Agnieszka Cudnoch-Jedrzejewska

Enhanced involvement of brain vasopressin V1 receptors in cardiovascular responses to stress in rats with myocardial infarction

Stress is one of the factors provoking cardiovascular complications. The purpose of the study was to explore the role of vasopressin (VP) in central control of arterial blood pressure and heart rate under resting conditions and during stimulation by an alarming stress (air jet stress) in myocardial infarct-induced cardiac failure. Six groups of male Sprague Dawley (SD) rats were subjected either to sham surgery (sham rats) or to ligation of a left coronary artery (infarcted rats). After 5 weeks both infarcted and sham rats were subjected either to intracerebroventricular infusion of artificial cerebrospinal fluid (aCSF) (sham aCSF and infarcted aCSF), [Arg8]-VP (sham VP and infarcted VP) or VP V1a receptor antagonist (d(CH2)5[Tyr(Me)2Ala-]VP, sham V1ANT and infarcted V1ANT). Air jet stress elicited significantly greater increases in mean arterial blood pressure (MABP) and heart rate in the infarcted aCSF than in the sham aCSF rats. Intracerebroventricular infusion of V1ANT significantly reduced resting MABP and MABP and heart rate increases in response to stress in the infarcted but not in the sham rats. Intracerebroventricular infusion of VP elicited a significant increase in resting MABP in the infarcted VP but not in the sham VP rats. The results provide evidence for enhanced engagement of the brain V1 VP receptors in regulation of resting MABP and in generation of exaggerated cardiovascular responses to air jet stress during the post-infarct state.

Sphingolipids in cardiovascular diseases and metabolic disorders

Many investigations suggest the pivotal role of sphingolipids in the pathogenesis of lifestyle diseases such as myocardial infarction, hypertension, stroke, diabetes mellitus type 2 and obesity. Some studies suggest that sphingolipids are important factors in cellular signal transduction. They serve as biologically active components of cell membrane and are involved in many processes such as proliferation, maturation and apoptosis. Recently, ceramide and sphingosine-1-phosphate have become the target of many investigations. Ceramide is generated in three metabolic pathways and many factors induce its production as a cellular stress response. Ceramide has proapoptotic properties and acts as a precursor for many other sphingolipids. Sphingosine-1-phosphate is a ceramide derivative, acting antiapoptotically and mitogenically and it is importantly involved in cardioprotection. Further research on the involvement of sphingolipids in cellular pathophysiology may improve the prevention and therapy of lifestyle diseases.

Interaction of AT1 receptors and V1a receptors-mediated effects in the central cardiovascular control during the post-infarct state.

UNLABELLED Experimental objectives. Because myocardial infarct is associated with overactivation of brain angiotensin II (ANG II) and vasopressin (AVP) V1a receptors we decided to determine whether AT1 and V1a receptors-mediated effects of ANG II and AVP interact in central cardiovascular control during the post-infarct state. Four groups of infarcted and four groups of sham-operated conscious rats entered the study. Results. In the infarcted rats cerebroventricular infusion of AT1 (AT1ANT, losartan) and V1a antagonist {V1aANT,d(CH(2))(5)[Tyr(Me)(2)Ala-NH(2)(9)]VP} and combined infusion of both these compounds performed 4 weeks after induction of the infarct significantly and comparably reduced mean arterial blood pressure (MABP) in comparison to control experiments (artificial cerebrospinal fluid infusion). In the sham rats MABP was not affected by any of the infusions. In control experiments MABP and HR responses to an alarming air jet stress were significantly higher in the infarcted than in the sham rats. Both responses were normalized with the same effectiveness by administration of AT1ANT, V1aANT and AT1ANT+V1aANT. In the sham rats administration of these compounds did not affect MABP and HR responses to stress. CONCLUSION The results provide evidence for interaction of AT1 and V1a receptors-mediated effects of ANG II and AVP in the central cardiovascular control during the post-infarct state.

Brain vasopressin V1 receptors contribute to enhanced cardiovascular responses to acute stress in chronically stressed rats and rats with myocardial infarcton

