Nischarin Is Not the Functional I1 Imidazoline Receptor Involved in Blood Pressure Regulation.

Imidazoline receptor antisera selected/Nischarin was proposed several years ago as the functional entity for the I1 medullary receptors (I1Rs) targeted, together with α2-adrenoceptors, by the centrally acting antihypertensive drugs, such as clonidine. The objective of this study was to test this assumption using a pyrroline analog of clonidine, LNP599, which, unlike clonidine and related compounds, displays high selectivity toward I1Rs. Cardiovascular effects of LNP599 (3 mg/kg intravenous) were evaluated in anesthetized, artificially ventilated nischarin mutant rats expressing a truncated form of nischarin lacking the putative imidazoline binding site.

Protective effects of the imidazoline-like drug lnp599 in a marmoset model of obesity-induced metabolic disorders.

Background/objectives: Overweight and obesity are undoubtable risk factors for type 2 diabetes and cardiovascular diseases and significantly contribute to the global morbi-mortality. We previoulsy reported that LNP599, a pharmacological imidazoline-like activator of hepatic AMPK/adiponectin signaling, protects against the development of adiposity and obesity and the associated cardio-metabolic disorders, suggesting that it may be a suitable drug candidate for a therapeutic approach targeting the development of obesity at very early stages. The objective of the present study was to evaluate the metabolic effects of LNP599 in a model of diet-induced overweight and metabolic disorders in a nonhuman primate, the common marmoset (Callithrix jacchus), and more particularly to establish the impact of the compound on cholesterol homeostasis, i.

Barrel cortex VIP/ChAT interneurons suppress sensory responses in vivo.

Cortical interneurons expressing vasoactive intestinal polypeptide (VIP) and choline acetyltransferase (ChAT) are sparsely distributed throughout the neocortex, constituting only 0.5% of its neuronal population. The co-expression of VIP and ChAT suggests that these VIP/ChAT interneurons (VChIs) can release both γ-aminobutyric acid (GABA) and acetylcholine (ACh).

Increased expression of blood muscarinic receptors in patients with reflex syncope.

Aims: Pathophysiology of reflex syncope is not fully understood but a vagal overactivity might be involved in this syncope. Previously, overexpression of muscarinic M2 receptors and acetylcholinesterase was found in particular in the heart and in lymphocytes of rabbits with vagal overactivity as well as in hearts of Sudden Infant Death Syndromes. The aim of this present study was to look at M2 receptor expression in blood of patients with reflex syncope.

NEAT1 is overexpressed in Parkinson's disease substantia nigra and confers drug-inducible neuroprotection from oxidative stress.

Recent reports attribute numerous regulatory functions to the nuclear paraspeckle-forming long noncoding RNA, nuclear enriched assembly transcript 1 (NEAT1), but the implications of its involvement in Parkinson's disease (PD) remain controversial. To address this issue, we assessed NEAT1 expression levels and cell type patterns in the substantia nigra (SN) from 53 donors with and without PD, as well as in interference tissue culture tests followed by multiple in-house and web-available models of PD. PCR quantification identified elevated levels of NEAT1 expression in the PD SN compared with control brains, an elevation that was reproducible across a multitude of disease models.

Effects of imidazoline-like drugs on liver and adipose tissues, and their role in preventing obesity and associated cardio-metabolic disorders.

Background/objectives: We previously observed that selective agonists of the sympatho-inhibitory I imidazoline receptors (LNP ligands) have favorable effects on several cardiovascular and metabolic disorders defining the metabolic syndrome, including body weight. The objectives of this study were to explore the effects of LNPs on adiposity and the mechanisms involved, and to evaluate their impact on metabolic homeostasis.

Methods: Young Zucker fa/fa rats were treated with LNP599 (10 mg/kg/day) for 12 weeks.

Comparison of bioimpedance spectroscopy and X-Ray micro-computed tomography for total fat volume measurement in mice.

