Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. A novel slowly activating voltage-dependent K+ current was observed in isolated nerve terminals from rat neurohypophysis using the whole-cell configuration of the patch-clamp technique. 2. The activation kinetics of the slow current could be fitted assuming Hodgkin--Huxley-type kinetics, an exponential, n, of 1.3 and activation time constants decreasing from 4 s at -50 mV to 0.7s at +40 mV. 3. A positive shift of reversal potential was observed when [K+] was increased in the bath solution. The current is carried mainly but not exclusively by K+ ions. 4. When intracellular free [Mg2+] was low (approximately 60 microM), average current density was 74 pA pF-1 at membrane potentials around 0 mV. In 83% of nerve terminals current amplitude was > 10 pA pF-1. 5. The slow current was never observed when the pipette contained 4.6 mM free Mg2+. At a physiological level of free Mg2+ (0.5 mM) the average current density was 16 pA pF-1. 6. When nerve terminals were analysed after patch-clamp experiments for vasopressin content by immunodetection, no difference in current amplitude was found between the terminals containing vasopressin and all analysed terminals. 7. The voltage dependence of activation was fitted by a Boltzmann equation giving a half-activation potential of -37 mV and a slope factor of about 9 mV. 8. Tail current deactivation kinetics was biexponential with time constants of 0.12 and 1.5s. Kinetics was dependent on the duration of the activating pulse. 9. Noise analysis of the slow current indicated a single-channel current of 0.33 pA at +6 mV, corresponding to a single-channel conductance of 4.3 pS. 10. This is the first demonstration of a current similar to the slow K+ current, IKs, in a neurone, suggesting that a protein similar to the IKs-inducing channel protein IsK (minK) may be present in peptidergic nerve terminals. 11. The activation properties are consistent with a role of the slow current in inhibition of excitability, at least at the level of the nerve terminal.
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PMID:A slowly activating voltage-dependent K+ current in rat pituitary nerve terminals. 900 56

The effects of extracellular Mg2+ on receptor-mediated Ca(2+)-permeable non-selective cation currents were investigated in a cultured aortic smooth muscle cell line (A7r5) from rat thoracic aorta, using the whole-cell voltage-clamp technique. Under the Cs(+)-containing internal solution, both vasopressin and endothelin-1 (100 nM) activated a long-lasting inward current with a high noise level. The reversal potential of these agonists-induced current was approximately +0 mV, and was not significantly altered by the replacement of [Cl-]i or [Cl-]o, suggesting that the inward current was a cation-selective channel. La3+ and Cd2+ (1 mM) almost completely abolished the vasopressin or endothelin-induced non-selective cation current; however, nifedipine (10 microM) failed to inhibit it significantly. Extracellular Mg2+ (3-20 mM) also markedly inhibited the vasopressin- or endothelin-induced non-selective cation current in a concentration-dependent manner. When a non-hydrolysable GTP-analogue, GTP gamma S (1 mM), was applied from the patch pipette, the non-selective cation current was gradually activated even in the absence of agonist (vasopressin or endothelin-1), probably due to the direct activation of GTP-binding proteins coupled to the receptors. Extracellular Mg2+ (3-20 mM) also suppressed the activation of non-selective cation current induced by GTP gamma S, suggesting that the inhibitory sites of Mg2+ are not located on the receptors. These results suggest that extracellular Mg2+ inhibits receptor-mediated non-selective cation current, which may contribute to the relaxation effects of Mg2+ in vascular smooth muscle cells.
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PMID:Extracellular Mg2+ inhibits receptor-mediated Ca(2+)-permeable non-selective cation currents in aortic smooth muscle cells. 904 6