The present study was designed to determine the role of central vasopressin 1 receptors (V(1)R) in the regulation of cardiovascular parameters in chronically stressed infarcted rats and sham-operated rats under resting conditions and during exposure to acute alarming stress. The experiments were performed on four groups of conscious sham-operated and four groups of infarcted rats subjected to intraventricular infusion of either vehicle or a V(1)R antagonist (V(1)RANT). Two groups of infarcted and two groups of sham-operated rats were subjected to mild chronic stressing. Mean arterial blood pressure (MABP) and heart rate (HR) were determined under resting conditions and after exposure to acute stress (air jet). During vehicle infusion, MABP and HR increases in response to acute stress in the infarcted rats not subjected to chronic stress, and in the infarcted and sham-operated chronically stressed rats, were significantly greater than in the sham-operated rats not exposed to chronic stress. However, MABP and HR responses to acute stress in the chronically stressed infarcted rats and chronically stressed sham-operated rats did not differ. V(1)RANT abolished differences in cardiovascular responses to acute stress between the experimental groups. Resting cardiovascular parameters were not affected by any of the experimental treatments. It is concluded that chronic stressing enhances the pressor and tachycardic responses to acute stress in the sham-operated rats but does not further intensify these responses in infarcted rats.The results provide evidence that central V(1)Rs are involved in potentiation of cardiovascular responses to acute stress in chronically stressed rats, infarcted rats, and chronically stressed infarcted rats.

The role of epidermal sphingolipids in dermatologic diseases.

Sphingolipids, a group of lipids containing the sphingoid base, have both structural and biological functions in human epidermis. Ceramides, as a part of extracellular lipids in the stratum corneum, are important elements of the skin barrier and are involved in the prevention of transepidermal water loss. In addition, ceramides regulate such processes as proliferation, differentiation and apoptosis of keratinocytes. Another important sphingolipid, sphingosine-1-phosphate (S1P), inhibits proliferation and induces differentiation of keratinocytes. A recent clinical study of the efficacy and safety of ponesimod (a selective modulator of the S1P receptor 1) suggested that sphingolipid metabolism may become a new target for the pharmacological treatment of psoriasis. The role of sphingolipids in some dermatologic diseases, including psoriasis, atopic dermatitis and ichthyoses was summarized in this article.

High-fat diet and chronic stress reduce central pressor and tachycardic effects of apelin in Sprague-Dawley rats.

Central application of apelin elevates blood pressure and influences neuroendocrine responses to stress and food consumption. However, it is not known whether the central cardiovascular effects of apelin depend also on caloric intake or chronic stress. The purpose of the present study was to determine the effects of intracerebroventricular administration of apelin on blood pressure (mean arterial blood pressure) and heart rate in conscious Sprague–Dawley rats consuming either a normal‐fat diet (NFD) or high‐fat diet (HFD) for 12 weeks. During the last 4 weeks of the food regime, the rats were exposed (NFDS and HFDS groups) or not exposed (NFDNS and HFDNS groups) to chronic stress. Each group was divided into two subgroups receiving intracerebroventricular infusions of either vehicle or apelin. Apelin elicited significant increase of mean arterial blood pressure and heart rate in the NFDNS rats. This effect was abolished in the HFDNS, HFDS and NFDS groups. HFD resulted in a significant elevation of blood concentrations of total cholesterol, triglycerides glucose and insulin. Chronic stress reduced plasma concentration of total and high‐density lipoprotein cholesterol, and increased plasma corticosterone concentration and APJ receptor mRNA expression in the hypothalamus, whereas a combination of a HFD with chronic stress resulted in the elevation of plasma triglycerides, total cholesterol and low‐density lipoprotein cholesterol, and in increased plasma corticosterone concentration, apelin concentration and APJ receptor mRNA expression in the hypothalamus. It is concluded that a HFD and chronic stress result in significant suppression of the central pressor action of apelin, and cause significant though not unidirectional changes of metabolic and endocrine parameters.

Oxytocin differently regulates pressor responses to stress in WKY and SHR rats: the role of central oxytocin and V1a receptors.

Abstract The role of central oxytocin in the regulation of cardiovascular parameters under resting conditions and during acute stress was investigated in male normotensive Wistar-Kyoto (WKY; n = 40) and spontaneously hypertensive rats (SHR; n = 28). In Experiment 1, mean arterial blood pressure (MABP) and heart rate (HR) were recorded in WKY and SHR rats at rest and after an air-jet stressor during intracerebroventricular (ICV) infusions of vehicle, oxytocin or oxytocin receptor (OTR) antagonist. In Experiment 2, the effects of vehicle, oxytocin and OTR antagonist were determined in WKY rats after prior administration of a V1a vasopressin receptor (V1aR) antagonist. Resting MABP and HR were not affected by any of the ICV infusions either in WKY or in SHR rats. In control experiments (vehicle), the pressor response to stress was significantly higher in SHR. Oxytocin enhanced the pressor response to stress in the WKY rats but reduced it in SHR. During V1aR blockade, oxytocin infusion entirely abolished the pressor response to stress in WKY rats. Combined blockade of V1aR and OTR elicited a significantly greater MABP response to stress than infusion of V1a antagonist and vehicle. This study reveals significant differences in the regulation of blood pressure in WKY and SHR rats during alarming stress. Specifically, the augmentation of the pressor response to stress by exogenous oxytocin in WKY rats is caused by its interaction with V1aR, and endogenous oxytocin regulates the magnitude of the pressor response to stress in WKY rats by simultaneous interaction with OTR and V1aR.

