K+ Channels and Beta3 Adrenergic Receptors as New Pharmacological Targets for Overactive Bladder Treatment

Overactive bladder (OAB) is a pathophysiological condition which is characterized by the urinary bladder\u27s failure to achieve proper storage of urine. OAB has a tremendous impact on the patient\u27s quality of life by disturbing his sleep, work, and sexual activity. About 17% of Americans are affected with this disease and most patients experience symptoms of urgency, frequent urination, and abnormally elevated detrusor smooth muscle (DSM) contractility. Despite, numerous attempts to treat the disorder in the past with antimuscarinics and now with beta3 adrenergic receptors (beta3-AR agonists), OAB still remains a serious public health issue because the long term efficacy of these drugs remains questionable. Therefore, it is critical to explore new avenues and design new strategies in order to help improve the quality of life of more than 33 million people. K+ channels and beta3-AR have been shown to be key regulators of smooth muscle excitability and contractility in various species; however, information about their expression and functional role in the DSM of humans was limited. In our study, we first investigated the molecular expression of several K+ channels in human DSM cells using RT-PCR, qPCR, western blot, and immunostaining techniques, then tested their ability to affect DSM contractility by using isometric DSM tension recordings and selective pharmacological modulators. We found that two Ca2+-activated K+ channels including BK and SK3 channels as well as several voltage-gated K+ channels including Kv2.1, Kv2.2, Kv7.4, and Kv7.5 channels were expressed in human DSM cells. We also found that pharmacological inhibition of BK or SK3 channels with iberiotoxin, a BK channel blocker or apamin, a SK channel blocker, respectively, significantly increased human DSM spontaneous and nerve-evoked contractions in vitro. Similarly, pharmacological inhibition of Kv2 channels with stromatoxin-1, a Kv2 channel antagonist or Kv7 channels with XE991, a Kv7 channel antagonist, also increased human DSM spontaneous phasic and nerve-evoked contractions in vitro. On the other hand, application of retigabine, a Kv7 channel activator induced relaxation of human DSM strips spontaneous phasic and nerve-evoked contractions. As for the role of beta3-AR in human DSM, we found that pharmacological activation of beta3-AR with BRL37344, a beta3-AR agonist causes relaxation of human DSM nerve-evoked contractions in vitro. We further demonstrated that the beta3-AR mediated relaxation observed during nerve-evoked contractions was facilitated by BK channel activity. Finally, we obtained direct evidence suggesting that the decrease in BK channels expression and function is associated with symptoms of neurogenic detrusor overactivity. In conclusion our study suggest that pharmacological modulation of K+ channels (BK, SK3, Kv2, and Kv7 channels) or beta3-AR affect DSM contractility, therefore making K+ channels and beta3-AR likely drug targets for the treatment of OAB

Examining Similarities and Differences among Pharmacy Educational Mobile Applications

The use of educational mobile applications (EMAs) to enhance student learning experience is gaining considerable interest across college campuses in the U.S. Some EMAs are more commendable than others because of their ability to effectively help students study lecture materials, learn new concepts, prepare for exams, and improve their overall academic performance. The aim of this commentary is to highlight the major EMAs currently available to pharmacy students while addressing the similarities and differences between them.   Type:  Commentar

Emerging role of the calcium-activated, small conductance, SK3 K ⁺ channel in distal tubule function: Regulation by TRPV4