Extracellular Ca2+ is required for the action of oxytocin and both the hormone and its receptor have binding sites for divalent metal cations. To characterize the cation-bound form of oxytocin, we monitored the binding of Ca2+ and Mg2+ to oxytocin as well as peptides representing its ring and tail regions in trifluoroethanol, a lipid-mimetic solvent, using CD and fluorescence spectroscopy. Binding Ca2+ (Kd approximately 50 microM) caused drastic CD and fluorescence changes leading to a helical conformation. Mg2+ caused CD changes smaller than and opposite to Ca2+. However, the helical structure was enhanced when both Ca2+ and Mg2+ were present together. CD changes in the tail peptide of oxytocin showed its ability to bind Ca2+ and Mg2+ whereas the vasopressin tail peptide did not bind either cation. CD spectral changes on Ca2+ and Mg2+ binding to tocinoic acid (the ring moiety of oxytocin) were much smaller than those of oxytocin. These data suggest that the tail segment of oxytocin potentiates Ca2+ binding by the ring. While vasopressin displayed a CD spectrum similar to that of oxytocin, CD spectra of its cation-bound forms were markedly different from those of oxytocin; the Ca(2+)-induced CD changes in vasopressin were very much smaller and of opposite sign, and Mg(2+)-induced ones significantly larger than in oxytocin. Taken together, our observations bring out the structural differences between oxytocin and vasopressin in the context of their interaction with Ca2+ and Mg2+. This may be relevant to understanding the differences in the bioactive conformations and receptor interactions of the two hormones.
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PMID:Interaction of oxytocin with Ca2+: I. CD and fluorescence spectral characterization and comparison with vasopressin. 906 67

This study examines the effects of magnesium on vascular tone and reactivity in mesenteric resistance arteries from 17-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Third-order branches of mesenteric arteries were mounted in a pressurized flow chamber and studied with constant flow and transmural pressure. The mesenteric arteries were perfused extra- and intra-luminally with physiological salt solution containing a normal (1.2 mmol/L), high (4.8 mmol/L), or low (0.15 mmol/L) magnesium concentration. Vascular reactivity to norepinephrine and vasopressin was examined when the agonists were applied extraluminally. High magnesium increased lumen diameter and decreased media thickness whereas low magnesium decreased lumen diameter and increased media thickness in mesenteric arteries from both SHR and WKY rats. The effects of magnesium on vascular tone were less in arteries from SHR compared with normotensive controls (p < 0.05). Low magnesium potentiated norepinephrine-induced vasoconstriction in SHR (p < 0.001) but not in WKY. Low magnesium did not modify vasopressin-induced vasoconstriction in either SHR or WKY. High magnesium attenuated vasopressin- and norepinephrine-induced vasoconstriction in SHR (p < 0.01), whereas high magnesium attenuated only norepinephrine-induced vasoconstriction in WKY (p < 0.001). These data suggest that magnesium has differential modulatory effects on vascular tone and reactivity in mesenteric resistance arteries of SHR and WKY. Magnesium may play an important role in the modulation of peripheral resistance in hypertension.
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PMID:Effect of magnesium on vascular tone and reactivity in pressurized mesenteric resistance arteries from spontaneously hypertensive rats. 919 55

