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PubMed2002

Chronic in utero plasma hyperosmolality alters hypothalamic arginine vasopressin synthesis and pituitary arginine vasopressin content in newborn lambs.

OBJECTIVE: Arginine vasopressin is synthesized in the hypothalamus and secreted by the posterior pituitary gland in response to plasma hypertonicity. Previous studies suggest that in utero and neonatal exposure of rat pups to prolonged alterations of plasma osmolality may permanently alter (imprint) arginine vasopressin synthesis and secretion, thus adult responses to osmotic challenges. Little is known, however, of the potential for imprinting of neuroendocrinologic systems in precocial species. In view of the frequent occurrence of altered maternal and fetal plasma tonicity (eg, maternal dehydration, hyperemesis), we sought to determine the effect of prolonged maternal hypertonicity on arginine vasopressin gene expression and pituitary gland content in neonatal sheep. STUDY DESIGN: Pregnant ewes at 119 +/- 3 days of gestation were water restricted to achieve and maintain plasma hypertonicity (10-20 mOsm/kg above baseline level) until normal term delivery. Newborns were provided maternal nursing ad libitum. Within 24 hours after birth, study neonatal lambs (n = 6) and age-matched control neonatal lambs (n = 5) were killed, and the pituitary gland and hypothalamus were removed and frozen immediately. Pituitary arginine vasopressin content was determined by radioimmunoassay, and hypothalamic arginine vasopressin gene expression was quantified with Northern blot. Differences in pituitary arginine vasopressin content and hypothalamic arginine vasopressin gene expression (arginine vasopressin/ beta-actin ratio) between study and control newborn lambs were analyzed by unpaired t test. RESULTS: In response to maternal water restriction, maternal plasma osmolality increased from 307 +/- 0.9 mOsm/kg to 325 +/- 1.3 mOsm/kg, and plasma sodium increased from 147 +/- 1.3 mEq/L to 156 +/- 1.2 mEq/L. The maternal plasma hyperosmolality and hypernatremia were maintained until normal term delivery. At the time of death, study (in utero dehydrated) lambs had higher plasma sodium (150 +/- 0.4 mEq/L vs 146.5 +/- 1.5 mEq/L; P <.05) and chloride (112.8 +/- 1.0 mEq/L vs 108.5 +/- 1.5 mEq/L; P <.05) levels, and lower potassium (4.5 +/- 0.2 mEq/L vs 5.5 +/- 0.3 mEq/L; P <.05) concentrations than control newborn lambs. Both newborn groups had similar plasma osmolality (320.0 +/- 1.3 mOsm/kg vs 318.0 +/- 3.4 mOsm/kg). Total pituitary arginine vasopressin content was significantly greater in the study than in the control newborn lambs (8.3 +/- 2.8 microg vs 1.6 +/- 1.3 microg; P <.05). Conversely, hypothalamic arginine vasopressin messenger RNA levels were lower in the study newborn lambs than in the control newborn lambs (arginine vasopressin/beta-actin ratio: 0.29 +/- 0.01 vs 0.68 +/- 0.15; P <.05). CONCLUSION: Despite the presence of plasma hypernatremia, prolonged elevation of fetal plasma tonicity increases newborn pituitary arginine vasopressin content yet decreases hypothalamic arginine vasopressin gene expression. The present study suggests that prolonged prenatal exposure to plasma hypertonicity may imprint the hypothalamic-pituitary arginine vasopressin regulatory system.

Animals↗
PubMed1998

Intrahypothalamic vasopressin release. An inhibitor of systemic vasopressin secretion?

