[1-.beta.-Mercapto-.beta.,.beta.-diethylpropionic acid]-8-lysine-vasopressin, a potent inhibitor of 8-lysine-vasopressin and of oxytocin

Dyckes, Douglas F.; Nestor, John J.; Ferger, Martha F.; Vigneaud, Vincent du

doi:10.1021/jm00248a028

Cited by 42 publications

(22 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For brain glucose retention, arterial-venous glucose differences across the brain were estimated in micromoles per milliliter. Since blood glucose levels in abdominal aorta were indistinguishable from those in carotid artery at each sampling time, 0.10 ml of arterial blood (abdominal aorta) and 0.10 ml of venous blood (jugular sinus) were collected from the cannulated vessels; in a complete sampling period, 1.2 ml of blood were taken (Ͻ8% of total blood volume in rats) (16). To compensate for fluid loss, the rats received an injection of 0.3 ml of saline after each pair of samples was taken (1,5).…”

Section: Methodsmentioning

confidence: 99%

“…As with CBR stimulation, the effects of AVP were dependent on the presence of the adrenal glands. The pharmacological blockade of V1a receptors with a selective antagonist (16) abolished the hyperglycemic reflex initiated by hypoxic CBR stimulation. We conclude that AVP is an important mediator of the hyperglycemic reflex and cerebral glucose retention that occurs after CBR stimulation.…”

mentioning

confidence: 97%

See 1 more Smart Citation

Arginine-vasopressin mediates central and peripheral glucose regulation in response to carotid body receptor stimulation with Na-cyanide

Montero

Mendoza²,

Valles³

et al. 2006

Journal of Applied Physiology

View full text Add to dashboard Cite

Arginine-vasopressin mediates central and peripheral glucose regulation in response to carotid body receptor stimulation with Na-cyanide. J Appl Physiol 100: 1902-1909, 2006. First published February 23, 2006 doi:10.1152/japplphysiol.01414.2005.-Hypoxic stimulation of the carotid body receptors (CBR) results in a rapid hyperglycemia with an increase in brain glucose retention. Previous work indicates that neurohypophysectomy inhibits this hyperglycemic response. Here, we show that systemic arginine vasopressin (AVP) induced a transient, but significant, increase in blood glucose levels and increased brain glucose retention, a response similar to that observed after CBR stimulation. Comparable results were obtained after intracerebral infusion of AVP. Systemic AVP-induced changes were maintained in hypophysectomized rats but were not observed after adrenalectomy. Glycemic changes after CBR stimulation were inhibited by pharmacological blockage of AVP V1a receptors with a V1a ]-vasopressin). Importantly, local application of micro-doses of this antagonist to the liver was sufficient to abolish the hyperglycemic response after CBR stimulation. These results suggest that AVP is a mediator of the hyperglycemic reflex and cerebral glucose retention following CBR stimulation. We propose that hepatic activation of AVP V1a receptors is essential for this hyperglycemic response.chemoreceptors; central nervous system respiration RECENT WORK SUGGESTS that the carotid body receptors (CBR), in addition to their classical role sensing O 2 , CO 2 , and pH levels (19,43), also function as receptors of glucose concentration entering the cephalic circulation (1,5,30,41,42). Changes in blood glucose concentration in the carotid sinusbody influence the amount of glucose retained by the brain (6), and the injection of sodium cyanide (NaCN) into the local circulation of the carotid sinus induces a rapid hyperglycemic reflex with a rise in brain glucose retention (1). Unloading of carotid baroreceptors also induces rapid glucose adjustments to regulate plasma osmolality during hemorrhage (28). Experimentally induced low-glucose levels increase catecholamine secretion from carotid body glomus cells in a concentrationdependent manner (41), indicating that this structure is very sensitive to glucose concentration.The efferent pathway for the glycemic reflexes initiated in the carotid sinus region is not fully understood. Previous experiments indicate the participation of the neurohypophysis and adrenal glands, suggesting that the effects of these two glands on CBR hyperglycemic reflexes are humoral (2). A reflex discharge of neurohypophyseal secretion occurs after centripetal stimulation of the vagus nerve (23), and it is known that peripheral receptors connected to the vagus nerve (aortic baro-and chemoreceptors) or associated with the glossopharyngeal nerve (carotid baro-and chemoreceptors) mediate some of their effects through the pituitary (44). It is not known, however, what factors secreted by neurohypophysis are required to elicit...

