Leg pain in neuropathic postural tachycardia syndrome is associated with altered muscle membrane properties

Purpose In neuropathic postural tachycardia syndrome, peripheral sympathetic dysfunction leads to excessive venous blood pooling during orthostasis. Up to 84% of patients report leg pain and weakness in the upright position. To explore possible pathophysiological processes underlying these symptoms, the present study examined muscle excitability depending on body position in patients with neuropathic postural tachycardia syndrome and healthy subjects. Methods In ten patients with neuropathic postural tachycardia syndrome and ten healthy subjects, muscle excitability measurements were performed repeatedly: in the supine position, during 10 min of head-up tilt and during 6 min thereafter. Additionally, lower leg circumference was measured and subjective leg pain levels were assessed. Results In patients with neuropathic postural tachycardia syndrome, muscle excitability was increased in the supine position, decreased progressively during tilt, continued to decrease after being returned to the supine position, and did not completely recover to baseline values after 6 min of supine rest. The reduction in muscle excitability during tilt was paralleled by an increase in lower leg circumference as well as leg pain levels. No such changes were observed in healthy subjects. Conclusions This study provides evidence for the occurrence of orthostatic changes in muscle excitability in patients with neuropathic postural tachycardia syndrome and that these may be associated with inadequate perfusion of the lower extremities. Insufficient perfusion as a consequence of blood stasis may cause misery perfusion of the muscles, which could explain the occurrence of orthostatic leg pain in neuropathic postural tachycardia syndrome.

Role of Detrusor PDGFRα+ Cells in Cyclophosphamide-Induced Detrusor Overactivity

Cyclophosphamide (CYP)-induced cystitis is a rodent model that shares many features common to the cystitis occurring in patients, including detrusor overactivity (DO). Platelet-derived growth factor receptor alpha positive (PDGFRα+) cells regulate muscle excitability in murine bladders during filling. PDGFRα+ cells express small conductance Ca2+-activated K+ channels (predominantly SK3) that provide stabilization of membrane potential during filling. We hypothesized that down-regulation of the regulatory functions of PDGFRα+ cells and/or loss of PDGFRα+ cells generates the DO in CYP-treated mice. After CYP treatment, transcripts of Pdgfrα and Kcnn3 were reduced, and PDGFRα and SK3 protein was also reduced in detrusor muscle extracts. The distribution of PDGFRα+ cells was also reduced. Inflammatory markers were increased in CYP-treated detrusor muscles. An SK channel agonist, CyPPA, increased outward current and hyperpolarization in PDGFRα+ cells. This response was significantly depressed in PDGFRα+ cells from CYP-treated bladders. Ex vivo cystometry showed increased transient contractions in CYP-treated bladders, and the sensitivity of these bladders to apamin was reduced, reflecting the reduction in the SK conductance expressed by PDGFRα+ cells. In summary, PDGFRα+ cells were reduced and the SK3 conductance was downregulated in CYP-treated bladders. These changes are consistent with the development of DO after CYP treatment.

Potential Benefits of Flavonoids on the Progression of Atherosclerosis by Their Effect on Vascular Smooth Muscle Excitability

Flavonoids are a group of secondary metabolites derived from plant-based foods, and they offer many health benefits in different stages of several diseases. This review will focus on their effects on ion channels expressed in vascular smooth muscle during atherosclerosis. Since ion channels can be regulated by redox potential, it is expected that during the onset of oxidative stress-related diseases, ion channels present changes in their conductive activity, impacting the progression of the disease. A typical oxidative stress-related condition is atherosclerosis, which involves the dysfunction of vascular smooth muscle. We aim to present the state of the art on how redox potential affects vascular smooth muscle ion channel function and summarize if the benefits observed in this disease by using flavonoids involve restoring the ion channel activity.

Effects of low-load blood flow restriction exercise to failure and non-failure on myoelectric activity: a meta-analysis

Objectives: To compare the short- and long-term effects of low load blood flow restriction (LL-BFR) versus low- (LL-RT) or high-load (HL-RT) resistance training with free blood flow on myoelectric activity, and investigate the differences between failure and non-failure protocols. Data Source: We identified sources by searching the MEDLINE/PUBMED, CINAHL, WEB OF SCIENCE, CENTRAL, SCOPUS, SPORTDiscus, and PEDro electronic databases. Study Selection: We screened titles and abstracts of 1048 articles using our inclusion criteria. A total of 39 articles were selected for further analysis. Data Extraction: Two reviewers independently assessed the methodological quality of each study and extracted data from studies. A meta-analytic approach was used to compute standardized mean differences (SMD ± 95% confidence intervals (CI)). Subgroup analyses were conducted for both failure or non-failure protocols. Data Synthesis: The search identified n = 39 articles that met the inclusion criteria. Regarding the short-term effects, LL-BFR increased muscle excitability compared with LL-RT during non-failure exercises (SMD 0.61, 95% CI 0.34 to 0.88), whereas HL-RT increased muscle excitability compared with LL-BFR regardless of voluntary failure (SMD −0.61, 95% CI −1.01 to 0.21) or not (SMD −1.13, CI −1.94 to −0.33). Concerning the long-term effects, LL-BFR increased muscle excitability compared with LL-RT during exercises performed to failure (SMD 1.09, CI 0.39 to 1.79). Conclusions: Greater short-term muscle excitability levels are observed in LL-BFR than LL-RT during non-failure protocols. Conversely, greater muscle excitability is present during HL-RT compared with LL-BFR, regardless of volitional failure. Furthermore, LL-BFR performed to failure increases muscle excitability in the long-term compared with LL-RT.

Electro-Steric Mechanism of CLC-2 Chloride Channel Activation

Two-pore voltage-gated CLC chloride channels control neuronal and muscle excitability. They share a dimeric structure but their activation mechanism remains unresolved. Here we determine the step-by-step activation mechanism of the broadly expressed CLC-2 channel using homology modelling, molecular dynamic simulations and functional studies. We establish that a two-leaf gate formed by Tyr561-H2O-Glu213 flanked by Lys568/Glu174 and Lys212 closes the canonical pore. Activation begins when a hyperpolarization-propelled intracellular chloride occupies the pore and splits Tyr561-H2O-Glu213 by electrostatic/steric repulsion. Unrestrained Glu213 rotates outwardly to bind Lys212 but the pore remains closed. Protonation breaks the Glu213-Lys212 interaction while another chloride occupies the pore thus catalysing chloride exit via Lys212. Also, we found that the canonical pore is uncoupled from a cytosolic cavity by a Tyr561-containing hydrophobic gate that prevents Glu213 protonation by intracellular protons. Our data provide atomistic details about CLC-2 activation but this mechanism might be common to other CLC channels.