Vasopressin and oxytocin are released into the extracellular space of the supraoptic (SON) and paraventricular nuclei (PVN). The dendrites of these neurones contain a high density of neurosecretory granules, and exocytotic profiles have been visualised by electron microscopy. Release within the SON has been measured using microperfusion techniques; release is tetrodotoxin-independent, calcium-dependent, and is activated by a range of physiological stimuli, including suckling, dehydration, haemorrhage and stress. Release of vasopressin into the SON is regulated by a number of forebrain and brainstem areas. Dendritic release does not necessarily parallel neurohypophyseal release, and may occur semi-independently of spike activity in the soma and axons. The physiological consequences of dendritic vasopressin release are not clear, vasopressin and oxytocin appear to induce further vasopressin and oxytocin release from the dendrites. In contrast, by combining retrodialysis and electrophysiology we have shown that, unlike oxytocin which excites oxytocin neurones, vasopressin inhibits the electrical activity of vasopressin neurones, and hence suppresses vasopressin release from the pituitary. Thus, vasopressin released from dendrites may act on vasopressin neurones to regulate their phasic activity by an auto-inhibitory action within the SON. Since dendritic vasopressin release is increased and prolonged after various stimuli, this mechanism may act to restrain excitation of vasopressin neurones (and hence vasopressin secretion from the neurohypophysis) during continuing stimulation.

Animals↗
PubMedDate not supplied

Vasopressin receptors in human seminal vesicles: identification, pharmacologic characterization, and comparison with the vasopressin receptors present in the human kidney.

Because of the presence of a high density of vasopressin receptors in the epithelial cells of porcine seminal vesicles similar to the V2 vasopressin receptors of renal tubules, human seminal vesicles and kidney were investigated using quantitative binding and adenylate cyclase studies. Tissues were obtained at surgery from 17 patients with urologic diseases. A homogeneous class of vasopressin binding sites have been found in both seminal vesicles and renal medulla. However, the vasopressin receptors present in these tissues are different in terms of ligand specificity and adenylate cyclase activation. In seminal vesicles, the V1 vasopressin antagonist d(CH2)5 TyrMeAVP is 36-fold, more potent than the V2 agonist dVDAVP in displacing [3H]AVP binding, while in the medullopapillary portion of kidney dVDAVP is 24-fold, more selective than d(CH2)5 TyrMeAVP for the arginine vasopressin binding site. Furthermore, arginine vasopressin induces a dose-dependent increase in adenylate cyclase activity in renal membranes, while it was ineffective in seminal vesicle membranes. These results indicate that a very high affinity (0.2 nM), low capacity (14 fmoles/mg protein) class of vasopressin receptors is present in human seminal vesicles, having pharmacologic characteristics similar to the V1 subtype of vasopressin receptors. The presence of a high affinity (1.6 nM), high capacity (350 fmoles/mg protein) V2 subtype of vasopressin receptors in human renal membranes is also confirmed. The density of the vasopressin receptors present in human seminal vesicles is inversely correlated with patient age, consistent with a physiologic role for vasopressin in the regulation of accessory sex gland activity.

Adenylyl Cyclases↗
PubMed2003

Vasopressin differentially modulates non-NMDA receptors in vasopressin and oxytocin neurons in the supraoptic nucleus.

Magnocellular neurons of the supraoptic nucleus release the neuropeptides oxytocin and vasopressin from their dendrites to regulate their synaptic inputs. This study aims to determine the cellular mechanism by which vasopressin modulates excitatory synaptic transmission. Presumably by electroporation through perforated patch, we were able to successfully introduce biocytin into cells in which we performed an electrophysiological study. This method enabled us to determine that roughly half of the recorded neurons were immunoreactive to oxytocin-associated neurophysin and showed two characteristic features: an inward rectification and a sustained outward rectification. The remaining half showed a linear voltage-current relationship and was immunoreactive to vasopressin-associated neurophysin. Using these electrophysiological characteristics and post hoc immunohistochemistry to identify vasopressin or oxytocin neurons, we found that vasopressin decreased evoked EPSCs in vasopressin neurons while increasing EPSCs in oxytocin neurons. In both types of neurons, EPSC decay constants were not affected, indicating that desensitization of non-NMDA receptors did not underlie the EPSC amplitude change. In vasopressin neurons, both vasopressin and a V1a receptor agonist, F-180, decreased AMPA-induced currents, an effect blocked by a V1a receptor antagonist SR49059. In oxytocin neurons, AMPA-induced currents were facilitated by vasopressin, whereas F-180 had no effect. An oxytocin receptor antagonist blocked the facilitatory effect of vasopressin. Thus, we conclude that vasopressin inhibits EPSCs in vasopressin neurons via postsynaptic V1a receptors, whereas it facilitates EPSCs in oxytocin neurons through oxytocin receptors.

