Effects of vasopressin during a pulmonary hypertensive crisis induced by acute hypoxia in a rat model of pulmonary hypertension

Background

A pulmonary hypertensive crisis (PHC) can be a life-threatening condition. We established a PHC model by exposing rats with monocrotaline (MCT)-induced pulmonary hypertension to acute hypoxia, and investigated the effects of vasopressin, phenylephrine, and norepinephrine on the PHC.

Advances in the neurophysiology of magnocellular neuroendocrine cells

Hypothalamic magnocellular neuroendocrine cells have unique electrical properties and a remarkable capacity for morphological and synaptic plasticity. Their large somatic size, their relatively uniform and dense clustering in the supraoptic and paraventricular nuclei, and their large axon terminals in the neurohypophysis make them an attractive target for direct electrophysiological interrogation. Here, we provide a brief review of significant recent findings in the neuroplasticity and neurophysiological properties of these neurones that were presented at the symposium “Electrophysiology of Magnocellular Neurons” during the 13th World Congress on Neurohypophysial Hormones in Ein Gedi, Israel in April 2019. Magnocellular vasopressin (VP) neurones respond directly to hypertonic stimulation with membrane depolarisation, which is triggered by cell shrinkage‐induced opening of an N‐terminal‐truncated variant of transient receptor potential vanilloid type‐1 (TRPV1) channels. New findings indicate that this mechanotransduction depends on actin and microtubule cytoskeletal networks, and that direct coupling of the TRPV1 channels to microtubules is responsible for mechanical gating of the channels. Vasopressin neurones also respond to osmostimulation by activation of epithelial Na⁺ channels (ENaC). It was shown recently that changes in ENaC activity modulate magnocellular neurone basal firing by generating tonic changes in membrane potential. Both oxytocin and VP neurones also undergo robust excitatory synapse plasticity during chronic osmotic stimulation. Recent findings indicate that new glutamate synapses induced during chronic salt loading express highly labile Ca²⁺‐permeable GluA1 receptors requiring continuous dendritic protein synthesis for synapse maintenance. Finally, recordings from the uniquely tractable neurohypophysial terminals recently revealed an unexpected property of activity‐dependent neuropeptide release. A significant fraction of the voltage‐dependent neurohypophysial neurosecretion was found to be independent of Ca²⁺ influx through voltage‐gated Ca²⁺ channels. Together, these findings provide a snapshot of significant new advances in the electrophysiological signalling mechanisms and neuroplasticity of the hypothalamic‐neurohypophysial system, a system that continues to make important contributions to the field of neurophysiology.     

Subtle sex differences in vasopressin mRNA expression in the embryonic mouse brain

Arginine vasopressin (AVP) is a neuropeptide which acts centrally to modulate numerous social behaviors. One receptor subtype through which these effects occur is the AVP 1a receptor (AVPR1A). The modulatory effects of Avp via the AVPR1A varies by species as well as sex, since both AVP and the AVPR1A tend to be expressed more prominently in males. Beyond these neuromodulatory effects there are also indications that the AVP system may play a role in early development to, in part, organize sex‐specific neural circuitry that is important to sexually dimorphic social behaviors in adulthood. However, to date, AVP's role in early development is poorly understood, particularly with respect to its differential effect on males and females. In order to determine the timing and distribution of the AVP system in early brain development, we examined the brains of male and female C57BL/6J mice between embryonic day (E) 12.5 and postnatal day (P) 2 and quantified Avp and Avpr1a mRNA using qPCR and AVPR1A protein using receptor autoradiography. The mRNA for Avp was measurable in males and females starting at E14.5, with males producing more than females, while Avpr1a mRNA was found as early as E12.5, with no difference in expression between sexes. AVPR1A binding was observed in both sexes starting at E16.5, and while there were no observed sex differences, binding density and the number of neuroanatomical areas did increase over time. These data are significant as they provide the first whole‐brain characterization of the vasopressin system in the embryonic mouse. Further, these findings are consistent with data from other species, that have documented a sex difference in the vasopressin system during early brain formation.     