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 97%

Arginine-vasopressin mediates central and peripheral glucose regulation in response to carotid body receptor stimulation with Na-cyanide

Montero

Mendoza²,

Valles³

et al. 2006

Journal of Applied Physiology

View full text Add to dashboard Cite

show abstract

“…The integrated uterine activity over a 10-min period after each injection was considered the response. Effective molar concentrations of antagonists were estimated using the assumption introduced by Dyckes et al (24) that peptides injected iv in rats initially distribute in a volume of 67 ml/kg, and these were used in calculating estimated in vivo pA 2 values. We must state clearly that these estimates are for convenience in comparing our results in vivo to those obtained in vitro; as true pA 2 determinations they are invalid.…”

Section: Assay Methodsmentioning

confidence: 99%

The Design of Effectivein VivoAntagonists of Rat Uterus and Milk Ejection Responses to Oxytocin*

et al. 1980

View full text Add to dashboard Cite

Several new synthetic analogs of the oxytocin antagonist [1-deaminopenicillamine]oxytocin have been prepared and tested for their abilities to inhibit responses to oxytocin by the isolated rat uterus in the absence and presence of Mg++, by the rat uterus in situ, and by the rat mammary gland in situ. Substituting 2-O-methyltyrosine in [1-deaminopenicillamine]oxytocin strikingly enhances antagonism of all uterin responses, and [1-deaminopenicillamine, 2-O-methyltyrosine]oxytocin and its 4-threonine analog are also potent inhibitors of the milk ejection response. Substituting 2-phenylalanine in [1-deaminopenicillamine]oxytocin also enhances antagonistic activities in all uterine assays, but [1-deaminopenicillamine, 2-phenylalanine]oxytocin retains agonistic activity on milk ejection assays. From these studies we can conclude that changes in the 1-position (1-deaminopenicillamine substitution) and the 2-position (2-O-methyltyrosine or 2-phenylalanine substitution) can have additive effects on antagonistic activities. Substitution of an 8-ornithine also enhances inhibitory potency in vivo, and this effect may also be additive to those of the substitutions in 1- and 2-positions. These findings provide many clues that may lead to the design of even more effective antagonists; several of the analogs reported here appear to the most effective antagonists of oxytocin in vivo yet reported and may be useful agents in further studies on the physiological functions of endogenous oxytocin.

show abstract

“…In practice, this concentration is estimated by finding concentrations above and below the effective concentration and interpolating on a logarithmic scale. In the rat in vivo assays, the effective dose (ED) of antagonist is divided by an arbitrarily assumed volume of distribution of 67 ml=kg to allow estimation of its molar concentration for the pA 2 [70]. Synthetic argininevasopressin and oxytocin which had been standardized in vasopressor and oxytocic units against the USP Posterior Pituitary Reference Standard were used as working standards in all bioassays.…”

mentioning

confidence: 99%

Position Three in Vasopressin Antagonist Tolerates Conformationally Restricted and Aromatic Amino Acid Substitutions: A Striking Contrast with Vasopressin Agonists

