Systemic leukotriene B₄ receptor antagonism lowers arterial blood pressure and improves autonomic function in the spontaneously hypertensive rat

KEY POINTS: Evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B(4) (LTB(4)), a potent chemoattractant involved in the inflammatory response, but its mode of action is poorly understood. In the SHR, we observed an increase in T cells and macrophages in the brainstem; in addition, gene expression profiling data showed that LTB(4) production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. When LTB(4) receptor 1 (BLT1) receptors were blocked with CP‐105,696, arterial pressure was reduced in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in systolic blood pressure (BP) indicators. These data provide new evidence for the role of LTB(4) as an important neuro‐immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension. ABSTRACT: Accumulating evidence indicates an association between hypertension and chronic systemic inflammation in both human hypertension and experimental animal models. Previous studies in the spontaneously hypertensive rat (SHR) support a role for leukotriene B(4) (LTB(4)), a potent chemoattractant involved in the inflammatory response. However, the mechanism for LTB(4)‐mediated inflammation in hypertension is poorly understood. Here we report in the SHR, increased brainstem infiltration of T cells and macrophages plus gene expression profiling data showing that LTB(4) production, degradation and downstream signalling in the brainstem of the SHR are dynamically regulated during hypertension. Chronic blockade of the LTB(4) receptor 1 (BLT1) receptor with CP‐105,696, reduced arterial pressure in the SHR compared to the normotensive control and this reduction was associated with a significant decrease in low and high frequency spectra of systolic blood pressure, and an increase in spontaneous baroreceptor reflex gain (sBRG). These data provide new evidence for the role of LTB(4) as an important neuro‐immune pathway in the development of hypertension and therefore may serve as a novel therapeutic target for the treatment of neurogenic hypertension

Inflammatory pathways are central to posterior cerebrovascular artery remodelling prior to the onset of congenital hypertension

Cerebral artery hypoperfusion may provide the basis for linking ischemic stroke with hypertension. Brain hypoperfusion may induce hypertension that may serve as an auto-protective mechanism to prevent ischemic stroke. We hypothesised that hypertension is caused by remodelling of the cerebral arteries, which is triggered by inflammation. We used a congenital rat model of hypertension and examined age-related changes in gene expression of the cerebral arteries using RNA sequencing. Prior to hypertension, we found changes in signalling pathways associated with the immune system and fibrosis. Validation studies using second harmonics generation microscopy revealed upregulation of collagen type I and IV in both tunica externa and media. These changes in the extracellular matrix of cerebral arteries pre-empted hypertension accounting for their increased stiffness and resistance, both potentially conducive to stroke. These data indicate that inflammatory driven cerebral artery remodelling occurs prior to the onset of hypertension and may be a trigger elevating systemic blood pressure in genetically programmed hypertension. </jats:p

Cep126 is required for pericentriolar satellite localisation to the centrosome and for primary cilium formation

BACKGROUND INFORMATION: The centrosome is the primary microtubule-organising centre of animal cells and it has crucial roles in several fundamental cellular functions, including cell division, cell polarity, and intracellular transport. The mechanisms responsible for this are not completely understood. RESULTS: The poorly characterised protein CEP126 localises to the centrosome, pericentriolar satellites and the base of the primary cilium. Suppression of CEP126 expression results in dispersion of the pericentriolar satellites and disruption of the radial organisation of the microtubules, and induces disorganisation of the mitotic spindle. Moreover, CEP126 depletion or the transfection of a CEP126 truncation mutant in hTERT-RPE-1 and IMCD3 cells impairs the formation of the primary cilium. CONCLUSIONS: We propose that CEP126 is a regulator of microtubule organisation at the centrosome that acts through modulation of the transport of pericentriolar satellites, and consequently, of the organisation of cell structure

Impact of gonadectomy on sympatho-vagal balance in male and female normotensive rat

OBJECTIVE: It is well established that autonomic nervous system and sympatho-vagal balance plays an important role in maintaining arterial blood pressure (ABP) (Salman IM., 2016) and that autonomic regulation of ABP differs between males and females (Hart EC et al., 2014). We hypothesised that sex hormones affect blood pressure via the autonomic nervous system and that the late development of hypertension in females is due to protective effects of ovarian steroids in females rather than due to detrimental effects of testosterone in males. DESIGN AND METHOD: We used adult, 12 months old, Wistar female and male, intact and gonadectomised rats (n = 8, per each group). Resting ABP was recorded by radio-telemetry. Heart rate (HR) and ABP variability were calculated using Spike2 software. Effect of gender and gonadectomy were assessed by two-way Anova. RESULTS: Females had lower systolic (S)BP compared to males (121 ± 1 vs 128 ± 2 mmHg; P < 0.05). Intact (81 ± 2 mmHg) but not ovariectomised (89 ± 2 mmHg) females had lower diastolic (D)BP compared to males (91 ± 1 mmHg; P < 0.01). Moreover, intact (353 ± 6bpm) but not ovariectomised (307 ± 5 bpm) females had higher HR compared to males (353 ± 6bpm; P < 0.001). However, ovariectomy did not influence the higher respiratory rate in females vs males (91 ± 3 vs 78 ± 3 bpm; P < 0.001).Power spectra analysis of SBP shows that males (22.4 ± 3) and ovariectomised females (26.9 ± 3) had lower High Frequency percentage vs females (38 ± 3; P < 0.05) suggesting that female hormones affect ABP by modulating the parasympathetic activity. The Very Low Frequency percentage was higher in males vs females (40 ± 4 vs 28 ± 4; P < 0.05) suggesting that sympathetic vasomotor tone might play an important role in the differential regulation of SBP between males and females. CONCLUSIONS: Altogether, this results show that female hormones have a positive effect on ABP and that they affect ABP via modulating parasympathetic activity. Further analyses of BP and HR variability at different ages are needed to determine the interaction between age, BP and gender