Differential sensitisation to central cardiovascular effects of angiotensin II in rats with a myocardial infarct: Relevance to stress and interaction with vasopressin

The purpose of the present study was to elucidate if rats with myocardial infarction manifest altered responsiveness to central cardiovascular effects of low doses of angiotensin II (ANG II), and if ANG II and vasopressin (VP) cooperate in the central regulation of cardiovascular functions at rest and during stress. Conscious Sprague–Dawley rats with myocardial infarction induced by left coronary artery ligation, or sham-ligated (SL) controls were infused intracerebroventricularly with artificial cerebrospinal fluid (aCSF), ANG II, ANG II + VP or ANG II + V1a receptor antagonist (V1ANT) 4 weeks after cardiac surgery. In the infarcted but not in the SL rats, the resting mean arterial blood pressure (MABP) was significantly elevated by infusions of ANG II and ANG II + VP, while infusion of ANG II + V1ANT was not effective. During administration of aCSF, the pressor, and tachycardic responses to an air-jet stressor were significantly greater in the infarcted than in the SL rats. In the SL rats, the pressor responses to the stressor were significantly greater during infusions of ANG II, ANG II + VP and ANG II + V1ANT than during infusion of aCSF. The tachycardic response in the SL rats was enhanced only by the combined infusion of ANG II + VP. In the infarcted rats, the pressor and the tachycardic responses to the stressor were similar in all groups. It is concluded that: (1) under resting conditions the infarcted rats manifest sensitisation to the central pressor effect of ANG II and that this effect depends on concomitant stimulation of V1a VP receptors, (2) central ANG II may enhance the pressor response to an alarming stressor in the SL rats through an action which does not depend on the concomitant stimulation of V1a receptors, (3) the cooperative action of ANG II and VP is required for intensification of the tachycardic response to the alarming stressor in the SL rats and (4) exaggeration of the cardiovascular responses to the alarming stressor in the infarcted rats cannot be further augmented by an additional stimulation of central ANG II receptors or combined stimulation of ANG II and VP receptors.

Down-regulation of V1a vasopressin receptors in the cerebellum after myocardial infarction

Vasopressin V1a receptors (V1aR) were found in the cerebellum but their functional role has not been determined. As V1aR are engaged in the central regulation of the cardiovascular system and anxiogenic behavior and their role increases in the heart failure and stress, we decided to find out whether expression of V1aR is altered after myocardial infarction and chronic stressing. RT-PCR and Western blot analysis were performed to determine V1aR mRNA and protein expression in the cerebellum of four groups of rats (control sham-operated, infarcted, chronically stressed and infarcted chronically stressed). The myocardial infarct was produced by left coronary artery ligation, and chronic stressing by exposing the rat for four weeks to different types of mild stressors. The rats were sacrificed four weeks after the myocardial surgery or sham operation. Expressions of V1aR mRNA and protein were significantly lower in the infarcted and infarcted chronically stressed rats than in the sham-operated controls and chronically stressed not infarcted rats. No significant differences were found between the sham-operated controls and chronically stressed rats and between the infarcted rats and infarcted rats exposed to chronic stressing. It is concluded that V1aR mRNA and protein expressions are significantly down-regulated in the rats with the post-infarct heart failure but they are not affected by mild chronic stressing.

Mechanism of action of three newly registered drugs for multiple sclerosis treatment

Multiple sclerosis (MS) is a disease of suspected autoimmune origin leading to neurodegeneration. The disease pathomechanism is considered to be primarily based on neuroinflammation directed against myelin antigens caused by autoreactive T cells. MS etiology remains still unknown, which makes it difficult to create an efficient therapy, therefore, MS treatment targets mechanisms involved in disease pathology. In this review, we present the mechanism of action of three newly registered drugs for MS. Dimethyl fumarate (DMF) is an agent presenting a broad spectrum of action. Its main activity is based on activating the nuclear factor E2 dependent pathway leading to antioxidant enzyme synthesis. DMF in general suppresses the pro-inflammatory immune activity and exerts a neuroprotective action. Teriflunomide is a more focused drug, acting as an inhibitor of pyrimidines synthesis, important for rapidly dividing cells such as activated lymphocytes. Similarly, alemtuzumab, an anti-CD52 antibody, causes depletion of mainly lymphocytes. Since in MS pathology, T and B cells are involved, this mode of action is promising.