Differential roles of endothelin-1 ETA and ETB receptors and vasoactive intestinal polypeptide in regulation of the airways and the pulmonary vasculature in isolated rat lung

The available treatment strategies against pulmonary hypertension include the administration of endothelin-1 (ET-1) receptor subtype blockers (ET(A) and ET(B) antagonists); vasoactive intestinal polypeptide (VIP) has recently been suggested as a potential new therapeutic agent. We set out to investigate the ability of these agents to protect against the vasoconstriction and impairment of lung function commonly observed in patients with pulmonary hypertension. An ET(A) blocker (BQ123), ET(B) blocker (BQ788), a combination of these selective blockers (ET(A) + ET(B) blockers) or VIP (V6130) was administered into the pulmonary circulation in four groups of perfused normal rat lungs. Pulmonary vascular resistance (PVR) and forced oscillatory lung input impedance (Z(L)) were measured in all groups under baseline conditions and at 1 min intervals following ET-1 administrations. The airway resistance, inertance, tissue damping and elastance were extracted from the Z(L) spectra. While VIP, ET(A) blocker and combined ET(A) and ET(B) blockers significantly prevented the pulmonary vasoconstriction induced by ET-1, ET(B) blockade enhanced the ET-1-induced increases in PVR. In contrast, the ET(A) and ET(B) blockers markedly elevated the ET-1-induced increases in airway resistance, while VIP blunted this constrictor response. Our results suggest that VIP potently acts against the airway and pulmonary vascular constriction mediated by endothelin-1, while the ET(A) and ET(B) blockers exert a differential effect between airway resistance and PVR.     

The choroid plexus--cerebrospinal fluid system: undervaluated pathway of neuroendocrine signaling into the brain

The cerebrospinal fluid (CSF) is a major part of the extracellular fluid of the central nervous system. The function of the CSF and the tissue that secretes it, the choroid plexus (CP) has traditionally been thought as providing the brain with essential nutrients, removing products of neuronal activity of the central nervous system, and providing mechanical support for the brain's fragile cellular network. More recent studies suggest, however, that the CP and CSF system play a much more active role in the function of the central nervous system being a target, source and pathway for neuroendocrine signaling within the brain.     

Antioxidative properties of hydrogen sulfide may involve in its antiadhesive action on blood platelets

Background

Hydrogen sulfide (H₂S) is a signaling molecule in different systems, including the cardiovascular system. However, mechanisms involved in the relationship between the action of H₂S and hemostasis process are still unclear.

Objective and methods

The present work was designed to study the effects of hydrogen sulfide on adhesion of blood platelets in vitro. Platelet suspensions were preincubated (5–30 min) with NaHS as a hydrogen sulfide donor at the final concentrations of 0.00001–10 mM. Then, for platelet activation thrombin (0.1 U/mL) or TRAP, peptide with the sequence Ser-Phe-Leu-Leu-Arg-Asn (SFLLRN; 20 μM) was used. We also measured the effects of H₂S on superoxide anion radicals (O₂^−•) production in blood platelets.

Results

We observed that adhesion to collagen and to fibrinogen of resting platelets preincubated with NaHS was changed, and this process was statistically significant (for 0.00001–5 mM NaHS, p < 0.05; 10 mM, p < 0.01). The inhibitory effect of NaHS on adhesion of thrombin – or TRAP – stimulated platelets to collagen was found (for 0.00001 and 0.0001 mM NaHS, p < 0.05; 0.001–1 mM NaHS, p < 0.01; 5 and 10 mM NaHS, p < 0.001). Hydrogen sulfide reduced also the thrombin- or TRAP-induced platelet adhesion to fibrinogen (for 0.00001 and 0.0001 mM NaHS, p < 0.05; 0.001–1 mM NaHS, p < 0.01; 5 and 10 mM NaHS, p < 0.001). Moreover, H₂S caused a dose-dependent reduction of O₂^−• produced in platelets (p < 0.05).

Conclusion

The results obtained that the antioxidative activity of H₂S may involve in its antiadhesive properties on blood platelets.     

Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy

Central serous chorioretinopathy (CSCR) is a vision-threatening eye disease with no validated treatment and unknown pathogeny. In CSCR, dilation and leakage of choroid vessels underneath the retina cause subretinal fluid accumulation and retinal detachment. Because glucocorticoids induce and aggravate CSCR and are known to bind to the mineralocorticoid receptor (MR), CSCR may be related to inappropriate MR activation. Our aim was to assess the effect of MR activation on rat choroidal vasculature and translate the results to CSCR patients. Intravitreous injection of the glucocorticoid corticosterone in rat eyes induced choroidal enlargement. Aldosterone, a specific MR activator, elicited the same effect, producing choroid vessel dilation -and leakage. We identified an underlying mechanism of this effect: aldosterone upregulated the endothelial vasodilatory K channel KCa2.3. Its blockade prevented aldosterone-induced thickening. To translate these findings, we treated 2 patients with chronic nonresolved CSCR with oral eplerenone, a specific MR antagonist, for 5 weeks, and observed impressive and rapid resolution of retinal detachment and choroidal vasodilation as well as improved visual acuity. The benefit was maintained 5 months after eplerenone withdrawal. Our results identify MR signaling as a pathway controlling choroidal vascular bed relaxation and provide a pathogenic link with human CSCR, which suggests that blockade of MR could be used therapeutically to reverse choroid vasculopathy.     

Chronic sciatic nerve injury impairs the local cutaneous neurovascular interaction in rats

Most studies of chronic nerve compression focus on large nerve function in painful conditions, and only few studies have assessed potential changes in the function of small nerve fibers during chronic nerve compression and recovery from compression. Cutaneous pressure-induced vasodilation is a neurovascular phenomenon that relies on small neuropeptidergic fibers controlling the cutaneous microvasculature. We aimed to characterize potential changes in function of these small fibers and/or in cutaneous microvascular function following short-term (1-month) and long-term (6-month) nerve compression and after release of compression (ie, potential recovery of function). A compressive tube was left on one sciatic nerve for 1 or 6 months and then removed for 1-month recovery in Wistar rats. Cutaneous vasodilator responses were measured by laser Doppler flowmetry in hind limb skin innervated by the injured nerve to assess neurovascular function. Nociceptive thermal and low mechanical thresholds were evaluated to assess small and large nerve fiber functions, respectively. Pressure-induced vasodilation was impaired following nerve compression and restored following nerve release; both impairment and restoration were strongly related to duration of compression. Small and large nerve fiber functions were less closely related to duration of compression. Our data therefore suggest that cutaneous pressure-induced vasodilation provides a non-invasive and mechanistic test of neurovascular function that gives direct information regarding extent and severity of damage during chronic nerve compression and recovery, and may ultimately provide a clinically useful tool in the evaluation of nerve injury such as carpal tunnel syndrome.     

The liver toxicity biomarker study phase I: markers for the effects of tolcapone or entacapone

The Liver Toxicity Biomarker Study is a systems toxicology approach to discover biomarkers that are indicative of a drug's potential to cause human idiosyncratic drug-induced liver injury. In phase I, the molecular effects in rat liver and blood plasma induced by tolcapone (a "toxic" drug) were compared with the molecular effects in the same tissues by dosing with entacapone (a "clean" drug, similar to tolcapone in chemical structure and primary pharmacological mechanism). Two durations of drug exposure, 3 and 28 days, were employed. Comprehensive molecular analysis of rat liver and plasma samples yielded marker analytes for various drug-vehicle or drug-drug comparisons. An important finding was that the marker analytes associated with tolcapone only partially overlapped with marker analytes associated with entacapone, despite the fact that both drugs have similar chemical structures and the same primary pharmacological mechanism of action. This result indicates that the molecular analyses employed in the study are detecting substantial "off-target" markers for the two drugs. An additional interesting finding was the modest overlap of the marker data sets for 3-day exposure and 28-day exposure, indicating that the molecular changes in liver and plasma caused by short- and long-term drug treatments do not share common characteristics.     

Intravenous immunoglobulin in the treatment of autoimmune bullous dermatoses: an update

High-dose intravenous immunoglobulin (IVIg) is being increasingly utilized as an off-label therapy for a variety of autoimmune and inflammatory conditions across various specialties. Numerous reports have shown that it is an effective treatment for autoimmune skin blistering disorders. Unlike most therapies for blistering disorders, IVIg is not immunosuppressive and has a favorable side effect profile. This has allowed its use to expand dramatically over the last decade. However, due to the rarity and severity of autoimmune skin blistering diseases, well-designed prospective trials are generally lacking. This work highlights major research developments and the best evidence to date regarding the treatment of autoimmune pemphigus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, pemphigoid gestationis, and linear IgA dermatosis with IVIg, providing an update on its efficacy, proposed mechanisms of action, side effect profile, and indications for use.