Animals↗
PubMed1991

Different effects of chronic Na+, Cl-, and K+ depletion on brain vasopressin mRNA and plasma vasopressin in young rats.

1. We studied the effects of selective chronic dietary sodium, chloride, or potassium depletion in young rats on vasopressin mRNA levels in the supraoptic and paraventricular nuclei, an index of vasopressin formation, and in plasma vasopressin levels, an index of vasopressin release. 2. All diets significantly increased plasma renin activity, contracted the extracellular fluid volume, and decreased serum osmolarity. 3. In the supraoptic nucleus, vasopressin mRNA levels were significantly decreased in the low-sodium group but were not significantly affected by chloride depletion. 4. There were no significant changes in vasopressin mRNA in the paraventricular nucleus after sodium or chloride dietary depletion. 5. After 2 weeks of potassium depletion, vasopressin mRNA levels were decreased in the supraoptic nucleus. When potassium depletion was prolonged for 3 weeks, vasopressin mRNA levels increased in both supraoptic and paraventricular nuclei. 6. Plasma vasopressin levels were high in animals subjected to dietary chloride depletion or to 3 weeks of potassium depletion. Dietary sodium depletion or 2 weeks of dietary potassium depletion did not significantly affect plasma vasopressin. 7. Our results show that chronic sodium, chloride, or potassium depletion differentially affect brain vasopressin mRNA and vasopressin release in young rats. 8. The effect of these diets may be mediated through changes in the extracellular fluid volume, serum osmolarity, and/or renin angiotensin system.

Animals↗
PubMed1997

L-, N- and T- but neither P- nor Q-type Ca2+ channels control vasopressin-induced Ca2+ influx in magnocellular vasopressin neurones isolated from the rat supraoptic nucleus.

1. The role of voltage-dependent Ca2+ channels during vasopressin and oxytocin actions on their respective neurones has been analysed by measuring intracellular Ca2+ concentration ([Ca2+]i) in individual, freshly dissociated magnocellular neurones from rat supraoptic nucleus (SO) using microspectrofluorimetry. 2. Pre-incubation of vasopressin-sensitive neurones with Cd2+ (100 microM), a non-discriminatory high-voltage-activated Ca2+ channel antagonist, or Ni2+ (50 microM), a blocker of T-type Ca2+ current, reduced [Ca2+]i responses by 77 and 19%, respectively. When Cd2+ was given together with Ni2+, the response was blocked by 92%. Similarly, when Ni2+ was pre-incubated with Cd2+, the response was blocked by approximately 84%. 3. Exposure of vasopressin sensitive neurones to a specific Ca2+ channel blocker, nicardipine (L-type) reduced vasopressin responses by 48% at 1 microM and 62% at 5 microM. Similarly, omega-conotoxin GVIA (omega-CgTX, N-type; 500 nM) inhibited the response by 46% with a stronger inhibition (75%) at 800 nM. By contrast, neither omega-agatoxin IVA (omega-Aga IVA; 300 nM), which blocks both P- and Q-type channels, nor synthetic omega-conotoxin MVIIC (omega-MVIIC; 100 or 500 nM), a Q-type blocker, affected vasopressin-induced [Ca2+]i responses. These antagonists, given together (nicardipine 5 microM + omega-CgTX 800 nM + omega-Aga IVA 300 nM), decreased vasopressin-induced [Ca2+]i responses by 76%. 4. In vasopressin-sensitive neurones, the presence of both nicardipine and omega-CgTX, reduced the K(+)-evoked [Ca2+]i increase by 61%. This blockade was increased by a further 21% with omega-Aga IVA, suggesting that N-, L- and P-type channels contribute to the depolarization-induced [Ca2+]i rise. In addition, omega-MVIIC alone reduced the K(+)-evoked [Ca2+]i release by 24%. Also the remaining K+ responses were further reduced by 60% when pre-incubated with L-N- and P-type blockers, suggesting the involvement of Q-type channels. 5. In oxytocin-sensitive neurones, the peak amplitude of the [Ca2+]i response was not affected by Cd2+ alone, by combined Cd2+ and Ni2+, or by the mixture of nicardipine, omega-CgTX and omega-Aga IVA. By contrast, the responses evoked by depolarization with K+ were blocked by Cd2+. Both nicardipine and omega-CgTX blocked 65% of K+ response and an additional block of approximately 18% was obtained with omega-Aga IVA, suggesting the involvement of L-, N- and P-type channels. In combination, these antagonists strongly inhibited (approximately 80% reduction) the K+ responses. Further reduction to 18% was made by the Q-type blocker omega-MVIIC. Pre-incubation with L-, N- and P-type blockers caused an additional block of 71%. 6. Some supraoptic neurones (5-10%) responded to both vasopressin and oxytocin, with only the [Ca2+]i responses induced by vasopressin blocked (> 90% inhibition) by the mixture of Ca2+ channel antagonists. 7. In conclusion, both vasopressin and oxytocin magnocellular SO neurones have been shown to express T-, L-, N-, P-, Q- and R-type Ca2+ channels in their somata. Our results show that the vasopressin-induced [Ca2+]i increase in vasopressin-sensitive neurones is mediated by L-, N- and T-type Ca2+ channels and not by P- and Q-type channels; Ca2+ channels are not involved in oxytocin action on oxytocin-sensitive neurones and L-, N-, P- and Q-type channels control the K(+)-induced [Ca2+]i increase in SO neurones.