The Ca2+-activated, maxi-K (BK) K+ channel, with low Ca2+-binding affinity, is expressed in the distal tubule of the nephron and contributes to flow-dependent K+ secretion. In the present study we demonstrate that the Ca2+-activated, SK3 (KCa2.3) K + channel, with high Ca2+-binding affinity, is also expressed in the mouse kidney (RT-PCR, immunoblots). Immunohistochemical evaluations using tubule specific markers demonstrate significant expression of SK3 in the distal tubule and the entire collecting duct system, including the connecting tubule (CNT) and cortical collecting duct (CCD). In CNT and CCD, main sites for K+ secretion, the highest levels of expression were along the apical (luminal) cell membranes, including for both principal cells (PCs) and intercalated cells (ICs), posturing the channel for Ca2+- dependent K+ secretion. Fluorescent assessment of cell membrane potential in native, split-opened CCD, demonstrated that selective activation of the Ca2+-permeable TRPV4 channel, thereby inducing Ca2+ influx and elevating intracellular Ca2+ levels, activated both the SK3 channel and the BK channel leading to hyperpolarization of the cell membrane. The hyperpolarization response was decreased to a similar extent by either inhibition of SK3 channel with the selective SK antagonist, apamin, or by inhibition of the BK channel with the selective antagonist, iberiotoxin (IbTX). Addition of both inhibitors produced a further depolarization, indicating cooperative effects of the two channels on Vm. It is concluded that SK3 is functionally expressed in the distal nephron and collecting ducts where induction of TRPV4-mediated Ca2+ influx, leading to elevated intracellular Ca2+ levels, activates this high Ca2+- affinity K+ channel. Further, with sites of expression localized to the apical cell membrane, especially in the CNT and CCD, SK3 is poised to be a key pathway for Ca2+-dependent regulation of membrane potential and K+ secretion. © 2014 Berrout et al

Language endangerment and language documentation in Africa

Non peer reviewe

Cyclic AMP-Dependent Regulation of Kv7 Voltage-Gated Potassium Channels

Voltage-gated Kv7 potassium channels, encoded by KCNQ genes, have major physiological impacts cardiac myocytes, neurons, epithelial cells, and smooth muscle cells. Cyclic adenosine monophosphate (cAMP), a well-known intracellular secondary messenger, can activate numerous downstream effector proteins, generating downstream signaling pathways that regulate many functions in cells. A role for cAMP in ion channel regulation has been established, and recent findings show that cAMP signaling plays a role in Kv7 channel regulation. Although cAMP signaling is recognized to regulate Kv7 channels, the precise molecular mechanism behind the cAMP-dependent regulation of Kv7 channels is complex. This review will summarize recent research findings that support the mechanisms of cAMP-dependent regulation of Kv7 channels

Head teacher induction: the experiences of two head teachers in community secondary school, Tanzania

Literature shows that head teachers play a critical role in managing the affairs of a school. To enable them to be efficient in this role, they need to be guided on how to do this especially if they are newly appointed. Despite the importance of induction to new school leaders, very few studies have been conducted on how head teacher induction influences their leadership practice much less in community secondary schools in Tanzania. This study therefore sought to explore the head teacher induction on leadership practices in two community secondary schools in Mtwara Municipal Council in Tanzania. The study adopted a multiple case study approach where the main focus was on two head teachers. Other participants involved in the study included two deputy head teachers of the two school, six teachers, three from each school and sixteen students from both schools. Data collection methods used were mainly the semi-structured interviews. Other methods were document analysis and observation. Study findings revealed that head teacher induction enables head teachers in budgeting, school development planning, and setting school visions and missions, and gives them the confidence and awareness to enact leadership. However, the findings revealed that head teacher induction courses were brief and hence not comprehensive enough in preparing the head teachers for their new roles. This study therefore calls for an increased time period induction for head teachers so as to benefit from the same. The study also highlights significant issues for policy and practice with regard to head teacher induction

HUBUNGAN LAMA MEROKOK, JUMLAH KONSUMSI BATANG ROKOK PER HARI, BODY MASS INDEX (BMI), DIABETES, DYSLIPIDEMIA, DAN HIPERTENSI DENGAN PENURUNAN PERFORMA FUNGSI EREKSI PADA PRIA BERUSIA 45-64 TAHUN YANG BERKUNJUNG KE RUMAH SAKIT X SURABAYA

