Inhibition of K⁺ outward currents by linopirdine in the cochlear outer hair cells of circling mice within the first postnatal week

Inhibition of K⁺ outward currents by linopirdine in the outer hair cells (OHCs) of circling mice (homozygous (cir/cir) mice), an animal model for human deafness (DFNB6 type), was investigated using a whole cell patch clamp technique. Littermate heterozygous (+/cir) and ICR mice of the same age (postnatal day (P) 0 –P6) were used as controls. Voltage steps from –100 mV to 40 mV elicited small inward currents (–100 mV~–70 mV) and slow rising K⁺ outward currents (–60 mV ~40 mV) which activated near –50 mV in all OHCs tested. Linopirdine, a known blocker of K⁺ currents activated at negative potentials (I(K,n)), did cause inhibition at varying degree (severe, moderate, mild) in K⁺ outward currents of heterozygous (+/cir) or homozygous (cir/cir) mice OHCs in the concentration range between 1 and 100 µM, while it was apparent only in one ICR mice OHC out of nine OHCs at 100 µM. Although the half inhibition concentrations in heterozygous (+/cir) or homozygous (cir/cir) mice OHCs were close to those reported in I(K,n), biophysical and pharmacological properties of K⁺ outward currents, such as the activation close to –50 mV, small inward currents evoked by hyperpolarizing steps and TEA sensitivity, were not in line with I(K,n) reported in other tissues. Our results show that the delayed rectifier type K⁺ outward currents, which are not similar to I(K,n) with respect to biophysical and pharmacological properties, are inhibited by linopirdine in the developing (P0~P6) homozygous (cir/cir) or heterozygous (+/cir) mice OHCs.

Role of Kv7 Channels in Vascular Dysfunction associated with Metabolic Syndrome

Vasoconstriction is regulated by various ion channels expressed in the plasma membrane of vascular smooth muscle cells. In particular, potassium (K+) channel activity determines resting membrane potential and regulates intracellular calcium (Ca2+) signaling. A number of studies have suggested that dysregulation of K+ channel activity is associated with increased myogenic tone or diminished vasorelaxation. Among the various families of K+ channels, voltage-dependent K+ channels (Kv channels) encoded by the KCNQ gene family (Kv7 channels or M channels) are widely expressed in various blood vessels isolated from mouse, rat, and human. Recent studies have demonstrated that a subunit of the Kv7 channel, Kv7.4, is down-regulated in the aorta and mesenteric and renal arteries of the Spontaneously Hypertensive Rat (SHR) model. Previous studies have also suggested that Kv7 channels play an important role in the regulation of vasorelaxation/vasoconstriction in response to activators/blockers. In addition, previous studies have indicated that hypertension, diabetes mellitus, and cerebrovascular disease result in development of vascular dysfunction associated with Kv7 abnormalities in various animal models. This review focuses on the potential role of the Kv7 channel in vascular dysfunction.