Animals↗
PubMed1985

CSF vasopressin rhythm is effectively insulated from osmotic regulation of plasma vasopressin.

By using our method for continuous removal of cisternal cerebrospinal fluid (CSF) and intermittent sampling of blood from unanesthetized freely moving cats, we investigated the effect of osmotic-induced changes in plasma vasopressin on the daily rhythm of CSF vasopressin. Examination of the daily profiles of vasopressin and osmolality in the CSF and plasma of six euhydrated animals showed that CSF vasopressin concentrations exhibit a clear daily rhythm, whereas CSF osmolality and plasma vasopressin and osmolality do not exhibit such daily variation. A 48-h period of water deprivation caused marked sustained elevations in plasma vasopressin concentrations, which returned to basal levels on rehydration. In contrast, water deprivation had only a small effect on the CSF vasopressin rhythm. Although there was a significant elevation of the normally low nighttime CSF vasopressin levels during water deprivation in three of the four animals studied, high daytime vasopressin levels were unaltered and the daily rhythm was clearly evident before, during, and after the period of water removal in all animals. Changes between plasma vasopressin and osmolality were significantly correlated in all animals. Changes between plasma and CSF osmolality were significantly correlated in three of the four animals. The data indicate that the circadian regulation of the CSF vasopressin rhythm is effectively insulated from the osmotic regulation of plasma vasopressin.

Animals↗
PubMed1984

Vasopressin in cardiovascular control: role of circulating vasopressin.

Vasopressin has been shown to elicit vasoconstriction in unanaesthetized animals at plasma concentrations similar to those associated with its renal antidiuretic effect. The vasconstrictor effects of vasopressin do not normally translate into pressor responses until relatively high plasma concentrations are reached. This appears to be related to very effective buffering by the baroreceptor reflex. In the absence of afferent signals from the baroreceptors (surgical denervation, but more importantly, low arterial pressure), the vasoconstriction elicited by vasopressin represents a significant part of the mechanisms that determine blood pressure. Vasopressin is clearly involved in the short-term control of blood pressure in situations such as haemorrhage, other volume-depleted states and dehydration. However, it is only one of several short-acting mechanisms which complement each other in the defence against hypotensive stresses. Under different conditions, the cardiovascular effects of vasopressin seem to have a component related to the central nervous system control of the circulation. Whether or not circulating vasopressin interacts with the newly described network of extrahypothalamic projections from the paraventricular nucleus is yet conjectural. However, the presence in the brain of vasopressin-containing pathways and of various types of receptors to vasopressin, as well as the existence of cardiovascular effects elicited by central administration of antidiuretic hormone, suggests a role for cerebral vasopressin in the control of autonomic function. Slightly elevated levels of vasopressin have been found in various forms of hypertension. Yet, the role of vasopressin, when present, may be more related to its antidiuretic than to its vasoconstrictor properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Photoaffinity labelling of the renal V2 vasopressin receptor. Identification and enrichment of a vasopressin-binding subunit.

