Effects Of Potassium Channel Modulators Research Articles

Effects of potassium channel modulators on the responses of mammalian slowly adapting mechanoreceptors.

Introductionslowly adapting mechanoreceptors in the skin provide vital tactile information to animals. The ionic channels that underlie their functioning is the subject of intense research. Previous work suggests that potassium channels may play particular roles in the activation and firing of these mechanoreceptors.ObjectiveWe used a range of potassium channel blockers and openers to observe their effects on different phases of mechanoreceptor responses.MethodsExtracellular recording of neural activity of slowly adapting mechanoreceptors was carried out in an in vitro preparation of the sinus hair follicles taken from rat whisker pads. A range of potassium (K+) channel modulators were tested on these mechanoreceptor responses. The channel blockers tested were: tetraethylammonium (TEA), barium chloride (BaCl2), dequalinium, 4-aminopyridine (4-AP), paxilline, XE 991, apamin, and charybdotoxin.ResultsExcept for charybdotoxin and apamin, these drugs increased the activity of both types of slowly adapting units, St I and St II. Generally, both spontaneous and evoked (dynamic and static) activities increased. The channel opener NS1619 was also tested. NS1619 clearly decreased evoked activity (both dynamic and static) while leaving spontaneous activity relatively unaffected, with no clear discrimination of effects on the two types of St receptorConclusionThese findings are consistent with the targets of the drugs suggesting that K+ channels play an important role in the maintenance of spontaneous firing and in the production of and persistence of mechanoreceptor activity.

Effects of Potassium Channel Modulators on the Responses of Mammalian Slowly Adapting Mechanoreceptors

Effects of Potassium Channel Modulators on the Responses of Mammalian Slowly Adapting Mechanoreceptors

Effects of antipsychotic drugs and potassium channel modulators on spectral properties of local field potentials in mouse hippocampus and pre-frontal cortex

Local field potentials (LFPs) recorded intracranially display a range of location-specific oscillatory spectra which have been related to cognitive processes. Although the mechanisms producing LFPs are not completely understood, it is likely that voltage-gated ion channels which produce action potentials and patterned discharges play a significant role. It is also known that antipsychotic drugs (APDs) affect LFP spectra and a direct inhibitory effect on voltage-gated potassium channels has been reported. Additionally, voltage-gated potassium channels have been implicated in the pathophysiology of schizophrenia, a disorder for which APDs are primary therapies. In this study we sought to: i) better characterise the effects of two APDs on LFPs spectra and connectivity measures and ii) examine the effects of potassium channel modulators on LFPs and potential overlap of effects with APDs. Intracranial electrodes were implanted in hippocampus (HIP) and pre-frontal cortex (PFC) of C57BL/6J mice; power spectra, coherence and phase-amplitude cross-frequency coupling were measured. Drugs tested were APDs haloperidol and clozapine as well as voltage-gated potassium channel modulators (KVMs) 4-aminopyridine (4-AP), tetraethylammonium, retigabine and E−4031. Both APDs and KVMs significantly reduced gamma power except 4-AP, which conversely increased gamma power. Clozapine and retigabine additionally reduced gamma coherence between HIP and PFC, while 4-AP demonstrated the opposite effect. Phase-amplitude coupling between theta and gamma oscillations in HIP was significantly reduced by the administration of haloperidol and retigabine. These results provide previously undescribed effects of APDs on LFP properties and demonstrate novel modulation of LFP characteristics by KVMs that intriguingly overlap with the APD effects.