We have investigated the effects of mono-substitutions with the conformationally restricted amino acid, 1,2,3,4 tetrahydroisoquinoline-3-carboxylic acid (Tic) at position 3 in arginine vasopressin (AVP), at positions 2, 3 and 7 in potent non-selective cyclic AVP V2/V1a antagonists, in potent and selective cyclic and linear AVP V1a antagonists, in a potent and selective oxytocin antagonist and in a new potent linear oxytocin antagonist Phaa-D-Tyr(Me)-Ile-Val-Asn-Orn-Pro-Orn-NH2 (10). We report here the solid-phase synthesis of peptide 10 together with the following Tic-substituted peptides: 1. [Tic3]AVP: 2. dICH2)5[D-TIc2]VAVP: 3, d(CH2)5[D-Tyr(Et)2Tic3]VAVP: 4, d(CH2)5[Tic2Ala-NH2(9)]AVP: 5. d(CH2)5[Tyr]Me)2.Tic3,Ala-NH2(9)]AVP: 6. d(CH2)5 [Tyr(Me)2,Tic7]AVP: 7, Phaa-D-Tyr(Me)-Phe-Gln-Asn-Lys-Tic-Arg-NH2: 8, desGly-NH2,d[CH2]5[Tic2,Thr4]OVT: 9. desGly-NH2d(CH2)5[Tyr(Me)2Thr4, Tic7[OVT; 11, Phaa-D-Tic-Ile-Val-Asn-Orn-Pro-Orn-NH2, using previously described methods. The protected precursors were synthesized by the solid-phase method, cleaved, purified and deblocked with sodium in liquid ammonia to give the free peptides 1-11 which were purified by methods previously described. Peptides 1-11 were examined for agonistic and antagonistic potency in oxytocic (in vitro, without Mg2+) and AVP antidiuretic (V2-receptor) and vasopressor (V1a-receptor) assays. Tic3 substitution in AVP led to drastic losses of V2, V1a and oxytocic agonistic activities in peptide 1, L- and D-Tic2 substitutions led to drastic losses of anti-V2/anti-V1a and anti-oxytocic potencies in peptides 2, 4, 8 and 11 (peptide 2 retained substantial anti-oxytocic potency; pA2 = 7.25 +/- 0.025). Whereas Tic3 substitution in the selective V1a antagonist d(CH2)5[Tyr(Me)2,Ala-NH2(9)]AVP(C) led to a drastic reduction in anti-V1a potency (from anti-V1a pA2 8.75 to 6.37 for peptide 5, remarkably, Tic3 substitution in the V2/V1a antagonist d(CH2)5(D-Tyr(Et)2]VAVP(B) led to full retention of anti-V2 potency and a 95% reduction in anti-V1a potency. With an anti-V2 pA2 = 7.69 +/- 0.05 and anti-V1a pA2 = 6.95 +/- 0.03. d(CH2)5[D-Tyr(Et)2, Tic3]VAVP exhibits a 13-fold gain in anti-V2/anti-V1a selectivity compared to (B). Tic7 substitutions are very well tolerated in peptides 6, 7 and 9 with excellent retention of the characteristic potencies of the parent peptides. The findings on the effects of Tic3 substitutions reported here may provide promising leads to the design of more selective and possibly orally active V2 antagonists for use as pharmacological tools and as therapeutic clinical agents for the treatment of the syndrome of the inappropriate secretion of antidiuretic hormone (SIADH).
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PMID:An exploration of the effects of L- and D-tetrahydroisoquinoline-3-carboxylic acid substitutions at positions 2, 3 and 7 in cyclic and linear antagonists of vasopressin and oxytocin and at position 3 in arginine vasopressin. 922 85

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).
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PMID:Position three in vasopressin antagonist tolerates conformationally restricted and aromatic amino acid substitutions: a striking contrast with vasopressin agonists. 923 Apr 69

Hypothalamo-neurohypophysial magnocellular neurons display specific electrical activities in relation to the mode of release of their hormonal content (vasopressin or oxytocin). These activities are under strong glutamatergic excitatory control. The implication of NMDA receptors in the control of vasopressinergic and oxytocinergic neurons is still a matter of debate. We here report the first detailed characterization of functional properties of NMDA receptors in voltage-clamped magnocellular neurons acutely dissociated from the supraoptic nucleus. All cells responded to NMDA with currents that reversed polarity around 0 mV and were inhibited by D-2-amino-5-phosphonovalerate (D-APV) and by 100 microM extracellular Mg2+ (at -80 mV). Sensitivity to the co-agonist glycine (EC50, 2 microM) was low compared with most other neuronal preparations. The receptors displayed low sensitivity to ifenprodil, were insensitive to glycine-independent potentiation by spermine, and had a unitary conductance of 50 pS. No evidence was found for two distinct cell populations, suggesting that oxytocinergic and vasopressinergic neurons express similar NMDA receptors. Characterization of NMDA receptors at different postnatal ages revealed a transient increase in density of NMDA currents during the second postnatal week. This was accompanied by a specific decrease in sensitivity to D-APV, with no change in NMDA sensitivity or any other properties studied. Supraoptic NMDA receptors thus present characteristics that strikingly resemble those of reconstituted receptors composed of NR1 and NR2A subunits. Understanding the functional significance of the development of NMDA receptors in the supraoptic nucleus will require further knowledge about the maturation of neuronal excitability, synaptic connections and neurohormone release mechanisms.
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PMID:NMDA receptor properties in rat supraoptic magnocellular neurons: characterization and postnatal development. 924 Apr 1