To identify renal vasopressin receptor proteins, analogues of 1-deamino-vasopressin i.e. ([1-(2-mercapto)propionic acid]vasopressin, [Mpa1]VP) with photoreactive aryl-azido groups in position 4 and 8 of the vasopressin sequence were prepared. In the absence of ultraviolet light, these ligands exhibit a high binding affinity for the V2 vasopressin receptor in plasma membranes from bovine and rat kidney medulla (apparent dissociation constants 1.8 X 10(-9) M to 1.7 X 10(-8)M); the photoreactive analogues stimulate the renal vasopressin-sensitive adenylate cyclase. In photoaffinity labelling experiments with tritium-labelled ligands (34-50 Ci/mmol), a membrane protein from bovine kidney or rat kidney medulla with an apparent relative molecular mass (Mr) of 30 000 was preferentially and specifically labelled. The labelling of the 30 000-Mr protein was completely inhibited by a 10-100-fold molar excess of vasopressin; in contrast, angiotensin II, bradykinin or low-affinity analogues of vasopressin did not suppress the incorporation of the reactive ligands into this protein. The highest specific labelling yield and only a low amount of unspecific labelling was obtained with the analogue [Mpa1,Lys(N6-4-azidobenzoyl)8]VP. Preparative sodium dodecyl sulfate gel electrophoresis of bovine kidney membranes photolabelled with this analogue resulted in a 20-30-fold enrichment of the 30 000-Mr vasopressin-binding protein. Our results suggest that this photoreactive analogue of [1-deamino, 8-lysine]vasopressin is a suitable tool for further purification of the renal V2 vasopressin receptor binding subunit.

Adenylyl Cyclases↗
PubMed2006

Effects of YM218, a nonpeptide vasopressin V(1A) receptor-selective antagonist, on vasopressin-induced growth responses in human mesangial cells.

Mesangial cells are centrally-located glomerular pericytes with contractile, endocrine, and immunity-regulating functions. These cells are thought to maintain normal glomerular function, since mesangial cell proliferation and extracellular matrix formation are hallmarks of chronic glomerular disease. Vasopressin causes mesangial cell contraction, proliferation and hypertrophy. Consequently, the effects of YM218, a potent, nonpeptide vasopressin V(1A) receptor-selective antagonist, on the growth responses of human mesangial cells to vasopressin were investigated. YM218 showed high affinity for vasopressin V(1A) receptors, exhibiting a K(i) value of 0.18 nM. Vasopressin concentration-dependently increased intracellular Ca(2+) levels and induced hyperplasia and hypertrophy in cultured mesangial cells, YM218 potently inhibited these vasopressin-induced responses. These results clearly show that YM218 has both strong affinity for human mesangial cell vasopressin V(1A) receptors and great potency in inhibiting the vasopressin-induced growth responses of mesangial cells controlled by the vasopressin V(1A) receptors. The hyperplasia and hypertrophy of mesangial cells in vitro caused by vasopressin indicate its possible in vivo role in glomerular disease pathogenesis. Therefore, YM218 is a potent pharmacologic probe to investigate the physiologic and pathophysiologic roles of vasopressin in the development of renal disease.

Antidiuretic Hormone Receptor Antagonists↗
PubMed1997

Effects of SR 49059, an orally active V1a vasopressin receptor antagonist, on vasopressin-induced uterine contractions.