Phasic activity of urinary bladder smooth muscle in the streptozotocin-induced diabetic rat: Effect of potassium channel modulators

Increased phasic activity in the bladder smooth muscle of animal models and patients with detrusor overactivity has been suggested to underlie the pathophysiology of overactive bladder. Potassium (K+) channels are key regulators of bladder smooth muscle tone and thus may play a role in this altered phasic activity. In this study the effects of K+ channel modulators on the phasic activity of bladder strips from the streptozotocin-induced diabetic rat model of bladder dysfunction were investigated. Bladder strips from rats 1week following streptozotocin administration and age-matched controls were mounted in tissue baths at 37°C and the effects of K+ channel modulators on resting basal tension or phasic activity induced by a low concentration of carbachol (0.5μM) were investigated. Activation of BKCa channels by NS1619 had a minor inhibitory effect on carbachol-induced phasic activity of bladder strips from control and diabetic rats, and significantly inhibited amplitude only at 30μM. Activation of KATP channels by cromakalim inhibited the frequency of carbachol-induced phasic activity of bladder strips, although strips from diabetic rats showed a trend towards being less sensitive to cromakalim. The BKCa channel blocker iberiotoxin was able to induce phasic activity in resting tissues, with diabetic bladder strips demonstrating significantly enhanced phasic activity compared to controls. In contrast, inhibition of SKCa and KATP channels did not induce phasic activity in resting tissues. In conclusion, responses of diabetic rat bladder to BKCa and KATP channel modulators are altered, suggesting altered function and/or expression of channels which may contribute to bladder dysfunction in this model.

Effects of potassium channel modulators on myogenic spontaneous phasic contractile activity in human detrusor from neurogenic patients

To characterize the spontaneous contractile activity (SCA) developed by detrusor from patients with neurogenic detrusor overactivity (NDO) because the alteration of detrusor properties plays a critical role in the pathogenesis of detrusor overactivity, as well as to evaluate the role of K(ATP) and K(Ca) channels on this SCA because these channels regulate detrusor SCA in many species, including humans without overactive bladder (OAB). Human bladder samples were obtained from 44 patients undergoing cystectomy for bladder cancer with no known OAB symptoms and from 38 patients suffering from urodynamically diagnosed NDO. Detrusor strips with or without urothelium/suburothelium were mounted isometrically in organ baths filled with Krebs-HEPES (37 °C; 95% O(2) /5% CO(2) ). Strips were incubated with 10 µm pinacidil (K(ATP) opener) followed by 10 µm glibenclamide (K(ATP) blocker). In another set of experiments, strips were incubated with 30 µm NS-1619 (BK(Ca) opener) followed by 100 nm iberiotoxin (BK(Ca) blocker) or with 100 nm apamin (SK(Ca) blocker). SCA occurred more frequently with larger amplitude and area under the curve in detrusor strips from NDO patients compared to control patients. The presence of urothelium/suburothelium did not significantly modify SCA in either patient population. Pinacidil markedly inhibited SCA of detrusor strips from control and NDO patients. This effect was reversed by glibenclamide. By contrast, NS-1619 followed by iberiotoxin did not elicit any significant changes in SCA from NDO patients, contrary to control patients. K(ATP) and SK(Ca) channels regulate SCA of NDO patients' detrusor strips. By contrast, BK(Ca) channels are not involved in the regulation of detrusor SCA in NDO patients, whereas they regulate SCA in control patients. These results should be considered in the development of K(+) channels openers for the treatment of NDO. Moreover, SCA observed in vitro should be regarded as an in vitro modelling of human NDO.

Effect of Potassium Channel Modulators on Morphine Withdrawal in Mice

The present study was conducted to investigate the effect of potassium channel openers and blockers on morphine withdrawal syndrome. Mice were rendered dependent on morphine by subcutaneous injection of morphine; four hours later, withdrawal was induced by using an opioid antagonist, naloxone. Mice were observed for 30 minutes for the withdrawal signs ie, the characteristic jumping, hyperactivity, urination and diarrhea. ATP-dependent potassium (K+ATP) channel modulators were injected intraperitoneally (i.p.) 30 minutes before the naloxone. It was found that a K+ATP channel opener, minoxidil (12.5–50 mg/kg i.p.), suppressed the morphine withdrawal significantly. On the other hand, the K+ATP channel blocker glibenclamide (12.5–50 mg/kg i.p.) caused a significant facilitation of the withdrawal. Glibenclamide was also found to abolish the minoxidil’s inhibitory effect on morphine withdrawal. The study concludes that K+ATP channels play an important role in the genesis of morphine withdrawal and K+ATP channel openers could be useful in the management of opioid withdrawal. As morphine opens K+ATP channels in neurons, the channel openers possibly act by mimicking the effects of morphine on neuronal K+ currents.

