Regional and Systemic Haemodynamic Effects of Some Vasopressins: Structural Features of the Hormone which Prolong Activity

Abstract

Cardiac output and regional blood flows to myocardium, gut, uterus and kidney were determined in anaesthetised female rats by a single injection of 86RbC1. The haemodynamic responses were measured at various time intervals up to 2 h after single I.V. injections of lysine-vasopressin and the followin8 of its analogues: a) with extended peptide chains at the N-terminal (including "hormonogens") N -glycyl-glycyl-glycyl-lysine-vasopressin, Na-glycyl-glycyl-glycyl-arginine-vasopressin and N -D-va lyl-1 y s ine-vas o pr e s s in, b) I' carba" mod if i ca t ions de s amino-c ar baar g in ine-vas o p r e s s in, desamho-carba6-D-arginine8-vasopressin, desamino-carba6-ornithine8-vasopressin, desamino-dicarbaarginine-vasopressin and c) other steric alterationsdesamino-D-arginine8-vasopressin and desamino-N-methylarginine8-vasopressin. Sub-pressor doses of lysine-vasopressin were followed by marked reductions in gut and uterus blood flows which reached a peak at 10 min. and had completely receded by 6 0 min. The presence of steric alterations in the C-terminal tripeptide of the molecule-D-arginine or N-methylarginine in sequence position 8practically completely eliminated vascular activity. The same was true for N -D-valyl-lysine-vasopressin. None of the latter three analogues showed any inhibitor properties to the action of lysine-vasopressin. The two hormonogens (triglycyl N-terminal extensions) had to be given in doses 10 times greater to obtain a vasoconstrictor effect in gut and uterus equivalent in amplitude to that of lysine-vasopressin, but this effect was still present to the same degree 2 h later with the hormonogen of lysine-vasopressin, and was only starting to return to baseline values at the same time with the arginine-vasopressin hormonogen. The vascular potency of both mono-carba L-analogues was higher than that of lysine-vasopressin, and the effect was as prolonged as with the hormonogens. The dicarba analogue also showed a prolonged action, but with much reduced potency. No significant changes in renal or myocardial blood flows were observed at all. Molecular features of vasopressin smooth muscle activity were discussed, and a receptor model was proposed. It was suggested that the -S-s-, -SCH2 and -CHzCH2-bridges in the above analogues are not directly bound in the peptide-receptor complex and congtihte the limiting factor determining complex duration, or persistence of the active peptide in the "receptor compartment". These results provide an experimental basis for possible clinical application of triglycyl-vasopressin and carba-vasopressin in bleeding from both gut and utezus and for induction of menstruation.

Radioprotective Effect of Local Administration of Lysine-Vasopressin and Triglycyl-Lysine-Vasopressin on the Rectal Mucosa in Rats

“…This is probably slower cell renewal in the rectal mucosa compared small intestine (17) and to the good regenerative (18). This observation is also in accordance findings of Hubmann ( 19), Stenson (20) tration and radiotherapy did not change the results and this was expected since the gel-solution acts as a depot for the vasopressin and since this preparation has a longer duration (22). Lysine-vasopressin in the dose of 1 6 p g in Natrosol solution gave also significant radioprotection.…”

Beneficial effects of terlipressin in hepatorenal syndrome: A prospective, randomized placebo‐controlled clinical trial

“…Following intravenous administration, the glycyl residues are cleaved from hormonogen by endothelial peptidases allowing slow, prolonged release of lysine-VP. 9,10 It is postulated that the maintenance of low blood levels of the active agent would minimize systemic toxicity. Until now, only sporadic case reports [11][12][13] and an isolated pilot study 14 assessing the effect of terlipressin on renal function in patients of HRS have been published.…”

Actions of a New Vasopressin Analogue (1‐deamino‐6‐carba‐[8‐arginine]‐vasopressin) on Regional Blood Flow in Pregnant Guinea Pigs

“…This interpretation fits in well with the observation that the pressor response to 0.1 Fgkg of dCAVP in pregnant guinea pigs is smaller than that evoked by 10 pg/kg TGLVP (Sjoquist er al. 1977a), whereas these doses are equipotent in non-pregnant rats (Cort et al 1975).…”

“…1977b). The analogue has also been shown to reduce uterine blood flow in oestrogen-treated, non-pregnant rats (Cort et al 1975).…”