Copeptin concentration following cardiac surgery as a prognostic marker of postoperative acute kidney injury: a prospective cohort study

BackgroundCopeptin, the C-terminal portion of the arginine vasopressin precursor, is a novel candidate biomarker. This study investigated the prognostic value of copeptin levels following cardiac surgery for the occurrence of postoperative acute kidney injury.MethodsWe studied 23 patients who underwent cardiac surgery between January 2018 and December 2019. The primary endpoint was postoperative acute kidney injury onset. Copeptin levels were measured before, right after, and daily for 7 days. The patients were divided into two groups according to the copeptin levels: low (values <43.7 pmol/L) and high (values ≥43.7 pmol/L). Correlations between copeptin levels and variables, such as central venous pressure, were assessed by bivariate analysis.ResultsThe high copeptin group exhibited significantly higher levels of arginine vasopressin and cortisol following surgery, compared to those of the low copeptin group. The copeptin concentration following surgery was correlated to central venous pressure (P=0.03) and norepinephrine administered dose (P=0.008). Also, the copeptin levels right after surgery robustly predicted the onset of postoperative acute kidney injury (area under the receiver operating characteristic curve of 0.83, P=0.004).ConclusionsElevated copeptin levels in patients following cardiac surgery predicted postoperative acute kidney injury development. Therefore, the copeptin concentration after surgery could represent a promising clinical biomarker of the postoperative cardiac outcome.     

Sex differences in circadian timing systems: Implications for disease

Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic–pituitary–gonadal axis (HPG), the hypothalamic–adrenal–pituitary (HPA) axis, and sleep–arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions.     

Regional and Systemic Haemodynamic Effects of Some Vasopressins: Structural Features of the Hormone which Prolong Activity

Abstract. Cardiac output and regional blood flows to myocardium, gut, uterus and kidney were determined in anaesthetised female rats by a single injection of ⁸⁶RbCl. The haemodynamic responses were measured at various time intervals up to 2 h after single I. V. injections of lysine-vasopressin and the following of its analogues: a) with extended peptide chains at the N-terminal (including “hormonogens”) N^a-glycyl-glycyl-glycyl-lysine-vasopressin, N^a-glycyl-glycyl-glycyl-arginine-vasopressin and N^a-D-valyl-lysine-vasopressin, b) “carba” modifications desamino-carba⁶-arginine-vasopressin, desamino-carba⁶-D-arginine⁸-vasopressin, desamino-carba⁶-ornithine⁸-vasopressin, desamino-dicarba-arginine-vasopressin and c) other steric alterations - desamino-D-arginine⁸-vasopressin and desamino-N-methylarginine⁸-vasopressin. Sub-pressor doses of lysine-vasopressin were followed by marked reductions in gut and uterus blood flows which reached a peak at 10 min. and had completely receded by 60 min. The presence of steric alterations in the C-terminal tripeptide of the molecule- D-arginine or N-methylarginine in sequence position 8- practically completely eliminated vascular activity. The same was true for N^a-D-valyl-lysine-vasopressin. None of the latter three analogues showed any inhibitor properties to the action of lysine-vasopressin. The two hormonogens (triglycyl N-terminal extensions) had to be given in doses 10 times greater to obtain a vasoconstrictor effect in gut and uterus equivalent in amplitude to that of lysine-vasopressin, but this effect was still present to the same degree 2 h later with the hormonogen of lysine-vasopressin, and was only starting to return to baseline values at the same time with the arginine-vasopressin hormonogen. The vascular potency of both mono-carba L-analogues was higher than that of lysine-vasopressin, and the effect was as prolonged as with the hormonogens. The dicarba analogue also showed a prolonged action, but with much reduced potency. No significant changes in renal or myocardial blood flows were observed at all. Molecular features of vasopressin smooth muscle activity were discussed, and a receptor model was proposed. It was suggested that the -S-S-, -SCH2 and -CH₂CH₂-bridges in the above analogues are not directly bound in the peptide-receptor complex and constitute the limiting factor determining complex duration, or persistence of the active peptide in the “receptor compartment”. These results provide an experimental basis for possible clinical application of triglycyl-vasopressin and carba-vasopressin in bleeding from both gut and uterus and for induction of menstruation.