OBJECTIVE: To test the effect of SR 49059, an orally active, nonpeptide, selective and specific antagonist of the vasopressin V1a receptors in humans. DESIGN: A placebo-controlled, double-blind, cross-over trial. SETTING: The Department of Obstetrics and Gynaecology, Lund University Hospital, Sweden. PARTICIPANTS: Twelve healthy women, who had previously been sterilised by tubal ligation. INTERVENTIONS: The women participated on days 1, 2 or 3 of two menstrual cycles, with intrauterine pressure recordings and intravenous bolus injections of 10 pmol/kg body weight of lysine vasopressin given 1 h before and at 1, 2 and 3 h after oral administration of 300 mg of the study drug or of placebo. MAIN OUTCOME MEASURE: The area between the recording curve and zero level of pressure. Vital signs, safety parameters and drug plasma concentrations were also measured. RESULTS: The spontaneous uterine activity as well as the response to lysine vasopressin injections before administration of the test drugs were almost identical at the two experiments. Following intake of SR 49059 the area under the recording curve (0-10 min) after the second, third, and fourth injection of lysine vasopressin were reduced by 57, 42, and 66%, respectively, compared with placebo. Trough plasma concentrations of lysine vasopressin were markedly higher and systolic blood pressure slightly lower after antagonist administration than after placebo, whereas no significant difference between treatments was observed in diastolic pressure, heart rate or plasma osmolality. CONCLUSIONS: This study demonstrates for the first time a biological effect of an orally active vasopressin V1a antagonist in humans in vivo and the results support the importance of vasopressin in uterine activation. The differences between study drug and placebo treatments in lysine vasopressin levels and systolic blood pressure, but lack of difference in osmolality indicate that SR 49059 antagonises the effect of lysine vasopressin on the vasopressin V1a receptor, but not that on the vasopressin V2 one. It is suggested that SR 49059 be explored therapeutically in dysmenorrhoea.

Administration, Oral↗
PubMed1990

Effect of vasopressin on production of cerebrospinal fluid: possible role of vasopressin (V1)-receptors.

The goal of this study was to examine the role of arginine vasopressin in humoral regulation of choroid plexus function. Production of cerebrospinal fluid (CSF) was measured in anesthetized rabbits with an indicator dilution method, by using ventriculocisternal perfusion of artificial CSF containing blue dextran. Rabbits received either vehicle, vasopressin or vasopressin in the presence of the V1-antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(O-methyl)tyrosine]arginine vasopressin ([d(CH2)5Tyr(Me)]-AVP). Under control conditions, blood flow to the choroid plexus (measured with microspheres) averaged 369 +/- 26 (mean +/- SE) ml.min-1.100 g-1 and CSF production averaged 9.9 +/- 0.9 microliters/min. Intravenous infusion of vasopressin (2 mU.kg-1.min-1 for 90 min) decreased blood flow to the choroid plexus by 50-60% for the entire period of infusion. Vasopressin decreased production of CSF by 35 +/- 8%. Blood flow to the choroid plexus and production of CSF did not change significantly from control values in animals that received vehicle. In the presence of the V1-antagonist (10 micrograms/kg), infusion of vasopressin had no effect on blood flow to the choroid plexus or production of CSF. Thus circulating vasopressin, at plasma levels that are observed under physiological and pathophysiological conditions, has important effects on formation of CSF, as well as on blood flow to the choroid plexus. These findings are consistent with the hypothesis that effects of vasopressin on both variables are mediated through vasopressin (V1)-receptors.

Animals↗
PubMed1991

Up-regulation of renal adenylate cyclase-coupled vasopressin receptors after chronic administration of vasopressin antagonists to rats.

Chronic administration of vasopressin [antidiuretic hormone (ADH)] antagonists has been shown to produce a paradoxical antidiuresis in both ADH-replete and ADH-deplete (diabetes insipidus) rats. The antidiuretic effect is progressive, reaching maximal levels in 4 to 5 days, and sustained, persisting for at least 24 hr after cessation of treatment. The antidiuretic profiles associated with these antagonists do not coincide with the profiles of potent ADH agonists, arginine vasopressin and 1-deamino-8-D-arginine vasopressin. To investigate the mechanism of the antidiuretic effect of ADH antagonists, male diabetes insipidus rats were administered antagonists selective for the renal [adenylate cyclase-coupled (V2)] or pressor (phosphytidyl inositol-coupled) vasopressin receptor and urine output (volume and osmolality) and renal vasopressin receptor properties (concentration and affinity) were determined and compared to rats treated with arginine vasopressin or 1-deamino-8-D-arginine vasopressin. After acute administration, only the V2-acting antagonists were antidiuretic, but were 3 orders of magnitude less potent than 1-deamino-8-D-arginine vasopressin. Following chronic administration, all of the antagonists were antidiuretic, but the level of antidiuresis achieved with the phosphytidyl inositol-coupled vasopressin receptor-selective antagonist was 2- to 3-fold lower than for analogs with V2 activity. Maximal antidiuretic effects were realized in 5 days and were apparent at 24 hr after cessation of treatment. The antidiuretic activities and potencies of the ADH antagonists appeared to be increased following chronic antagonist administration. Finally, renal vasopressin receptor concentration was significantly elevated 24 hr after cessation of antagonist treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed2006