The decrease in erectile function performance is the inability to sustain an erection long enough during intercourse (NHS, 2014). The etiology of decrease in erectile function performance is multifactorial; organic factors, and psychogenic factors involved in the ability to get and maintain an erection (Agarwal et al., 2013). The decrease in erectile function performance in this study was measured using IIEF-5 questionnaire. This study is a cross-sectional observative research that use the results of the questionnaire answers of the respondents. Obtained a population of 161 people who were then screened to 109 people who fit the criteria of this research by using insidential sampling method. The results of this study showed a decrease in erectile function performance of 56.88% of the total respondents. Correlation test results showed a significant association of each variable age, duration of smoking, number of cigarettes per day, diabetes, dyslipidemia, and hypertension with a decrease in erectile function performance. Then for Body Mass Index (BMI) in this study did not show any significant relationship with decreased in erectile function performance. This is because the respondents in this study consist only of normal wight (18.5 to 24.9) and over weight (25 to 29.9). Advice given to avoid decrease in erectile function performance is to reduce cigarette consumption, and improve or treat an unhealthy condition such as BMI above normal, Diabetes, Dyslipidemia and hypertension. This study only retrieve data from the questionnaire so that the data are less and incomplete clear risk factors. Keywords : Erectile Function, IIEF-5, Duration of Smoking, Number of Cigarettes per Day, Diabetes, Dyslipidemia, Hypertension, Body Mass Index (BMI)

Molecular expression and pharmacological evidence for a functional role of kv7 channel subtypes in Guinea pig urinary bladder smooth muscle.

Voltage-gated Kv7 (KCNQ) channels are emerging as essential regulators of smooth muscle excitability and contractility. However, their physiological role in detrusor smooth muscle (DSM) remains to be elucidated. Here, we explored the molecular expression and function of Kv7 channel subtypes in guinea pig DSM by RT-PCR, qRT-PCR, immunohistochemistry, electrophysiology, and isometric tension recordings. In whole DSM tissue, mRNAs for all Kv7 channel subtypes were detected in a rank order: Kv7.1~Kv7.2Kv7.3~Kv7.5Kv7.4. In contrast, freshly-isolated DSM cells showed mRNA expression of: Kv7.1~Kv7.2Kv7.5Kv7.3~Kv7.4. Immunohistochemical confocal microscopy analyses of DSM, conducted by using co-labeling of Kv7 channel subtype-specific antibodies and α-smooth muscle actin, detected protein expression for all Kv7 channel subtypes, except for the Kv7.4, in DSM cells. L-364373 (R-L3), a Kv7.1 channel activator, and retigabine, a Kv7.2-7.5 channel activator, inhibited spontaneous phasic contractions and the 10-Hz electrical field stimulation (EFS)-induced contractions of DSM isolated strips. Linopiridine and XE991, two pan-Kv7 (effective at Kv7.1-Kv7.5 subtypes) channel inhibitors, had opposite effects increasing DSM spontaneous phasic and 10 Hz EFS-induced contractions. EFS-induced DSM contractions generated by a wide range of stimulation frequencies were decreased by L-364373 (10 µM) or retigabine (10 µM), and increased by XE991 (10 µM). Retigabine (10 µM) induced hyperpolarization and inhibited spontaneous action potentials in freshly-isolated DSM cells. In summary, Kv7 channel subtypes are expressed at mRNA and protein levels in guinea pig DSM cells. Their pharmacological modulation can control DSM contractility and excitability; therefore, Kv7 channel subtypes provide potential novel therapeutic targets for urinary bladder dysfunction

Protein expression of Kv7 channel subtypes in guinea pig DSM.

<p>Confocal images illustrate the staining for Kv7.1 (<b>A</b>), Kv7.2 (<b>B</b>), Kv7.3 (<b>C</b>), Kv7.4 (<b>D</b>), and Kv7.5 (<b>E</b>) channel subtype proteins in mucosa-free whole DSM tissue. Kv7 channel subtype proteins were detected by immunohistochemistry using subtype-specific antibodies. In all panels, α-smooth muscle actin is shown in green; cell nuclei are illustrated in blue; the specific Kv7 channel subtype protein expression is represented by red staining. The merged images of α-smooth muscle actin, nuclei, and the Kv7 channel protein expression are illustrated in the quadrant labeled “Merge”. Images were captured with a Carl Zeiss LSM 700 META confocal microscope (63x objective). Experiments were conducted on DSM tissue samples isolated from 3 different guinea pigs.</p