Inhibition of bladder activity by tibial nerve stimulation was investigated in α-chloralose-anesthetized cats with an intact spinal cord. Short-duration (3-5 min) tibial nerve stimulation at both low (5 Hz) and high (30 Hz) frequencies applied repeatedly during rhythmic isovolumetric bladder contractions was effective in inhibiting reflex bladder activity. Both frequencies of stimulation were also effective in inducing inhibition that persisted after the termination of the stimulation. The poststimulation inhibitory effect induced by the short-duration stimulation significantly increased bladder capacity to 181.6 ± 24.36% of the control capacity measured before applying the stimulation. Thirty-minute continuous stimulation induced prolonged poststimulation inhibition of bladder activity, which lasted for more than 2 h and significantly increased bladder capacity to 161.1 ± 2.9% of the control capacity. During the poststimulation periods, 5-Hz stimulation applied during the cystometrogram elicited a further increase (~30% on average) in bladder capacity, but 30-Hz stimulation was ineffective. These results in cats support the clinical observation that tibial nerve neuromodulation induces a long-lasting poststimulation inhibitory effect that is useful in treating overactive bladder symptoms.
Objective-The present study is aimed at investigating the interaction of TRPV4 with TRPC1 and the functional role of such an interaction in flow-induced Ca 2ϩ influx. Hemodynamic blood flow is an important physiological factor that modulates vascular tone. One critical early event in this process is a cytosolic Ca 2ϩ ([Ca 2ϩ ] i ) rise in endothelial cells in response to flow. Methods and Results-With the use of fluorescence resonance energy transfer, coimmunoprecipitation, and subcellular colocalization methods, it was found that TRPC1 interacts physically with TRPV4 to form a complex. In functional studies, flow elicited a transient [Ca 2ϩ ] i increase in TRPV4-expressing human embryonic kidney (HEK) 293 cells. Coexpression of TRPC1 with TRPV4 markedly prolonged this [Ca 2ϩ ] i transient; it also enabled this [Ca 2ϩ ] i transient to be negatively modulated by protein kinase G. Furthermore, this flow-induced [Ca 2ϩ ] i increase was markedly inhibited by anti-TRPC1-blocking antibody T1E3 and a dominant-negative construct TRPC1⌬567-793 in TRPV4-C1-coexpressing HEK cells and human umbilical vein endothelial cells. T1E3 also inhibited flow-induced vascular dilation in isolated rat small mesenteric artery segments. H emodynamic blood flow is one of most important physiological factors that control vascular tone. 1 Flow shear stress acts on the endothelium to stimulate the release of vasodilators, such as NO and endothelium-derived hyperpolarizing factors, causing endothelium-dependent vascular relaxation. 1 In many cases, a key early signal in this flowinduced vascular dilation is Ca 2ϩ influx in endothelial cells in response to flow. [2][3][4] There is intense interest in searching for the molecular identity of the channels that mediate flowinduced Ca 2ϩ influx. Several candidate channels have been proposed. In renal epithelial cells, polycystins 1 and 2 form a channel complex to allow Ca 2ϩ influx in response to flow. 5 In vascular endothelial cells, flow may activate P2X 4 purinoceptors, which are Ca 2ϩ -permeable channels, resulting in vascular dilation. 6 Interestingly, several recent studies 2,3 demonstrate that TRPV4 channels play a key role in flow-induced endothelial Ca 2ϩ influx and subsequent vascular dilation. TRP channels are a superfamily of cation channels that can be divided into 7 subfamilies, which include TRPC, TRPV, and 5 others. TRPV4 is a Ca 2ϩ -permeable channel in the influx involves TRPV4. For store-operated Ca 2ϩ influx, several possible candidates could be involved, which include stromal interaction molecule (STIM1), Orai, and TRPC1. 10,11 In the present studies, we explored the possible interaction between the flow-sensing TRPV4 and store-operated Ca The human TRPC1 gene (NM_003304) and the mouse TRPV4 gene (NM_022017) were cloned into pcDNA6 and pCAGGS vectors, respectively. HEK cells were transfected using a reagent (Lipofectamine 2000). HUVECs were transfected by electroporation using Nucleofector II. All genes except PKG1␣ were transiently transfected in...