Intrauterine pressure, ischemia markers, and experienced pain during administration of a vasopressin V1a receptor antagonist in spontaneous and vasopressin-induced dysmenorrhea.

BACKGROUND: A model to study the effect of vasopressin V1a antagonist in dysmenorrhea. METHODS: A double-blind, randomized, placebo-controlled, cross-over trial was performed. Eight patients with primary dysmenorrhea and eight tuballigated, healthy subjects participated on days 1-2 of two consecutive menstruations. At each menstruation a bolus injection of 10 pmol/kg of vasopressin was administered before and during infusion of either 300 microg/min of atosiban or placebo. Intrauterine pressure was measured as area under the curve throughout the experiments. Ischemia markers in plasma and pain recorded by a visual analog scale were measured before and after each vasopressin injection as well as before and after the start of either atosiban or placebo infusion. RESULTS: Vasopressin injections elevated area under the curve in both healthy volunteers and dysmenorrhea subjects. The vasopressin-induced rise in area under the curve was lower during atosiban administration than during infusion of placebo in both groups. None of the ischemia markers differed between or within groups at vasopressin injections or atosiban/placebo infusions. In subjects with dysmenorrhea the increase in pain following the administration of vasopressin was significantly lower during atosiban than during placebo infusion. Healthy volunteers experienced only slight discomfort after the vasopressin injections. CONCLUSIONS: Atosiban reduces vasopressin-induced intrauterine pressure in both healthy volunteers and dysmenorrheics, and reported pain in subjects with dysmenorrhea. The ischemia markers are not a useful biomarker index in women with dysmenorrhea. The dysmenorrhea pain evoked by vasopressin correlated poorly with area under the curve, which may suggest that the effect is mediated by more than one V1a-like receptor. We conclude that this model with recordings in healthy women is useful in the evaluation of drug candidates for primary dysmenorrhea.

Adult↗
PubMed2004

Intracellular calcium increase and somatodendritic vasopressin release by vasopressin receptor agonists in the rat supraoptic nucleus: involvement of multiple intracellular transduction signals.

Vasopressin neurones of the supraoptic nucleus are autoregulated by vasopressin released from their soma and dendrites. Vasopressin binds to specific autoreceptors to trigger an influx of Ca(2+), and this response involves both phospholipase C (PLC) and adenylate cyclase (AC) pathways that, in the periphery, are activated by V(1) (V(1a) and V(1b))- and V(2)-type receptors. To investigate the pathways involved in the [Ca(2+)](i) response, [Ca(2+)](i) measurements were made on freshly dissociated neurones using Fura-2 microspectrofluorimetry, and vasopressin release was measured from isolated supraoptic nuclei. The [Ca(2+)](i) increase and vasopressin release induced by the V(1a) agonist were strongly inhibited by a PLC blocker, an IP(3) receptor antagonist, and a PKC blocker. An AC inhibitor did not affect the V(1a) response, while PKA inhibitors significantly reduced the V(1a)-induced [Ca(2+)](i) and release responses. The [Ca(2+)](i) increase and vasopressin release elicited by the V(2) agonist were attenuated not only by AC pathway blockers, but also by PLC inhibitors. Surprisingly, the V(1b) agonist showed no [Ca(2+)](i) or vasopressin release response. In conclusion, the V(1a) agonist activates both PLC and AC pathway, confirming the functional expression of a V(1a) vasopressin receptor on vasopressin neurones. The V(2) agonist activation of both PLC and AC pathways could result from an action on the PLC-linked unknown receptor, and/or the AC-linked dual angiotensin II-vasopressin receptor.

Adenylyl Cyclases↗