Comparative reactivity of medicinal gold(I) compounds with the cyclic peptide vasopressin and its diselenide analogue.

The reactions of the medicinal gold(I) compound auranofin and its close analogues with vasopressin and the diselenide analogue were comparatively investigated by LC-electrospray MS/MS. Evidence is gained of the possible cleavage of the S-S and Se-Se bridges induced by Au(I). Notably, we found that, in the absence of reducing agents, the sulfur and selenium atoms are metallated only at high temperature (70 °C) with the preferential binding of gold to selenium. The reaction with the S-S bridge can take place at physiological temperature (37 °C) under reducing conditions. The implications of these results are discussed in the general frame of the reactivity of biologically relevant soft Lewis acids with peptides and proteins.

Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from Conus miliaris.

Cone snails produce a fast-acting and often paralyzing venom, largely dominated by disulfide-rich conotoxins targeting ion channels. Although disulfide-poor conopeptides are usually minor components of cone snail venoms, their ability to target key membrane receptors such as GPCRs make them highly valuable as drug lead compounds. From the venom gland transcriptome of Conus miliaris, we report here on the discovery and characterization of two conopressins, which are nonapeptide ligands of the vasopressin/oxytocin receptor family. These novel sequence variants show unusual features, including a charge inversion at the critical position 8, with an aspartate instead of a highly conserved lysine or arginine residue. Both the amidated and acid C-terminal analogues were synthesized, followed by pharmacological characterization on human and zebrafish receptors and structural investigation by NMR. Whereas conopressin-M1 showed weak and only partial agonist activity at hV1bR (amidated form only) and ZFV1a1R (both amidated and acid form), both conopressin-M2 analogues acted as full agonists at the ZFV2 receptor with low micromolar affinity. Together with the NMR structures of amidated conopressins-M1, -M2 and -G, this study provides novel structure-activity relationship information that may help in the design of more selective ligands.

Arginine vasopressin antagonism in heart failure: Current status and possible new directions.

Modulating neurohormonal imbalance is the cornerstone of successful therapy in patients with chronic heart failure with reduced ejection fraction (HFrEF). Plasma arginine vasopressin (AVP) levels are elevated in HFrEF and may contribute to disease progression by excess signaling at either the V1a or V2 receptors. The effects of V1a receptor antagonism are almost completely unexplored, but V1a signaling is closely related to that for angiotensin II and blocking that receptor deserves further study. Interfering with V2 signaling causes free water diuresis and improves congestion without worsening renal function when added to loop diuretics but alone did not improve outcomes when carried into the post-acute phase in one large study. Outcomes in chronic HFrEF are quite good while outcomes in acute HF remain poor. Therefore, further study of V2 or combined V1/V2 blockade of the effects of AVP would most likely yield positive results in patients with acute HF, perhaps especially as alternative, not adjunctive therapy to loop diuretics.

[The pathway of vasopressin as a pharmacological target in nephrology: a narrative review].

ADH is a hormone secreted by neurohypophysis that plays different roles based on the target organ. At the renal level, this peptide is capable of causing electrolyte-free water absorption, thus playing a key role in the hydro-electrolytic balance. There are pathologies and disorders that jeopardize this balance and, in this field, ADH receptor inhibitors such as Vaptans could play a key role. By inhibiting the activation pathway of vasopressin, they are potentially useful in euvolemic and hypervolemic hypotonic hyponatremia. However, clinical trials in heart failure have not given favourable results on clinical outcomes. Even in SIADH, despite their wide use, there is no agreement by experts on their use. Since vaptans inhibit the cAMP pathway in tubular cells, their use has been proposed to inhibit cystogenesis. A clinical trial has shown favourable effects on ADPKD progression. Because vaptans have been shown to be effective in models of renal cysts disorders other than ADPKD, their use has been proposed in diseases such as nephronophthisis and recessive autosomal polycystic disease. Other possible uses of vaptans could be in kidney transplantation and cardiorenal syndrome. Due to the activity of ADH in coagulation and haemostasis, ADH's activation pathway by Desmopressin Acetate could be a useful strategy to reduce the risk of bleeding in biopsies in patients with haemorrhagic risk.

