Synthetic oxytocin and vasopressin agonists and antagonists have become important tools for research and were instrumental in the identification of the four known receptor subtypes, V-1a, V-2, V-1b (V-3) and oxytocin,...
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Synthetic oxytocin and vasopressin agonists and antagonists have become important tools for research and were instrumental in the identification of the four known receptor subtypes, V-1a, V-2, V-1b (V-3) and oxytocin, of these peptide hormones. However, the relative lack of receptor selectivity, particularly of the antagonists, has limited their usefulness as experimental probes and their potential as therapeutic agents. We now present some findings from our continuing studies aimed at the design of more selective oxytocin and vasopressin agonists and antagonists and a structure-activity relationship update on our recently discovered novel hypotensive vasopressin peptides. Bioassays have been, and continue to be, of critical importance in leading to the discovery of the novel agonists, antagonists and hypotensive peptides reported here. This paper highlights three main aspects of these studies. (1) Replacement of the tyrosine(2) and/or phenylalanine(3) residues in the V-2 agonist deamino,[Val(4), D-Arg(8)]arginine-vasopressin (dVDAVP) by thienylalanine resulted in selective V-2 agonists with strikingly high potencies. However, the peptide solutions were unstable and lost activity over time. These highly potent V-2 agonists, which are devoid of vasopressor activity, are promising leads for improving drugs for treating diabetes insipidus, enuresis and coagulation disorders. (2) Diaminopropionic acid and diaminobutyric acid substitution at position-5 in oxytocin and in V-1a antagonists yielded, respectively, the first specific antagonist for the oxytocin receptor, desGly-NH2,d(CH2)(5)[D-Trp(2),Thr(4),Dap(5)]OVT and the first specific antagonist for the vasopressin V-1a receptor, d(CH2)(5)[Tyr(Me)(2),Dab(5)]AVP. The availability of single receptor subtype-specific or selective antagonists will enhance our ability to delineate receptor functions. Utilising these new receptor specific probes, we were able to show that the uterotonic action of vasopressin is mediated princ
Objective To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential. Design Receptor binding studies on transfected ...
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Objective To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential. Design Receptor binding studies on transfected cell lines. In vitro contractility studies of human myometrium. Setting The Research Laboratory of Sanofi Recherche, Centre de Toulouse, France and the Departments of Obstetrics and Gynecology, Lund University Hospital, Sweden and Bialystok University Hospital, Poland. Participants Nine women delivered by caesarean section preterm and 37 delivered at term for routine obstetric indications. Interventions The binding affinities of oxytocin, arginine vasopressin, atosiban (1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin), SR 49059 and SR 121463 for the human oxytocin and different subtypes of vasopressin receptors were determined. Concentration-response curves with oxytocin and arginine vasopressin were recorded on myometrium from preterm- and term-delivered women in control experiments and in the presence of 2.5 and 10 nmol/L of SR 49059. Furthermore, using term myometrium, the influence of SR 49059 and SR 121463 in concentrations of 3, 10, 30 and 100 nmol/L on responses to the EC50 concentrations of oxytocin and vasopressin were compared. Main outcome measures Receptor binding affinities. In vitro contractile effects and their inhibitions. Results Oxytocin had a high affinity for the oxytocin receptor (K-i in mean = 6.8 nmol/L) and bound, to some extent, to the vasopressin V-1a receptor (K-i = 349 nmol/L). Vasopressin displayed higher affinities for vasopressin V-1a, V-1b and V-2 receptors (K-i = 14, 0.8 and 4.2 nmol/L, respectively) than for the oxytocin receptor (K-i = 48 nmol/L). Atosiban and SR 49059 both had a high affinity for the vasopressin V-1a receptor (K-i = 4.7 and 7.2 nmol/L, respectively, and a moderate one for the oxytocin receptor (K-i = 397 and 340 nmol/L, respectively). SR 121463 exerted a predominant binding to the V-2 receptor (K-i = 3.0
The effect of prostaglandin synthesis inhibition on the redistribution of renal cortical blood flow in response to antidiuretic hormone (ADH) was examined using radioactive microspheres in water loaded, thiopental-ane...
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The effect of prostaglandin synthesis inhibition on the redistribution of renal cortical blood flow in response to antidiuretic hormone (ADH) was examined using radioactive microspheres in water loaded, thiopental-anesthetized dogs. Microsphere injections were made during a control and an ADH infusion period (0.35 mU/kg/min following a 20 mU/kg bolus) both before and after indomethacin pretreatment (8 mg/kg intravenously). Urinary prostaglandin E2 (PGE2) excretion in each period was measured by gas chromatography-mass spectrometry. ADH caused a marked redistribution of flow toward inner cortical zones from 19 +/- 1 to 25 +/- 2 ml/min (mean +/- SE, p less than 0.01). Fractional flow to inner zones was also significantly increased. Indomethacin pretreatment had no effect on the ADH-induced redistribution (17 +/- 2 vs. 24 +/- 2 ml/min, p less than 0.01), although urinary PGE2 excretion was suppressed by indomethacin by 60%. It is concluded that prostaglandins do not mediate the redistribution of intrarenal blood flow accompanying ADH administration.
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