VRQ397 (CRAVKY): a novel noncompetitive V2 receptor antagonist.

Vasopressin type 2 receptor (V2R) exhibits mostly important properties for hydroosmotic equilibrium and, to a lesser extent, on vasomotricity. Drugs currently acting on this receptor are analogs of the natural neuropeptide, arginine vasopressin (AVP), and hence are competitive ligands. Peptides that reproduce specific sequences of a given receptor have lately been reported to interfere with its action, and if such molecules arise from regions remote from the binding site they would be anticipated to exhibit noncompetitive antagonism, but this has yet to be shown for V2R. Six peptides reproducing juxtamembranous regions of V2R were designed and screened; the most effective peptide, cravky (labeled VRQ397), was characterized. VRQ397 was potent (IC(50) = 0.69 +/- 0.25 nM) and fully effective in inhibiting V2R-dependent physiological function, specifically desmopressin-L-desamino-8-arginine-vasopressin (DDAVP)-induced cremasteric vasorelaxation; this physiological functional assay was utilized to avoid overlooking interference of specific signaling events. A dose-response profile revealed a noncompetitive property of VRQ397; correspondingly, VRQ397 bound specifically to V2R-expressing cells could not displace its natural ligand, AVP, but modulated AVP binding kinetics (dissociation rate). Specificity of VRQ397 was further confirmed by its inability to bind to homologous V1 and oxytocin receptors and its inefficacy to alter responses to stimulation of these receptors. VRQ397 exhibited pharmacological permissiveness on V2R-induced signals, as it inhibited DDAVP-induced PGI(2) generation but not that of cAMP or recruitment of beta-arrestin2. Consistent with in vitro and ex vivo effects as a V2R antagonist, VRQ397 displayed anticipated in vivo aquaretic efficacy. We hereby describe the discovery of a first potent noncompetitive antagonist of V2R, which exhibits functional selectivity, in line with properties of a negative allosteric modulator.

[Supporting the conjugal system during the perinatal period: an experience in participatory research]. / Soutenir le système conjugal pendant la période périnatale: une expérience de recherche participatoire.

This article presents the process and results of a participatory study intended to develop and evaluate preventive interventions for couples in the process of becoming new parents. A total of 21 participants, 4 physicians, 8 couples, and an investigator, studied the interventions using a research approach derived from a constructivist paradigm, the fourth generation evaluation. Employing a family intervention model, the nurse guided and contributed to the investigation. The results enabled physicians to refine their perinatal care and facilitated the couples' adjustment to the arrival of their first child. The interventions, the research process, and the use of a family nursing model are promising for nursing applications.

[Is the family important in cardiovascular care?]. / La famille: est-elle si importante en soins cardiovasculaires?

Family care is an increasingly important component of nursing practice. A systemic perspective on a cardiac health problem compels nurses to consider the reciprocal relationship between the evolution of the illness and the patient's family dynamics. An increasing number of studies focus on how an illness impacts on the family and how the family can be either a source of stress for the patient or a welcome support. Based on various studies and on clinical examples from the authors' practice, this article stresses the importance for nurses to include the family in their cardiovascular nursing care whatever the clinical context or their expertise in family nursing. Systemic questioning that facilitates the sharing of the illness experience between family members and the exploration of the family's strengths and resources are nursing interventions that can be practiced in all clinical contexts. These interventions are important because they can considerably alleviate the patient's as well as and the family's suffering.

[Systemic nursing intervention in couples in which one member has cardiac insufficiency]. / Intervention systémique infirmière auprès de couples dont un des membres est atteint d'insuffisance cardiaque.

Chronic heart failure is a family affair since the spouse's quality of life is affected as much as that of the patient. This article deals with three clinical cases exploring the couple's perceptions of how the illness affected their marital relationship and how helpful the family systems nursing interventions have been. Three themes emerged from the analysis of the relationship between the evolution of the illness and the marital dynamics, and these are: a search for a balance between protectiveness/overprotectiveness, a reassessment of the marital relationship, and the adoption of new coping strategies. The family systems nursing interventions that were perceived as the most helpful were the systemic questionf1p4++ and the exploration of the couple's strengths and resources. These interventions allowed the couple to: 1) share their illness experience; 2) increase their understanding of the relationship between the illness and their marital dynamics, and 3) reflect on different ways to enhance their competence and resources in meeting with the challenges of this type of cardiac health problem.

A family systems nursing approach to hypertension.

This article focuses on a family systems nursing approach for essential hypertension. A case example is presented that describes the approach with a hypertensive woman with agoraphobia symptoms. A clinically significant decrease in the client's blood pressure occurred following the family sessions. Clinical observations of improved family relationships and symptom reduction corroborate research findings on the variables of perceived stress, anxiety levels and family coping resources. Interventions such as split-opinions, reframing, and rituals are described.

Dopaminergic transmission and (+)amphetamine-induced lethality in aggregated mice.

In aggregated mice the lethal dose 50% (LD50) of (+)amphetamine was found to be clearly lower than in isolated animals (dose ratio: 6:1), whereas with the pure dopamine uptake inhibitor GBR 12783, the ratio was only 2. Pretreatment of mice with GBR 12783 (20 or 40 mg/kg ip) did not reduce the lethality of (+)amphetamine (10 mg/kg) in aggregated mice. Taking into account their relative affinity for D1 and D2 dopamine receptors, various DA antagonists were opposed to (+)amphetamine (20 mg/kg) in aggregated mice. The specific D1 antagonist SCH 23390 was especially effective (ID50 10 micrograms/kg). The specific D2 antagonists (+/-) sulpiride and metoclopramide were effective for high doses (ID50 = 43 and 19 mg/kg respectively). The dopamine antagonists haloperidol and alpha-flupenthixol, less specific as regards D1 vs D2 receptors, had an ID50 of 66 and 186 micrograms/kg respectively. Association of the D1 antagonist SCH 23390 with the D2 antagonist (+/-) sulpiride resulted in an apparent additive effect for reducing the (+)amphetamine-induced lethality. A semi-chronic treatment with either the D1 agonist SKF 38393 (7 x 20 mg/kg) or (+)amphetamine (6 x 10 mg/kg) performed in isolated mice did not reduce the lethality induced by (+)amphetamine (20 mg/kg) in aggregated mice. The antagonism of the (+)amphetamine-induced lethality in aggregated mice, frequently used to screen meuroleptics, reveals their antagonistic activity towards D1 or D2 dopamine receptor types.