Vasopressin and alcohol: a multifaceted relationship.

BACKGROUND: Arginine vasopressin (VP) has been implicated in a number of neuropsychiatric disorders with an emphasis on situations where stress increased the severity of the disorder. Based on this hypothesized role for VP in neuropsychiatric disorders, much research is currently being undertaken in humans and animals to test VP as a target for treatment of a number of these disorders including alcohol abuse. OBJECTIVES: To provide a summary of the literature regarding the role of VP in alcohol- and stress-related behaviors including the use of drugs that target VP in clinical trials. RESULTS: Changes in various components of the VP system occur with alcohol and stress. Manipulating VP or its receptors can alter alcohol- and stress-related behaviors including tolerance to alcohol, alcohol drinking, and anxiety-like behavior. Finally, the hypothalamic-pituitary-adrenal axis response to alcohol is also altered by manipulating the VP system. However, clinical trials of VP antagonists have had mixed results. CONCLUSIONS: A review of VP's involvement in alcohol's actions demonstrates that there is much to be learned about brain regions involved in VP-mediated effects on behavior. Thus, future work should focus on elucidating relevant brain regions. By using previous knowledge of the actions of VP and determining the brain regions and/or systems involved in its different behavioral effects, it may be possible to identify a specific receptor subtype target, drug treatment combination, or specific clinical contexts that may point toward a more successful treatment.

Combined Catalase and ADH Inhibition Ameliorates Ethanol-Induced Myocardial Dysfunction Despite Causing Oxidative Stress in Conscious Female Rats.

BACKGROUND: Ethanol (EtOH)-evoked oxidative stress, which contributes to myocardial dysfunction in proestrus rats, is mediated by increases in NADPH oxidase (Nox) activity, malondialdehyde (MDA), and ERK1/2 phosphorylation. Whether these biochemical responses, which are triggered by alcohol-derived acetaldehyde in noncardiac tissues, occur in proestrus rats' hearts remains unknown. Therefore, we elucidated the roles of alcohol dehydrogenase (ADH), cytochrome P4502E1 (CYP2E1), and catalase, which catalyze alcohol oxidation to acetaldehyde, in these alcohol-evoked biochemical and hemodynamic responses in proestrus rats. METHODS: Conscious proestrus rats prepared for measurements of left ventricular (LV) function and blood pressure (BP) received EtOH (1.5 g/kg, intravenous [i.v.] infusion over 30 minutes) or saline 30 minutes after an ADH and CYP2E1 inhibitor, 4-methylpyrazole (4-MP) (82 mg/kg, intraperitoneal), a catalase inhibitor, 3-AT (0.5 g/kg, i.v.), their combination, or vehicle. LV function and BP were monitored for additional 60 minutes after EtOH or saline infusion before collecting the hearts for ex vivo measurements of LV reactive oxygen species (ROS), Nox activity, MDA, and ERK1/2 phosphorylation. RESULTS: EtOH reduced LV function (dP/dtmax and LV developed pressure) and BP, and increased cardiac Nox activity, ROS and MDA levels, and ERK1/2 phosphorylation. Either inhibitor partially, and their combination significantly, attenuated these responses despite the substantially higher blood EtOH level, and the increased cardiac oxidative stress and reduced BP caused by 3-AT alone or with 4-MP. The inhibitors reduced cardiac MDA level and reversed EtOH effect on cardiac and plasma MDA. CONCLUSIONS: EtOH oxidative metabolism plays a pivotal role in the EtOH-evoked LV oxidative stress and dysfunction in proestrus rats. Notably, catalase inhibition (3-AT) caused cardiac oxidative stress and hypotension.

Characterization of the effects of the vasopressin V2 receptor on sweating, fluid balance, and performance during exercise.

