Sympathetic denervation reverses developmental changes both in Ca(2+) sensitivity and in the expression of regulatory proteins back to the early post-natal phenotype in the rat saphenous artery. We conclude that trophic effects of sympathetic nerves govern functional remodelling of arteries during early post-natal development.

Our results suggest that the higher Ca -sensitivity of arterial contraction in 1-week-old compared to 10- to 12-week-old rats is due to a greater Rho-kinase activity. Constitutively active Rho-kinase contributes to MX-induced contraction in 10- to 12-week-old rats. In 1-week-old rats, additional Rho-kinase activation is involved. This remodelling of the Rho-kinase pathway is associated with its increased contribution to adrenergic arterial pressure responses.

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The viruses most commonly affecting the human respiratory tract include rhinoviruses, respiratory syncytial virus (RSV), influenza viruses, and coronaviruses (CoVs). The virus infection of the epithelial cells of the respiratory tract triggers an inflammation accompanied by the release of pro-inflammatory cytokines and chemokines including IL6, IL8(CXCL8), IL1β, and tumor necrosis factor α (TNFα). A subsequent acute inflammatory response in the lungs is accompanied by an increase in the production of cytokines and chemokines − CXCR3 receptor ligands – that are key players of acute inflammatory response that induce an influx of neutrophils and T cells into the lungs.We studied the pharmacodynamic activity of the new compound XC221GI to suppress the IL6 and IL8 of an experimental RSV infection in vitro in human lung carcinoma cells A549 and in vivo in the lungs of cotton rats. We also studied the effect of XC221GI on the production of the chemokines CXCL10, CXCL9, and CXCL11 in mouse bronchoalveolar lavage as well as on the influx of neutrophils into the mouse lungs after the intranasal administration of interferon γ (IFNγ).The obtained results demonstrate the anti-inflammatory activity of XC221GI, which suppresses the production of excessive levels of the key inflammatory markers IL6, IL8, CXCL10, CXCL9, and CXCL11 as well as the influx of neutrophils into the lungs thereby reducing lung pathology. These data confirm the effectiveness of XC221GI as a means of preventive anti-inflammatory therapy during a viral infection of the respiratory tract.

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Introduction Chronic cough heavily affects patients’ quality of life, and there are no effective licensed therapies available. Cough is a complication of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection, asthma, and other diseases. Patients with various diseases have a different profile of tussive responses to diverse cough triggers, thereby suggesting sundry mechanisms of neuronal dysfunctions. Previously, we demonstrated that the small molecule drug XC8 shows a clinical anti-asthmatic effect. The objective of the present study was to investigate the effect of XC8 on cough. Methods We studied the antitussive effect of XC8 on cough induced by agonists activating human transient receptor potential (TRP) cation channels TRPA1 or TRPV1 in guinea pigs. We checked the agonistic/antagonistic activity of XC8 on the human cation channels TRPA1, TRPV1, TRPM8, P2X purinoceptor 2 (P2X2), and human acid sensing ion channel 3 (hASIC3) in Fluorescent Imaging Plate Reader (FLIPR) assay. Results XC8 demonstrated clear antitussive activity and dose-dependently inhibited cough in guinea pigs induced by citric acid alone (up to 67.1%) or in combination with IFN-γ (up to 76.4%). XC8 suppressed cough reflexes induced by the repeated inhalation of citric acid (up to 80%) or by cinnamaldehyde (up to 60%). No activity of XC8 against cough evoked by capsaicin was revealed. No direct agonistic/antagonistic activity of XC8 on human TRPA1, TRPV1, TRPM8, P2X2, or hASIC3 was detected. Conclusions XC8 acts against cough evoked by the activation of TRPA1 (citric acid/cinnamaldehyde) but not TRPV1 (capsaicin) channels. XC8 inhibits the cough reflex and suppresses the cough potentiation by IFN-γ. XC8 might be of significant therapeutic value for patients suffering from chronic cough associated with inflammation.

The aim of this study was to reveal the changes of short-term cardiovascular variability in rats with sustained primary hypertension and correlate them with functional alterations of peripheral arteries. 12-month-old SHR as compared to Wistar rats demonstrated prominent reductions of mean arterial pressure and pulse interval spectral powers in the range 0.25-0.75 Hz. These alterations were associated with prominent reductions of cardiac baroreflex gain and constrictor responses of small arteries to electrical stimulation of sympathetic fibers and exogenous noradrenaline. We suggest that both central and peripheral mechanisms are responsible for the reduction of baroreflex arterial pressure oscillations in mature SHR.

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