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Measurement of Ion Concentration in the Unstirred Boundary Layer with Open Patch-Clamp Pipette: Implications in Control of Ion Channels by Fluid Flow

Fluid flow is an important environmental stimulus that controls many physiological and pathological processes, such as fluid flow-induced vasodilation. ...

Eulji University

MK801 and ketamine, which are phencyclidine (PCP) derivative N-methyl-d-aspartate receptor (NMDAr) blockers, reportedly enhance the function of 5-hydroxytryptamine (HT)-2A receptors (5-HTRs). Both are believed to directly affect the pathogenesis of schizophrenia, as well as hypertension. 5-HTR signaling involves the inhibition of Kv conductance. This study investigated the interaction of these drugs with Kv1.5, which plays important roles in 5-HTR signaling and in regulating the excitability of the cardiovascular and nervous system, and the potential role of this interaction in the enhancement of the 5-HTR-mediated response. Using isometric organ bath experiments with arterial rings and conventional whole-cell patch-clamp recording of Chinese hamster ovary (CHO) cells ectopically overexpressing Kv1.5, we examined the effect of ketamine and MK801 on 5-HTR-mediated vasocontraction and Kv1.5 channels. Both ketamine and MK801 potentiated 5-HTR-mediated vasocontraction. This potentiation of 5-HTR function occurred in a membrane potential-dependent manner, indicating the involvement of ion channel(s). Both ketamine and MK801 rapidly and directly inhibited Kv1.5 channels from the extracellular side independently of NMDArs. The potencies of MK801 in facilitating the 5-HTR-mediated response and blocking Kv1.5 were higher than those of ketamine. Our data demonstrated the direct inhibition of Kv1.5 channels by MK801/ketamine and indicated that this inhibition may potentiate the functions of 5-HTRs. We suggest that 5-HTR-Kv1.5 may serve as a receptor-effector module in response to 5-HT and is a promising target in the pathogenesis of MK801-/ketamine-induced disease states such as hypertension and schizophrenia.

Enhancement of 5-HT receptor function and blockade of Kv1.5 by MK801 and ketamine: implications for PCP derivative-induced disease models.

Mulberry (Morus alba) has been used in traditional oriental medicine since ages. Recently, it has been reported that mulberry produces hypotensive effects through the eNOS signaling pathway. However, the mechanism underlying the hypotensive effects of mulberry is not entirely clear. Moreover, the effects of mulberry on vascular remodeling events such as hyperplasia, an important etiology in the pathogenesis of hypertension and arteriosclerosis, are also ambiguous. Here, we hypothesized that an ethanolic extract of mulberry fruit (EMF) has beneficial effects on vascular remodeling and produces hypotensive effects. The effects of a 6-week oral administration of EMF were examined in spontaneously hypertensive rats (SHRs). The animals were divided into four groups: normotensive control (Wistar Kyoto rats), non-treated SHR, low-dose (100 mg/kg) EMF-treated SHR, and high-dose (300 mg/kg) EMF-treated SHR. Our results showed that the EMF-diet normalizes hypertension in SHRs in a dose-dependent manner, by preventing smooth muscle proliferation, thickening of the tunica media, and vascular hyper-reactivity. The endothelial functions were not substantially affected by the EMF diet in our experimental setting. In conclusion, we suggest that the mulberry fruit could act as a food supplement for reducing blood pressure in hypertensive subjects through its effects on smooth muscle proliferation and vascular contractility.

Effects of an ethanolic extract of mulberry fruit on blood pressure and vascular remodeling in spontaneous hypertensive rats.

Oxidative stress is associated with many cardiovascular diseases, such as hypertension and arteriosclerosis. Oxidative stress reportedly activates the L-type voltage-gated calcium channel (VDCC) and elevates [Ca] in many cells. However, how oxidative stress activates VDCC under clinical setting and the consequence for arteries are unclear. Here, we examined the hypothesis that hydrogen peroxide (HO) regulates membrane potential (Em) by altering Na influx through cation channels, which consequently activates VDCC to induce vasoconstriction in rat mesenteric arteries. To measure the tone of the endothelium-denuded arteries, a conventional isometric organ chamber was used. Membrane currents and Em were recorded by the patch-clamp technique. [Ca] and [Na] were measured with microfluorometry using Fura2-AM and SBFI-AM, respectively. We found that HO (10 and 100 µM) increased arterial contraction, and nifedipine blocked the effects of HO on isometric contraction. HO increased [Ca] as well as [Na], and depolarized Em. Gd (1 µM) blocked all these HO-induced effects including Em depolarization and increases in [Ca] and [Na]. Although both nifedipine (30 nM) and low Na bath solution completely prevented the HO-induced increase in [Na], they only partly inhibited the HO-induced effects on [Ca] and Em. Taken together, the results suggested that HO constricts rat arteries by causing Em depolarization and VDCC activation through activating Gd-and nifedipine-sensitive, Na-permeable channels as well as Gd-sensitive Ca-permeable cation channels. We suggest that unidentified Na-permeable cation channels as well as Ca-permeable cation channels may function as important mediators for oxidative stress-induced vascular dysfunction.

Sang Woong Park

Department of Emergency Medical Services

Eulji University

Measurement of Ion Concentration in the Unstirred Boundary Layer with Open Patch-Clamp Pipette: Implications in Control of Ion Channels by Fluid Flow

Sang Woong Park

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Emergency Medical Services

Eulji University

Measurement of Ion Concentration in the Unstirred Boundary Layer with Open Patch-Clamp Pipette: Implications in Control of Ion Channels by Fluid Flow

Department of Emergency Medical Services