A regulatory effect of arginine vasopressin (AVP) on sweat water conservation has been hypothesized but not definitively evaluated. AVP-mediated insertion of sweat and salivary gland aquaporin-5 (AQP5) water channels through activation of the vasopressin type 2 receptor (V2R) remains an attractive, yet unexplored, mechanism that could result in a more concentrated sweat with resultant decreased water loss. Ten runners participated in a double-blind randomized control treadmill trial under three separate pharmacological conditions: a placebo, V2R agonist (0.2 mg desmopressin), or V2R antagonist (30 mg tolvaptan). After a familiarization trial, runners ran for 60 min at 60% of peak speed followed by a performance trial to volitional exhaustion. Outcome variables were collected at three exercise time points: baseline, after the steady-state run, and after the performance run. Body weight losses were <2% across all three trials. Significant pharmacological condition effects were noted for urine osmolality [F = 84.98; P < 0.0001] and urine sodium concentration ([Na(+)]) [F = 38.9; P < 0.0001], which verified both pharmacological activation and inhibition of the V2R at the kidney collecting duct. Plasma osmolality and [Na(+)] demonstrated significant exercise (F = 26.0 and F = 11.1; P < 0.0001) and condition (F = 5.1 and F = 3.8; P < 0.05) effects (osmolality and [Na(+)], respectively). No significant exercise or condition effects were noted for either sweat or salivary [Na(+)]. Significant exercise effects were noted for plasma [AVP] (F = 22.3; P < 0.0001), peak core temperature (F = 103.3; P < 0.0001), percent body weight change (F = 6.3; P = 0.02), plasma volume change (F = 21.8; P < 0.0001), and thirst rating (F = 78.2; P < 0.0001). Performance time was not altered between conditions (P = 0.80). In summary, AVP acting at V2R does not appear to regulate water losses from body fluids other than renal excretion during exercise.

Conivaptan therapy in an infant with severe hyponatremia and congestive heart failure.

Conivaptan is a nonspecific arginine vasopressin receptor antagonist that has been used as therapy in adults who have hypervolemic hyponatremia due to congestive heart failure. Its use in children with congestive heart failure has not been reported. We describe the use of conivaptan in a 4-month-old infant girl with severe hypervolemic hyponatremia and heart failure. A therapeutic weight-based dose was extrapolated from the adult dose. Conivaptan therapy was administered for 48 hours, after which the patient recovered from her hyponatremia without untoward effects. Arginine vasopressin receptor antagonists such as conivaptan may be useful as therapy for hyponatremia associated with heart failure. Further studies are required before conivaptan can be recommended for routine use in children.

Pharmacokinetics, pharmacodynamics, and safety of tolvaptan, a nonpeptide AVP antagonist, during ascending single-dose studies in healthy subjects.

Two single-center, double-blind, randomized, placebo-controlled, sequentially enrolled studies were conducted. In study 1, 8 subjects (6 active/2 placebo) received 60-, 90-, 120-, 180-, or 240-mg tolvaptan/matching placebo. In study 2, 9 subjects (6 active/3 placebo) received 180-, 240-, 300-, 360-, 420-, or 480-mg tolvaptan/matching placebo. Increases in tolvaptan C(max) were less than dose-proportional and plateaued at doses greater than 240 mg; AUC(infinity) increased proportionally with dose. Changes in serum K(+), creatinine clearance, and Na(+), K(+), and osmolality urinary excretion were similar to the placebo group for the 0- to 24-hour interval following dosing. Changes were observed in plasma arginine vasopressin, serum aldosterone, and plasma renin activity but were not clinically significant. Increases were seen in mean serum Na(+) concentrations (4-6 mEq/L), plasma osmolality ( approximately 8 mOsm/kg), and free water clearance ( approximately 6 mL/min) throughout 0 to 24 hours; none of these increases was dose dependent. Only total urine volume excretion (0-72 hours postdose) increased linearly with dose. As plasma tolvaptan concentrations increased, the duration that the urine excretion rate remained above baseline rates also increased. The most frequent adverse events--excess thirst, frequent urination, and dry mouth--appeared to be related to the pharmacological action of tolvaptan. No dose-limiting toxicities were observed.