et al. 1997

View full text Add to dashboard Cite

We report the solid-phase synthesis and some pharmacological properties of 12 position three modified analogues (peptides 1-12) of the potent non-selective antagonist of the antidiuretic (V2-receptor), vasopressor (V1a-receptor) responses to arginine vasopressin (AVP) and of the uterine contracting (OT-receptor) responses to oxytocin (OT), [1(-beta mercapto-beta,beta-pentamethylenepropionic acid)-2-O-ethyl-D-tyrosine 4-valine] arginine vasopressin [d(CH2)5D-Tyr(Et)2VAVP] (A) and two analogues of (B) (peptides 13,14), the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid3 (Tic3) analogue of (A). Peptides 1-12 have the following substituents at position three in (A): (1) Pro; (2) Oic; (3) Atc; (4) D-Atc; (6) D-Phe; (7) Ile; (8) Leu; (9) Tyr; (10) Trp; (11) Hphe; (12) [HO]Tic; Peptide (13) is the Tyr-NH2(9) analogue of (B): Peptide (14) is the D-Cys(6) analogue of (B). All 14 new peptides were evaluated for agonistic and antagonistic activities in in vivo V2 and V1a assays and in vitro (no Mg2+)n oxytocic assays. With the exception of the D-Phe3 peptide (No. 6), which exhibits very weak V2 agonism (approximately 0.0017 U/mg), none of the remaining 13 peptides exhibit any agonistic activities in these assays. In striking contrast to their deleterious effects on agonistic activities in AVP, the Pro3, Oic3, Tyr3 and Hphe3 substitutions in (A) are very well tolerated, leading to excellent retention of V2, V1a and OT antagonistic potencies. All are more potent as V2 antagonists than the Ile3 and Leu3 analogues of (A). The Tyr-NH2(9) and D-Cys(6) substitutions in (B) are also well tolerated. The anti-V2 pA2 values of peptides 1-5 and 7-14 are as follows (1) 7.77 +/- 0.03; (2) 7.41 +/- 0.05; (3) 6.86 +/- 0.02; (4) 5.66 +/- 0.09; (5) approximately 5.2; (7) 7.25 +/- 0.08; (8) 6.82 +/- 0.06; (9) 7.58 +/- 0.05; (10) 7.61 +/- 0.08; (11) 7.59 +/- 0.07; (12) 7.20 +/- 0.05; (13) 7.57 +/- 0.1; (14) 7.52 +/- 0.06. All analogues antagonize the vasopressor responses to AVP, with anti-V1a pA2 values ranging from 5.62 to 7.64, and the in vitro responses to OT, with anti-OT pA2 values ranging from 5.79 to 7.94. With an anti-V2 potency of 7.77 +/- 0.03, the Pro3 analogue of (A) is surprisingly equipotent with (A), (anti-V2 pA2 = 7.81 +/- 0.07). These findings clearly indicate that position three in AVP V2/V1a antagonists, in contrast to position three in AVP agonists, is much more amenable to structural modification than had heretofore been anticipated. Furthermore, the surprising retention of V2 antagonism exhibited by the Pro3, Oic3, Tyr3, Trp3 and Hphe3 analogues of (A), together with the excellent retention of V2 antagonism by the Tyr-NH2(9) and D-Cys6 analogues of (B) are promising new leads to the design of potent and possibly orally active V2 antagonists for use as pharmacological tools and/or as radioiodinatable ligands and for development as potential therapeutic agents for the treatment of the hyponatremia caused by the syndrome of the inappropriate secretion of the antidiuretic hormone (SIADH).

show abstract

[1-.beta.-Mercapto-.beta.,.beta.-diethylpropionic acid]-8-lysine-vasopressin, a potent inhibitor of 8-lysine-vasopressin and of oxytocin

Cited by 42 publications

References 13 publications

Arginine-vasopressin mediates central and peripheral glucose regulation in response to carotid body receptor stimulation with Na-cyanide

Arginine-vasopressin mediates central and peripheral glucose regulation in response to carotid body receptor stimulation with Na-cyanide

The Design of Effectivein VivoAntagonists of Rat Uterus and Milk Ejection Responses to Oxytocin*

Position Three in Vasopressin Antagonist Tolerates Conformationally Restricted and Aromatic Amino Acid Substitutions: A Striking Contrast with Vasopressin Agonists

Contact Info

Product

Resources

About