Obesity and the metabolic syndrome are two pathologies whose prevalence are in a constant increase. Evaluation of the total fat mass but also of the distribution between visceral and subcutaneous adipose tissue are important factors while assessing the pathophysiology of these two pathologies. Computed tomography (CT) and bioimpedance (BIS) are the translational methods the most frequently used in human beings as well as in rodent models in longitudinal studies on adiposity and obesity.

Imidazoline-like drugs improve insulin sensitivity through peripheral stimulation of adiponectin and AMPK pathways in a rat model of glucose intolerance.

Altered adiponectin signaling and chronic sympathetic hyperactivity have both been proposed as key factors in the pathogenesis of metabolic syndrome. We recently reported that activation of I1 imidazoline receptors (I1R) improves several symptoms of the metabolic syndrome through sympathoinhibition and increases adiponectin plasma levels in a rat model of metabolic syndrome (Fellmann L, Regnault V, Greney H, et al. J Pharmacol Exp Ther 346: 370-380, 2013).

The Src homology and collagen A (ShcA) adaptor protein is required for the spatial organization of the costamere/Z-disk network during heart development.

Src homology and collagen A (ShcA) is an adaptor protein that binds to tyrosine kinase receptors. Its germ line deletion is embryonic lethal with abnormal cardiovascular system formation, and its role in cardiovascular development is unknown. To investigate its functional role in cardiovascular development in mice, ShcA was deleted in cardiomyocytes and vascular smooth muscle cells by crossing ShcA flox mice with SM22a-Cre transgenic mice.

A new pyrroline compound selective for I1-imidazoline receptors improves metabolic syndrome in rats.

Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for nonadrenergic I1-imidazoline receptors (I1Rs) may represent a new concept in MetS pharmacotherapy.

Constitutive overexpression of muscarinic receptors leads to vagal hyperreactivity.

Background: Alterations in muscarinic receptor expression and acetylcholinesterase (AchE) activity have been observed in tissues from Sudden Infant Death Syndrome (SIDS). Vagal overactivity has been proposed as a possible cause of SIDS as well as of vasovagal syncopes. The aim of the present study was to seek whether muscarinic receptor overexpression may be the underlying mechanism of vagal hyperreactivity.

Cardiac muscarinic receptor overexpression in sudden infant death syndrome.

Background: Sudden infant death syndrome (SIDS) remains the leading cause of death among infants less than 1 year of age. Disturbed expression of some neurotransmitters and their receptors has been shown in the central nervous system of SIDS victims but no biological abnormality of the peripheral vago-cardiac system has been demonstrated to date. The present study aimed to seek vago-cardiac abnormalities in SIDS victims.

Activation of CD47 receptors causes histamine secretion from mast cells.

Mast cells play pivotal roles in allergic and inflammatory processes via distinct activation pathways. Mucosal and serosal mast cells are activated by the IgE/FcepsilonRI pathway, while only serosal mast cells are activated by basic secretagogues. We show that CD47 receptors are expressed on rat peritoneal mast cells.

Cyclin dependent kinase inhibitors prevent apoptosis of postmitotic mouse motoneurons.

Recent evidence suggests that apoptosis in post-mitotic neurons involves an aborted attempt of cells to re-enter the cell cycle which is characterized by increased expression of cyclins, such as cyclin D1, prior to death. However, such cyclins activation prior to apoptotic cell death remains controversial. Many neurological disorders are characterized by neuronal loss, particularly amyotrophic lateral sclerosis (ALS).

Heptahelical and other G-protein-coupled receptors (GPCRs) signaling.

Heptahelical receptors are coupled to heterotrimeric GTP-binding proteins (G-proteins) which transduce most signals through their alpha and betagamma subunits to effectors, enzymes and ion channels. Of the 367 heptahelical receptors for endogenous ligands, about 330 are potential targets for drug discovery with agonist, antagonist or inverse agonist properties. The term G-protein-coupled receptors (GPCRs) is a broader functional definition rather than a structural one referring to heptahelical receptors specifically.

