Angiotensin type 1A receptors in C1 neurons of the rostral ventrolateral medulla modulate the pressor response to aversive stress

The rise in blood pressure during an acute aversive stress has been suggested to involve activation of angiotensin type 1A receptors (AT(1A)Rs) at various sites within the brain, including the rostral ventrolateral medulla. In this study we examine the involvement of AT(1A)Rs associated with a subclass of sympathetic premotor neurons of the rostral ventrolateral medulla, the C1 neurons. The distribution of putative AT(1A)R-expressing cells was mapped throughout the brains of three transgenic mice with a bacterial artificial chromosome-expressing green fluorescent protein under the control of the AT(1A)R promoter. The overall distribution correlated with that of the AT(1A)Rs mapped by other methods and demonstrated that the majority of C1 neurons express the AT(1A)R. Cre-recombinase expression in C1 neurons of AT(1A)R-floxed mice enabled demonstration that the pressor response to microinjection of angiotensin II into the rostral ventrolateral medulla is dependent upon expression of the AT(1A)R in these neurons. Lentiviral-induced expression of wild-type AT(1A)Rs in C1 neurons of global AT(1A)R knock-out mice, implanted with radiotelemeter devices for recording blood pressure, modulated the pressor response to aversive stress. During prolonged cage-switch stress, expression of AT(1A)Rs in C1 neurons induced a greater sustained pressor response when compared to the control viral-injected group (22 +/- 4 mmHg for AT(1A)R vs 10 +/- 1 mmHg for GFP; p < 0.001), which was restored toward that of the wild-type group (28 +/- 2 mmHg). This study demonstrates that AT(1A)R expression by C1 neurons is essential for the pressor response to angiotensin II and that this pathway plays an important role in the pressor response to aversive stress

Modeling the differentiation of A- and C-type baroreceptor firing patterns

The baroreceptor neurons serve as the primary transducers of blood pressure for the autonomic nervous system and are thus critical in enabling the body to respond effectively to changes in blood pressure. These neurons can be separated into two types (A and C) based on the myelination of their axons and their distinct firing patterns elicited in response to specific pressure stimuli. This study has developed a comprehensive model of the afferent baroreceptor discharge built on physiological knowledge of arterial wall mechanics, firing rate responses to controlled pressure stimuli, and ion channel dynamics within the baroreceptor neurons. With this model, we were able to predict firing rates observed in previously published experiments in both A- and C-type neurons. These results were obtained by adjusting model parameters determining the maximal ion-channel conductances. The observed variation in the model parameters are hypothesized to correspond to physiological differences between A- and C-type neurons. In agreement with published experimental observations, our simulations suggest that a twofold lower potassium conductance in C-type neurons is responsible for the observed sustained basal firing, whereas a tenfold higher mechanosensitive conductance is responsible for the greater firing rate observed in A-type neurons. A better understanding of the difference between the two neuron types can potentially be used to gain more insight into the underlying pathophysiology facilitating development of targeted interventions improving baroreflex function in diseased individuals, e.g. in patients with autonomic failure, a syndrome that is difficult to diagnose in terms of its pathophysiology.Comment: Keywords: Baroreflex model, mechanosensitivity, A- and C-type afferent baroreceptors, biophysical model, computational mode

Gastrointestinal pirfenidone adverse events in idiopathic pulmonary fibrosis depending on diet: the MADIET clinical trial

Individuals with IPF who follow a MUFA diet report a lower incidence of pirfenidone gastrointestinal adverse events than those that follow a SFA diet, which could explain the different prevalence in GI pirfenidone AEs reported by countries in IPF cohorts https://bit.ly/3LuzAUJ Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal interstitial lung disease (ILD) [1, 2]. Antifibrotic medications such as pirfenidone have been a turning point in the management of IPF, slowing of disease progression and improving survival [1–5]. eng research projects or scientific advice from Esteve-Teijin, Roche, Boehringer Ingelheim and Chiesi. V. Vicens-Zygmunt received fees for scientific advice from Boehringer Ingelheim. P. Rivera-Ortega declares speaker and consultation fees from Boehringer Ingelheim and Hoffmann-La Roche, and fees received for research projects from Boehringer Ingelheim, Hoffmann-La Roche, CSL Behring, FibroGen, Vicore Pharma AB, Gilead Sciences and Galecto; all research fees were paid to her institution. F. Bonella declares speaker and consultation fees from Boehringer Ingelheim, Hoffman La Roche and Fibrogene, outside the submitted work. E. Renzoni reports grants, lecture fees and advisory board fees from Boehringer Ingelheim, lecture fees from Roche and Chiesi, research grants from Raynaud's and Scleroderma, and support for attending meetings from Boehringer Ingelheim, outside the submitted work; all grants and fees were paid to her institution. A-M. Russell declares speaker and consultation fees from Boehringer Ingelheim and Hoffman-La Roche. T.M. Maher reports consultancy fees from AstraZeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pliant, Respivant Sciences, Roche/Genentech, Theravance Biopharma and Veracyte, and fees for presentations from Boehringer Ingelheim and Roche/Genentech. G. Suarez-Cuartin has received grants from Grifols, travel grants from Chiesi, Menarini and Boehringer Ingelheim, a speaker fee from Insmed, and advisory board fees from Insmed Inc. and Zambon. M. Wijsenbeek has received grants from Boehringer Ingelheim, The Netherlands Organisation for Health Research and Development, The Dutch Lung Foundation, Sarcoidose.nl and The Dutch Pulmonary Society, consulting fees from Boehringer Ingelheim, Galapagos, Bristol Myers Squibb, Galecto, Respivant, NeRRe Therapeutics, Horizon Therapeutics, PureTech health, Kinevant Sciences, Molecure and CLS Behring, speaker fees from Boehringer Ingelheim, Hoffman-La Roche, Novartis and CLS Behring, support for attending meetings from Boehringer Ingelheim, Galapagos and Hoffman-La Roche, and has participated in advisory boards of different patient associations (unpaid); all grants and fees were paid to her institution. C. Vancheri served on advisory committees of InterMune, Roche, AstraZeneca, Sanofi, Insmed, Zambon and Boehringer Ingelheim, and received lecture fees and nongovernmental research support from InterMune, Roche, Boehringer Ingelheim, Novartis, Chiesi, Menarini, AstraZeneca, GSK, Sanofi and Insmed. The rest of the authors have no relevant relationships to disclose.Published version, accepted version (12 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text