Solid-phase synthesis of 16 potent (selective and nonselective) in vivo antagonists of oxytocin

Manning, Maurice; Kruszynski, Marian; Bańkowski, Krzysztof; Olma, Aleksandra; Lammek, Bernard; Cheng, Ling; Kliś, Wieslaw A.; Seto, J.; Haldar, Jaya; Sawyer, Wilbur H.

doi:10.1021/jm00122a016

Cited by 112 publications

(69 citation statements)

References 8 publications

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“…In the present investigation, we chose a dose approximately 10-fold higher than in the previous study, because in our experience sensitivity to infused peptides tends to be lowered during anaesthesia. The antagonist has negligible effects on vasopressin V 2 receptors (Manning et al 1989) and, although it has been reported to partially block V 1 receptors (Manning et al 1989), it had no effect on arterial pressure in the present study. (In any case, plasma vasopressin concentrations did not reach pressor levels.)…”

Section: Resultscontrasting

confidence: 59%

Contribution of endogenous oxytocin to sodium excretion in anaesthetized, surgically operated rats

Walter¹,

Forsling²,

Shirley³

2000

Journal of Endocrinology

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In order to determine the possible role of endogenous oxytocin in controlling electrolyte and water excretion in animals whose renal function is being assessed by invasive techniques, rats were anaesthetized and subjected to micropuncture surgery. Clearance measurements were made in the presence and absence of the potent oxyto- 9 ]-vasotocin. In rats infused with vehicle alone, glomerular filtration rate (GFR), sodium excretion and urine flow rate remained stable. In contrast, in antagonisttreated rats GFR was modestly reduced (P<0·05), and there were large falls in both absolute and fractional sodium excretion (P<0·01 in each case) and absolute and fractional water excretion (P<0·05 in each case), indicating effects on both filtered load and fractional tubular reabsorption.The antinatriuresis was not accompanied by a change in the fractional excretion of lithium, suggesting that proximal tubular function is unaffected by oxytocin receptor antagonism; nor was it accompanied by a change in the fractional excretion of potassium, suggesting that the tubular effect is located beyond the potassium secretory site, i.e. downstream of the cortical collecting tubule.We conclude that circulating plasma concentrations of oxytocin during anaesthesia and moderate surgery are sufficient to enhance GFR and reduce fractional tubular sodium and water reabsorption. This has important implications for the interpretation of invasive studies such as micropuncture.

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Section: Resultscontrasting

confidence: 59%

Contribution of endogenous oxytocin to sodium excretion in anaesthetized, surgically operated rats

Walter¹,

Forsling²,

Shirley³

2000

Journal of Endocrinology

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“…Therefore, we used a selective oxytocin antagonist and an agonist to determine if oxytocin receptors participate in the luminal action of AVP. When 10-6 M GN-OVT, a selective oxytocin antagonist (15), was in the lumen together with AVP, the effect of luminal AVP was inhibited (Fig. 8).…”

Section: Resultsmentioning

confidence: 97%

Immunohistochemical localization of V2 vasopressin receptor along the nephron and functional role of luminal V2 receptor in terminal inner medullary collecting ducts.

Nonoguchi¹,

Owada²,

Kobayashi³

et al. 1995

J. Clin. Invest.

124

102

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We investigated immunohistochemical localization of V2 vasopressin receptor along the nephron using a specific polyclonal antibody. Staining was observed in some of thick ascending limbs and all of principal and inner medullary collecting duct (IMCD) cells. Not only basolateral but also luminal membrane was stained in collecting ducts, especially in terminal IMCD (tIMCD).To learn the functional role of luminal V2 receptor in tIMCD, we studied the luminal effects of arginine vasopressin (AVP) on osmotic water permeability (Pf), urea permeability (Pu), and cAMP accumulation using isolated perfused rat tIMCD. In the absence of bath AVP, luminal AVP caused a small increase in cAMP accumulation, Pf and Pu, confirming the presence of V2 receptor in the lumen of tIMCD. In contrast, luminal AVP inhibited Pf and Pu by 30-65% in the presence of bath AVP by decreasing cAMP accumulation via Vla or oxytocin receptors and by an unknown mechanism via V2 receptors in the luminal membrane of tIMCD.These data show that V2 receptors are localized not only in the basolateral membrane but also in the luminal membrane of the distal nephron. Luminal AVP acts as a negative feedback system upon the basolateral action of AVP in tIMCD. (J. Clin. Invest. 1995. 96:1768-1778

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“…In females, continuous infusion of OXT into the lateral ventricle via osmotic minipumps reduces anxiety in lactating rats [74] as well as in virgin female rats nonselected for anxiety [86]. Furthermore, the same treatment/ application method leads to decreased anxiety in virgin HAB rats, whereas chronic administration of a selective OXT-R antagonist (OXT-A) [87] results in increased anxiety in virgin LAB rats [88]. Regarding MA in HAB mothers, a high amount of OXT is released especially in the PVN and the central amygdala (CeA) during the display of MA (for details see below) [3].…”

Section: (I) the Mother's Innate Anxiety Affects Maternal Aggressionmentioning

confidence: 99%

Maternal aggression in rodents: brain oxytocin and vasopressin mediate pup defence

Bosch

2013

Phil. Trans. R. Soc. B

170

181

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The most significant social behaviour of the lactating mother is maternal behaviour, which comprises maternal care and maternal aggression (MA). The latter is a protective behaviour of the mother serving to defend the offspring against a potentially dangerous intruder. The extent to which the mother shows aggressive behaviour depends on extrinsic and intrinsic factors, as we have learned from studies in laboratory rodents. Among the extrinsic factors are the pups' presence and age, as well as the intruders' sex and age. With respect to intrinsic factors, the mothers' innate anxiety and the prosocial brain neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) play important roles. While OXT is well known as a maternal neuropeptide, AVP has only recently been described in this context. The increased activities of these neuropeptides in lactation are the result of remarkable brain adaptations peripartum and are a prerequisite for the mother to become maternal. Consequently, OXT and AVP are significantly involved in mediating the fine-tuned regulation of MA depending on the brain regions. Importantly, both neuropeptides are also modulators of anxiety, which determines the extent of MA. This review provides a detailed overview of the role of OXT and AVP in MA and the link to anxiety.

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Solid-phase synthesis of 16 potent (selective and nonselective) in vivo antagonists of oxytocin

Cited by 112 publications

References 8 publications

Contribution of endogenous oxytocin to sodium excretion in anaesthetized, surgically operated rats

Contribution of endogenous oxytocin to sodium excretion in anaesthetized, surgically operated rats

Immunohistochemical localization of V2 vasopressin receptor along the nephron and functional role of luminal V2 receptor in terminal inner medullary collecting ducts.

Maternal aggression in rodents: brain oxytocin and vasopressin mediate pup defence

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