Search for an endogenous cannabinoid-mediated effect in the sympathetic nervous system.

Activation of CB(1) cannabinoid receptors by exogenous agonists causes presynaptic inhibition of neurotransmitter release from axon terminals. In the central nervous system, presynaptic CB(1) receptors can also be activated by endogenous cannabinoids (endocannabinoids) released from postsynaptic neurons. Except in the vas deferens, there is no indication of endocannabinoid-mediated presynaptic inhibition in the sympathetic nervous system.

Central effects of the cannabinoid receptor agonist WIN55212-2 on respiratory and cardiovascular regulation in anaesthetised rats.

1 The primary aim was to study the central respiratory effects of cannabinoids (CB). To this end, the cannabinoid receptor agonist WIN55212-2 was injected into the cisterna magna of urethane-anaesthetised rats and changes in respiratory parameters were observed. The secondary aim was to observe the centrally elicited cardiovascular actions of WIN55212-2.

Modulation of the baroreceptor reflex by alpha 2A-adrenoceptors: a study in alpha 2A knockout mice.

1. Our objective was to determine whether alpha(2A)-adrenoceptors modulate the baroreceptor reflex. The efficacy of the reflex was evaluated by measuring the spontaneous blood pressure and heart rate variability at rest and the heart rate responses to evoked changes in blood pressure.

Analysis of the respiratory effects of cannabinoids in rats.

The objective of the present study was to evaluate the respiratory effects of cannabinoids and their influence on cardiovascular homeostasis.In spontaneously breathing urethane-anaesthetised rats, intravenous injection of the two synthetic cannabinoid receptor agonists WIN55212-2 and CP55940 strongly and dose-dependently lowered mean arterial pressure, heart rate and the plasma noradrenaline concentration. The cardiovascular depressive effects were associated with a large decrease in respiratory rate, hypoxia, hypercapnia and blood acidosis.

The peripheral sympathetic nervous system is the major target of cannabinoids in eliciting cardiovascular depression.

Our objective was to identify the sites of interaction of cannabinoids with cardiovascular sympathetic regulation in the rat. Effects on sympathetic tone were first determined in anaesthetised animals following i.v.

Effects of cannabinoids on adrenaline release from adrenal medullary cells.

1. The objective of the present study was to analyse the peripheral effects of cannabinoids on adrenaline release from adrenal chromaffin cells. 2.

Effects of cannabinoids on sympathetic and parasympathetic neuroeffector transmission in the rabbit heart.

Cannabinoids elicit marked cardiovascular responses. It is not clear how peripheral effects on the autonomic nervous system contribute to these responses. The aim of the present study was to characterize the peripheral actions of cannabinoids on the autonomic innervation of the heart.

Cannabinoids cause central sympathoexcitation and bradycardia in rabbits.

Systemically administered cannabinoids elicit marked cardiovascular effects, and the role of the central and the peripheral nervous system in these effects is not clarified. The aim of this study was to characterize the actions of cannabinoids on cardiovascular regulatory centers in conscious rabbits. A catheter for administration of drugs into the cisterna cerebellomedullaris and an electrode for recording renal sympathetic nerve activity were implanted under halothane anesthesia.

Physical exercise, aortic blood pressure, and aortic wall elasticity and composition in rats.

With a training schedule (8 weeks' treadmill running at 30 m/min up a 10% incline 5 d/wk for 90 min/day), we investigated whether exercise modifies aortic wall dimensions, composition (calcium and elastin content), or stiffness in normotensive 6-month-old male Wistar WAG/Rij rats. Maximal oxygen uptake was measured in half of the rats (n=10 per group). Wall stiffness was evaluated in the other half (9 trained and 10 untrained) on the basis of changes in thoracoabdominal pressure pulse wave velocity and differences in amplitude between the peripheral and central aortic pressure signals.