Effects of potassium channel modulators on human detrusor smooth muscle myogenic phasic contractile activity: Potential therapeutic targets for overactive bladder

Objectives Increased urinary bladder detrusor smooth muscle phasic contractility has been suggested to be associated with idiopathic bladder overactivity (OAB). We examined the role of voltage-dependent l-type calcium channels, adenosine triphosphate-sensitive potassium (K ATP) channels, and calcium-activated potassium (BK Ca and SK Ca) channels in the regulation of human detrusor phasic contractile activity. Methods Isolated human bladder strip phasic contractions were measured and quantified as the mean area under the force-time curve, amplitude, and frequency of phasic contractions in 22 bladder samples. Results Human detrusor strips displayed myogenic phasic contractions in the presence of atropine (10 −6 M), phentolamine (10 −6 M), propranolol (10 −6 M), suramin (10 −5 M), and tetrodotoxin (10 −6 M). The l-type calcium channel inhibitor nifedipine (300 nM) abolished the contractile activity. Blockade of K ATP channels by glibenclamide (1 and 10 μM) did not alter myogenic contractions. In contrast, the K ATP channel opener pinacidil (10 μM) markedly inhibited phasic contractility. Iberiotoxin (100 nM) and apamin (100 nM), potent and selective inhibitors of BK Ca and SK Ca channels, respectively, significantly increased the area under the force-time curve and the amplitude of contractions. Conclusions Phasic contractions of human detrusor are dependent on calcium entry through l-type calcium channels. BK Ca and SK Ca channels play a key role in the modulation of human detrusor smooth muscle phasic contractility. Furthermore, these observations support the concept that increasing conductance through K ATP, BK Ca, and SK Ca channels may represent attractive pharmacologic targets for decreasing phasic contractions of detrusor smooth muscle in OAB.

Effects of potassium channel modulators on myotropic responses of aortic rings of pregnant rats.

The contribution of potassium channels [ATP-sensitive potassium (K(ATP)) and high-conductance calcium-activated potassium (BK(Ca)) channels] in the resistance of aortic rings of term pregnant rats to phenylephrine (Phe), arginine vasopressin (AVP), and KCl was investigated. Concentration-response curves to tetraethylammonium (TEA), a nonselective K(+) channel inhibitor, were obtained in the absence or presence of KCl. TEA induced by itself concentration-dependent responses only in aortic rings of nonpregnant rats. These responses to TEA could be modulated in both groups of rings by preincubation with different concentrations of KCl. Concentration-response curves to Phe, AVP, and KCl were obtained in the absence or presence of cromakalim or NS-1619 (K(ATP) and BK(Ca) openers, respectively) and glibenclamide or iberiotoxin (K(ATP) and BK(Ca) inhibitors, respectively). Cromakalim significantly inhibited the responses to the three agonists in a concentration-dependent manner in both groups of rats. Alternatively, in the pregnant group of rats, glibenclamide increased the sensitivity to all three agonists. NS-1619 also inhibited the response to all agonists. With AVP and KCl, its effect was greater in aortic rings of pregnant than nonpregnant rats. Finally, iberiotoxin increased the sensitivity to all three agents. This effect was more important in aortic rings of nonpregnant rats and was accompanied by an increase of the maximal response to Phe and AVP. These results suggest that potassium channels are implicated in the control of basal membrane potential and in the blunted responses to these agents during pregnancy.

Effect of potassium channel modulators in mouse forced swimming test.