Effects of arginine-vasopressin (AVP) on neurons in the central amygdaloid nucleus (ACe) were investigated with rat brain slice preparations using extracellular recording methods. Of 160 ACe neurons tested, 70 cells (44%) were excited and 9 cells (6%) were inhibited by bath application of AVP at 3 x 10(-7) M. The excitatory effects of AVP were dose-dependent and the threshold concentration was approximately 10(-10) to 10(-9) M. The excitatory effects of AVP persisted under blockade of synaptic transmission by perfusing with Ca2+-free and high-Mg2+ medium, whereas the inhibitory effects were abolished by synaptic blockade. AVP-induced effects were mimicked by a V1-receptor agonist and completely blocked by a selective V1-antagonist. V2-agonist produced no effects on ACe neurons and V2-antagonist had no effect on AVP-induced excitation. These results showed that the excitatory effect of AVP on ACe neurons was produced by a direct action through the V1-receptors, whereas the inhibitory response of ACe neurons to AVP seemed to be produced by an indirect action. The results of this study suggest that AVP is involved in the amygdala-relevant functions as a neurotransmitter or a neuromodulator.
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PMID:Effects of vasopressin and involvement of receptor subtypes in the rat central amygdaloid nucleus in vitro. 936 24

The aim of this study was to investigate the effects of the antidiuretic hormone arginine vasopressin (AVP), which is released in vivo during dehydration and hypovolemia to prevent further water loss, on the activity of neurons in the subfornical organ (SFO). The SFO is a brain structure with an open blood-brain barrier and is critically involved in angiotensin II (ANG II)-dependent water intake. SFO neurons were recorded extracellularly in tissue slices of the rat brain and were tested for responsiveness to AVP and ANG II. About one-half of 159 neurons tested with an AVP concentration of 10(-6) M in the superfusion medium were responsive, and approximately equal proportions were excited and inhibited. Neurons exhibiting the different response types did not differ from each other with respect to spontaneous discharge rate, latency, and duration of the response. Excitatory and inhibitory responses to AVP were dose dependent and reversible, and their threshold concentrations (10(-8) to 10(-9) M) were similar. Superfusion with a medium low in Ca2+ and high in Mg2+ showed that the excitatory effect is most likely direct, whereas the inhibitory effect largely depends on inhibitory synaptic interaction. About one-half of the SFO neurons excited by ANG II (10(-7) M) were responsive to AVP (10(-6) M), and equal proportions were inhibited and excited. Both excitatory and inhibitory AVP actions were blocked by the V1-receptor antagonist, Manning compound, and neurons responsive to AVP did not respond to the V2-receptor agonist [deamino-Cys1,D-Arg8]vasopressin. It is concluded that AVP, probably released from synaptic terminals, may increase or decrease the activity of neurons in the SFO, many of which are activated by ANG II. In contrast to previous experiments on ducks, in which the exclusively excitatory effect of the avian antidiuretic hormone arginine vasotocin on ANG II-sensitive SFO neurons correlates well with the dipsogenic effect of both peptides, a greater functional heterogeneity exists among AVP-responsive neurons in the rat SFO.
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PMID:Heterogeneous actions of vasopressin on ANG II-sensitive neurons in the subfornical organ of rats. 943 67

Previous experiments demonstrated that excitatory amino acids participate in the osmotic regulation of vasopressin secretion, but the specific involvement of N-methyl-D-aspartic acid (NMDA) receptors was not evaluated. This was demonstrated in the present studies. NMDA stimulated vasopressin release from perifused explants of the hypothalamo-neurohypophyseal system (HNS), and osmotic stimulation of vasopressin release was inhibited by MK-801 (10 microM) and AP5 (100 microM) NMDA receptor antagonists. The effective concentration of NMDA was dependent upon the Mg2+ concentration of the perifusate with stimulation observed at 1 microM NMDA in Mg2+-replete compared with 5 microM in low-Mg2+ medium. Previous experiments also demonstrated that estradiol and dihydrotestosterone (DHT) inhibited osmotically stimulated vasopressin secretion, and a nongenomic mechanism of action was suggested by the ability of steroids conjugated to bovine serum albumin to replicate the effect. Experiments were performed to explore the potential role of NMDA receptors in this mechanism. Estradiol (50 pg/ml) and DHT (3 ng/ml) inhibited NMDA stimulated vasopressin release in perifused HNS explants. These results suggest a role of NMDA receptors in the mediation of vasopressin secretion in osmotically stimulated release. Furthermore, estradiol and DHT may exert their inhibitory effect on osmotically stimulated vasopressin release via the NMDA receptor.
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PMID:N-methyl-D-aspartic acid stimulation of vasopressin release: role in osmotic regulation and modulation by gonadal steroids. 974 85


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