Transcutaneous electrical nerve inhibition using medium frequency alternating current.

Transcutaneous medium-frequency alternating electrical current is defined as an alternating current between 1 and 10 kHz and is capable of producing an instant, reversible block. This study aims to evaluate the efficacy of sensory perception and force production of the index and middle finger after transcutaneous medium-frequency alternating electrical current stimulation of the distal median nerve. A single-center prospective interventional cohort study was conducted in adult healthy volunteers at the Jessa Hospital, Hasselt, Belgium. Two different electrodes (PALS & 3M) were placed on the distal median nerve, which was located using a Sonosite X-Porte Ultrasound transducer, with the first electrode being placed on the skin at the level of the transverse carpal ligament and the second electrode 7 cm proximally to the first electrode. The tactile sensation was evaluated with Semmes-Weinstein monofilament test and sensation of pressure/pain was evaluated with an algometer. Peak force production was assessed with an electronic dynamometer. All measurements were performed at baseline and tMFAEC stimulation frequencies of 2 and 10 kHz in a randomized manner. Statistical analysis was performed with a one-way ANOVA with repeated measures test or a Friedman rank sum test, followed by the Wilcoxon signed rank test adjusted with Bonferroni correction. A p-value < 0.05 was considered statistically significant. From 9 to 13th of April 2021, 25 healthy volunteers were included in the Jessa Hospital, Hasselt, Belgium. A statistically significant reduction in tactile sensation during 2 kHz and 10 kHz stimulation compared to baseline was observed (2.89 ± 0.22 (PALS2); 3.35 ± 0.25 (3M2) and 2.14 ± 0.12 (PALS10); 2.38 ± 0.12 (3M10) versus - 1.75 ± 0.09 (baseline), p < 0.0001). 3M electrodes showed a tendency towards the elevation of pressure pain threshold compared to baseline. No significant difference in mean peak forces of the index and middle fingers after transcutaneous medium-frequency alternating electrical current stimulation with 2 and 10 kHz was found. This study demonstrates that transcutaneous medium-frequency alternating electrical current stimulation on the distal median nerve inhibits tactile sensory nerve activity in the index and middle finger when stimulation of 2 kHz and, to a lesser extent, 10 kHz was applied. A reduction of motor nerve activity was not observed but force production measurements may be prone to error.Trial registration: clinicaltrials.gov on 01/04/2021. NCT-Number: NCT04827173.

Additive effects of the Rho kinase inhibitor Y-27632 and vardenafil on relaxation of the corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure.

OBJECTIVES: To evaluate the expression of the Rho/Rho-associated protein kinase (ROCK) pathway in the corpus cavernosum of patients with severe erectile dysfunction (ED) compared with healthy human corpus cavernosum, and to test the functional effects of two Rho kinase inhibitors (RKIs) on erectile tissue of patients with severe ED, which did not respond to phosphodiesterase type 5 inhibitors (PDE5Is). PATIENTS AND METHODS: Human corpus cavernosum samples were obtained after consent from men undergoing penile prosthesis implantation (n = 7 for organ bath experiments, n = 17 for quantitative PCR [qPCR]). Potent control subjects (n = 5) underwent penile needle biopsy. qPCR was performed for the expression of RhoA and ROCK subtypes 1 and 2. Immunohistochemistry staining against ROCK and α smooth muscle actin (αSMA) was performed on the corpus cavernosum of patients with ED. Tissue strips were precontracted with phenylephrine and incubated with 1 µm of the PDE5I vardenafil or with DMSO (control). Subsequently, increasing concentrations of the RKIs azaindole or Y-27632 were added, and relaxation of tissue was quantified. RESULTS: The expression of ROCK1 was unchanged (P > 0.05), while ROCK2 (P < 0.05) was significantly upregulated in patients with ED compared with controls. ROCK1 and ROCK2 protein colocalized with αSMA, confirming the presence of this kinase in cavernous smooth muscle cells and/or myofibroblasts. After incubation with DMSO, 10 µm azaindole and 10 µm Y-27632 relaxed precontracted tissues with 49.5 ± 7.42% (P = 0.1470 when compared with vehicle) and 85.9 ± 10.3% (P = 0.0016 when compared with vehicle), respectively. Additive effects on relaxation of human corpus cavernosum were seen after preincubation with 1 µm vardenafil. CONCLUSION: The RKI Y-27632 causes a significant relaxation of corpus cavernosum in tissue strips of patients with severe ED. The additive effect of vardenafil and Y-27632 shows that a combined inhibition of Rho-kinase and phosphodiesterase type 5 could be a promising orally administered treatment for severe ED.

BmBKTx1, a novel Ca2+-activated K+ channel blocker purified from the Asian scorpion Buthus martensi Karsch.

BmBKTx1 is a novel short chain toxin purified from the venom of the Asian scorpion Buthus martensi Karsch. It is composed of 31 residues and is structurally related to SK toxins. However, when tested on the cloned rat SK2 channel, it only partially inhibited rSK2 currents, even at a concentration of 1 microm. To screen for other possible targets, BmBKTx1 was then tested on isolated metathoracic dorsal unpaired median neurons of Locusta migratoria, in which a wide variety of ion channels are expressed. The results suggested that BmBKTx1 could specifically block voltage-gated Ca(2+)-activated K(+) currents (BK-type). This was confirmed by testing the BmBKTx1 effect on the alpha subunits of BK channels of the cockroach (pSlo), fruit fly (dSlo), and human (hSlo), heterologously expressed in HEK293 cells. The IC(50) for channel blocking by BmBKTx1 was 82 nm for pSlo and 194 nm for dSlo. Interestingly, BmBKTx1 hardly affected hSlo currents, even at concentrations as high as 10 microm, suggesting that the toxin might be insect specific. In contrast to most other scorpion BK blockers that also act on the Kv1.3 channel, BmBKTx1 did not affect this channel as well as other Kv channels. These results show that BmBKTx1 is a novel kind of blocker of BK-type Ca(2+)-activated K(+) channels. As the first reported toxin active on the Drosophila Slo channel dSlo, it will also greatly facilitate studying the physiological role of BK channels in this model organism.