We also wish to express our appreciation to Dr. Norman Sutin for helpful conversations and for allowing us the use of the facilities at Brookhaven National Laboratory for several experiments.

Application of information derived from a three-dimensional model of vasopressin bound to its antidiuretic receptor resulted in the design and synthesis of a bicyclic vasopressin analog, [5,8-cyclo(1-beta-mercaptopropionic acid,2-phenylalanine,5-aspartic acid,8-lysine)]vasopressin. The analog acts as an antagonist of the antidiuretic activity of vasopressin.

Replacement of the aliphatic isoleucine residue in position 3 of oxytocin (the first corner position of the beta-turn in the 20-membered ring of the solution conformation of the hormone) by phenylalanine has been shown to result in analogues with reduced affinity and intrinsic activity when tested by the individual dose-response procedure on the isolated rat uterus. Studies of effects of structural modifications have been extended to include two additional beta-turn corner positions. First, the dose-response behavior of [Leu4]oxytocin and [Phe4]oxytocin, two analogues in which the Glu4 side chain in the second corner position of the beta-turn in the 20-membered ring has been substituted by hydrophobic and bulky groups, was compared with that of oxytocin. Second, the solid-phase synthesis and biological properties of [Phe3,Leu4,Met8]oxytocin and [Phe3,4,Met8]oxytocin are described. The presence of leucine or phenylalanine in position 4 evokes a drastic reduction in both the affinity and intrinsic uterotonic activity of the resulting analogues, with phenylalanine significantly more effective in reducing intrinsic activity than leucine (p less than 0.001).

Orthostatic cardiovascular reflexes were evaluated in conscious cynomolgus monkeys during interruption of the renin-angiotensin system with the renin inhibitor: RIP (Pro-His-Pro-Phe-His-Phe-Phe-Val-Tyr-Lys-OH). RIP was synthesized via solid phase techniques and purified to homogeneity. In vitro studies indicated that it exhibited classical competitive inhibition of renin with a KI of 2.3 microM. In vivo, RIP at 2 mg/kg per min inhibited renin and angiotensin I pressor responses indicating that it was not a specific renin inhibitor at this dose. However, in spite of the nonspecificity, RIP did not affect the supine blood pressure of sodium-replete monkeys, but did evoke hypotension in supine sodium depleted monkeys. RIP did not elicit significant orthostatic hypotension in either sodium-replete or sodium depleted monkeys. The cardiovascular effects of RIP described in this study appear to be due to inhibition of the renin-angiotensin system.