Impact of gonadectomy on sympatho-vagal balance in male and female normotensive rat

OBJECTIVE: It is well established that autonomic nervous system and sympatho-vagal balance plays an important role in maintaining arterial blood pressure (ABP) (Salman IM., 2016) and that autonomic regulation of ABP differs between males and females (Hart EC et al., 2014). We hypothesised that sex hormones affect blood pressure via the autonomic nervous system and that the late development of hypertension in females is due to protective effects of ovarian steroids in females rather than due to detrimental effects of testosterone in males. DESIGN AND METHOD: We used adult, 12 months old, Wistar female and male, intact and gonadectomised rats (n = 8, per each group). Resting ABP was recorded by radio-telemetry. Heart rate (HR) and ABP variability were calculated using Spike2 software. Effect of gender and gonadectomy were assessed by two-way Anova. RESULTS: Females had lower systolic (S)BP compared to males (121 ± 1 vs 128 ± 2 mmHg; P < 0.05). Intact (81 ± 2 mmHg) but not ovariectomised (89 ± 2 mmHg) females had lower diastolic (D)BP compared to males (91 ± 1 mmHg; P < 0.01). Moreover, intact (353 ± 6bpm) but not ovariectomised (307 ± 5 bpm) females had higher HR compared to males (353 ± 6bpm; P < 0.001). However, ovariectomy did not influence the higher respiratory rate in females vs males (91 ± 3 vs 78 ± 3 bpm; P < 0.001).Power spectra analysis of SBP shows that males (22.4 ± 3) and ovariectomised females (26.9 ± 3) had lower High Frequency percentage vs females (38 ± 3; P < 0.05) suggesting that female hormones affect ABP by modulating the parasympathetic activity. The Very Low Frequency percentage was higher in males vs females (40 ± 4 vs 28 ± 4; P < 0.05) suggesting that sympathetic vasomotor tone might play an important role in the differential regulation of SBP between males and females. CONCLUSIONS: Altogether, this results show that female hormones have a positive effect on ABP and that they affect ABP via modulating parasympathetic activity. Further analyses of BP and HR variability at different ages are needed to determine the interaction between age, BP and gender

Postępowanie w niespodziewanych trudnych drogach oddechowych u dzieci — stanowisko Sekcji Anestezjologii i Intensywnej Terapii Dziecięcej, Sekcji Przyrządowego Udrażniania Dróg Oddechowych Polskiego Towarzystwa Anestezjologii i Intensywnej Terapii oraz Po

Tracheal intubation may be defined as an artificial airway established in order to provide mechanical ventilation of the lungs during surgical procedures under general anaesthesia, treatment in an intensive care unit, as well as in emergency situations. Difficulties encountered during intubation may cause hypoxia, hypoxic brain injury and, in extreme situations, may result in the patient’s death. There may be unanticipated and anticipated difficult airway. Children form a specific group of patients as there are significant differences in both anatomy and physiology. There are some limitations in equipment used for the airway management in children. There are only few paediatric difficult airway guidelines available, some of which have significant limitations. The presented algorithm was created by a group of specialists who represent the Polish Society of Anaesthesiology and Intensive Therapy, as well as the Polish Neonatology Society. This algorithm is intended for the unanticipated difficult airway in children and can be used in all age groups. It covers both elective intubation, as well as rescue techniques. A guide forms an integral part of the algorithm. It describes in detail all stages of the algorithm considering some modifications in a specific age group, e.g. neonates. The main aim of Stage I is to optimise conditions for face mask ventilation, laryngoscopy and intubation. Stage IIA focuses on maximising the chances of successful intubation when face mask ventilation is possible. Stage IIB outlines actions aimed at improving face mask ventilation. Stage IIIA describes the use of a SAD (Supraglottic Airway Device) during effective face mask ventilation or in a CICV (Cannot Intubate, Cannot Ventilate) situation. Stage IIIB outlines intubation through a SAD. Stage IV describes rescue techniques and outlines possible options of either proceeding with surgery or postponing it, depending on clinical situation

Additional file 1: Figure S1. of Impact of gonadectomy on blood pressure regulation in ageing male and female rats

Specificity of AGTR1 antibody assessed by blocking peptide