Abstract-TRPC1 (transient receptor potential canonical 1) is a Ca 2ϩ -permeable cation channel involved in diverse physiological function. TRPC1 may associate with other proteins to form a signaling complex, which is crucial for channel function. In the present study, we investigated the interaction between TRPC1 and large conductance Ca 2ϩ -sensitive K ϩ channel (BK Ca ). With the use of potentiometric fluorescence dye DiBAC 4 (3), we found that store-operated Ca 2ϩ influx resulted in membrane hyperpolarization of vascular smooth muscle cells (VSMCs). The hyperpolarization was inhibited by an anti-TRPC1 blocking antibody T1E3 and 2 BK Ca channel blockers, charybdotoxin and iberiotoxin. These data were confirmed by sharp microelectrode measurement of membrane potential in VSMCs of intact arteries. Furthermore, T1E3 treatment markedly enhanced the membrane depolarization and contraction of VSMCs in response to several contractile agonists including phenylephrine, endothelin-1, and U-46619. In coimmunoprecipitation experiments, an antibody against BK Ca ␣-subunit [BK Ca (␣)] could pull down TRPC1, and moreover an anti-TRPC1 antibody could reciprocally pull down BK Ca (␣). Double-labeling immunocytochemistry showed that TRPC1 and BK Ca were colocalized in the same subcellular regions, mainly on the plasma membrane, in VSMCs. These data suggest that, TRPC1 physically associates with BK Ca in VSMCs and that Ca 2ϩ influx through TRPC1 activates BK Ca to induce membrane hyperpolarization. The hyperpolarizing effect of TRPC1-BK Ca coupling could serve to reduce agonist-induced membrane depolarization, thereby preventing excessive contraction of VSMCs to contractile agonists. (Circ Res. 2009;104:670-678.)
Naloxone (an opioid receptor antagonist) was used to examine the role of opioid mechanisms in bladder reflexes and in somatic afferent inhibition of these reflexes by tibial nerve stimulation (TNS). Experiments were conducted in α-chloralose-anesthetized cats when the bladder was infused with saline or 0.25% acetic acid (AA). The bladder volume was measured at the first large-amplitude (>30 cmH(2)O) contraction during a cystometrogram and termed "estimated bladder capacity" (EBC). AA irritated the bladder, induced bladder overactivity, and significantly (P < 0.0001) reduced EBC to 14.3 ± 1.9% of the saline control. TNS (5 Hz, 0.2 ms) at 4 and 8 times the threshold (T) intensity for inducing an observable toe movement suppressed AA-induced bladder overactivity and significantly increased EBC to 41.5 ± 9.9% (4T, P < 0.05) and 46.1 ± 7.9% (8T, P < 0.01) of the saline control. Naloxone (1 mg/kg iv) completely eliminated TNS inhibition of bladder overactivity. Naloxone (0.001-1 mg/kg iv) did not change EBC during AA irritation. However, during saline infusion naloxone (1 mg/kg iv) significantly (P < 0.01) reduced EBC to 66.5 ± 8.1% of the control EBC. During saline infusion, TNS induced an acute increase in EBC and an increase that persisted following the stimulation. Naloxone (1 mg/kg) did not alter either type of inhibition. However, naloxone administered during the poststimulation inhibition decreased EBC. These results indicate that opioid receptors have different roles in modulation of nociceptive and nonnociceptive bladder reflexes and in somatic afferent inhibition of these reflexes, raising the possibility that opioid receptors may be a target for pharmacological treatment of lower urinary tract disorders.
Synthetic ion channels that mimic the functions of natural ion channels are of great interest in chemistry, biochemistry, biology, and materials science. In this paper, we present a novel small synthetic molecule that self-assembles to form chloride channels in lipid bilayers. This compound is the smallest molecule known to form potent synthetic chloride ion channels. It can also partition into plasma membranes of living cells and therein increase anion permeability. This compound has the potential to become a novel lead compound for the treatment of human diseases associated with Cl- channel dysfunctions.
Peptide self-assembled nanostructures are very popular in many biomedical applications. Drug delivery is one of the most promising applications among them. The tremendous advantages for peptide self-assembled nanostructures include good biocompatibility, low cost, tunable bioactivity, high drug loading capacities, chemical diversity, specific targeting, and stimuli responsive drug delivery at disease sites. Peptide self-assembled nanostructures such as nanoparticles, nanotubes, nanofibers, and hydrogels have been investigated by many researchers for drug delivery applications. In this review, the underlying mechanisms for the self-assembled nanostructures based on peptides with different types and structures are introduced and discussed. Peptide self-assembled nanostructures associated promising drug delivery applications such as anticancer drug and gene drug delivery are highlighted. Furthermore, peptide self-assembled nanostructures for targeted and stimuli responsive drug delivery applications are also reviewed and discussed.
We demonstrate imaging over the visible band using a single planar diffractive lens. This is enabled via multi-level diffractive optics that is designed to focus over a broad wavelength range, which we refer to as an achromatic diffractive lens (ADL). We designed, fabricated and characterized two ADLs with numerical apertures of 0.05 and 0.18. Diffraction-limited focusing is demonstrated for the NA = 0.05 lens with measured focusing efficiency of over 40% across the entire visible spectrum (450 nm to 750 nm). We characterized the lenses with a monochromatic and a color CMOS sensor, and demonstrated video imaging under natural sunlight and other broadband illumination conditions. We use rigorous electromagnetic simulations to emphasize that ADLs can achieve high NA (0.9) and large operating bandwidth (300 nm in the visible spectrum), a combination of metrics that have so far eluded other flat-lens technologies such as metalenses. These planar diffractive lenses can be cost-effectively manufactured over large areas and thereby, can enable the wide adoption of flat, low-cost lenses for a variety of imaging applications.
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