1. The effect of intracerebroventricular (i.c.v.) administration of different potassium channel blockers (tetraethylammonium, apamin, charybdotoxin, gliquidone), potassium channel openers (pinacidil, minoxidil, cromakalim) and aODN to mKv1.1 on immobility time was evaluated in the mouse forced swimming test, an animal model of depression. 2. Tetraethylammonium (TEA; 5 microg per mouse i.c.v.), apamin (3 ng per mouse i.c.v.), charybdotoxin (1 microg per mouse i.c.v.) and gliquidone (6 microg per mouse i.c.v.) administered 20 min before the test produced anti-immobility comparable to that induced by the tricyclic antidepressants amitriptyline (15 mg kg(-1) s.c.) and imipramine (30 mg kg(-1) s.c.). 3. By contrast pinacidil (10-20 microg per mouse i.c.v.), minoxidil (10-20 microg per mouse i.c.v.) and cromakalim (20-30 microg per mouse i.c.v.) increased immobility time when administered in the same experimental conditions. 4. Repeated administration of an antisense oligonucleotide (aODN) to the mKv1.1 gene (1 and 3 nmol per single i.c.v. injection) produced a dose-dependent increase in immobility time of mice 72 h after the last injection. At day 7, the increasing effect produced by aODN disappeared. A degenerate mKv1.1 oligonucleotide (dODN), used as control, did not produce any effect in comparison with saline- and vector-treated mice. 5. At the highest effective dose, potassium channels modulators and the mKv1.1 aODN did not impair motor coordination, as revealed by the rota rod test, nor did they modify spontaneous motility as revealed by the Animex apparatus. 6. These results suggest that modulation of potassium channels plays an important role in the regulation of immobility time in the mouse forced swimming test.

ATP-Sensitive Potassium Channels Regulate In Vivo Dopamine Release in Rat Striatum

ATP-sensitive K+ channels (KATP) are distributed in a variety of tissues including smooth muscle, cardiac and skeletal muscle, pancreatic β-cells and neurons. Since KATP channels are present in the nigrostriatal dopamine (DA) pathway, the effect of potassium-channel modulators on the release of DA in the striatum of conscious, freely-moving rats was investigated. The extracellular concentration of DA was significantly decreased by the KATP-channel opener (−)-cromakalim but not by diazoxide. (−)-Cromakalim was effective at 100 and 1000 μM concentrations, and the maximum decrease was 54% below baseline. d-Amphetamine significantly increased extracellular DA levels at the doses of 0.75 and 1.5 mg/kg, s.c. with a 770% maximum increase. (—)-Cromakalim had no effect on d-amphetamine-induced DA release, while glyburide, a KATP blocker, significantly potentiated the effects of a low dose of d-amphetamine. These data indicate that K+ channels present in the nigrostriatal dopaminergic terminals modulate basal release as well as evoked release of DA.

Effect of potassium channel modulators on male sexual behavior.

In the adult sexually experienced male rat, the intracerebroventricular (i.c.v.) injection of pinacidil, a KATP channel opener, at the dose of 100-150-300 micrograms/rat worsened the copulatory performance in the presence of a receptive female, whereas the administration of glibenclamide, a KATP channel blocker, at the dose of 0.5 and 3 mg/kg intraperitoneally (i.p.) had an improving effect. These data indicate that KATP channels in target neurons may play an important role in the physiology of male sexual behavior.

Effect of potassium channel modulators on the release of glutamate induced by ischaemic-like conditions in rat hippocampal slices

The effects of the potassium channel openers lemakalim, RP 52891 and galanin and the potassium channel blockers glibenclamide and gliquidone were evaluated by the release of endogenous glutamate from rat hippocampal slices subjected to a brief period of ischaemia (2–10 min). Ischaemia was mimicked by incubating slices in a glucose free medium equilibrated with 95% N 2 5% CO 2 . These conditions evoked a release of glutamate which was insensitive to tetrodotoxin and Ca 2+ indicating a non-vesicular origin. The release of glutamate evoked by a 6- or 8-min period of ischaemia was reduced by 25–40% in the presence of lemakalim (10 μM), RP 52891 (10 μM) or galanin (0.3 μM), whereas it was enhanced by 60 to 100% in the presence of glibenclamide (1 μM) and gliquidone (2 μM). These observations suggest that cellular damage resulting from ischaemia induced excessive release of glutamate in the hippocampus may be partly reduced by potassium channel openers, and conversely increased by sulfonylureas.