SEARCH · Search PubMed

Results for “Pinacidil”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 685 records · Page 38Linked to original sources

PubMed2001

Sulfonylurea receptors inhibit the epithelial sodium channel (ENaC) by reducing surface expression.

In the kidney the epithelial Na+ channel (ENaC) is co-expressed with the sulfonylurea receptor (SUR), an ABC protein that shares a high degree of homology with the cystic fibrosis transmembrane conductance regulator (CFTR) and reportedly modifies ENaC in various preparations. To investigate a possible regulatory relationship between SUR and ENaC, we performed co-expression studies on Xenopus laevis oocytes, which were assayed for amiloride-sensitive currents (DeltaIami). Moreover, a chemiluminescence assay was used to investigate the surface expression of extracellular hemagglutinin-tagged SUR1 (SUR1-HA) or HA-tagged ENaC (ENaC-HA). In oocytes co-injected with SUR1/ENaC (or SUR2B/ENaC) DeltaIami was reduced by congruent with 53% (or congruent with 45%) compared to DeltaIami measured in matched control oocytes injected with ENaC alone. The inhibitory effect of SUR on DeltaIami was preserved in oocytes expressing ENaC with C-terminally truncated subunits. Co-expression of SURs did not confer sensitivity of DeltaIami to diazoxide, pinacidil, tolbutamide, or glibenclamide. ENaC does not facilitate the surface expression of SUR1-HA, which is known to be retained in the endoplasmatic reticulum (ER) by an ER-retention/retrieval signal. SUR1-HAAAA, a mutant that lacks this signal, still inhibits ENaC currents. Chemiluminescence was reduced by congruent with 49% in oocytes co-expressing ENaC-HA/SUR1 compared to that in control oocytes expressing ENaC-HA alone. We conclude that SUR does not interact with ENaC at the level of the plasma membrane but that it inhibits DeltaIami by reducing surface expression of the channel.

ATP-Binding Cassette Transporters↗

PubMed1996

K+ channel openers protect hippocampal neurons against oxidative injury and amyloid beta-peptide toxicity.

Potassium channel openers (KCOs) such as diazoxide and levochromakalim can protect cardiac myocytes against ischemic injury and neurons against excitotoxic injury, presumably because of their ability to hyperpolarize the plasma membrane and reduce calcium influx. We now report that diazoxide, levocromakalim (LCC), and to a lesser extent pinacidil, protect cultured rat hippocampal neurons against oxidative injury induced by exposure to FeSO4 and amyloid beta-peptide (A beta). Imaging studies of intracellular peroxide levels revealed that KCOs suppressed the generation of peroxides induced by FeSO4 and A beta. KCOs were effective in protecting neurons against oxidative insults in the presence of the K+ channel blockers glibenclimide and 4-aminopyridine indicating that their protective mechanism involved actions in addition to activation of K+ channels. The data suggest that KCOs may be of therapeutic value in an array of neurodegenerative disorders that involve oxidative injury.

Amyloid beta-Peptides↗

PubMed1992

Pharmacological interaction experiments differentiate between glibenclamide-sensitive K+ channels and cyclic GMP as components of vasodilation by nicorandil.

The relaxant effect of the vasodilator drug, nicorandil, was studied in circular strips of bovine coronary arteries. To differentiate between relaxation caused by cyclic GMP (cGMP) and by hyperpolarization, the influence of cGMP was blocked with methylene blue and that of hyperpolarization with the inhibitor of ATP-dependent K+ channels, glibenclamide. Methylene blue and glibenclamide inhibited nicorandil-induced relaxation to similar extents. Cromakalim-induced relaxation but not that due to sodium nitroprusside (nitroprusside-Na) was inhibited by glibenclamide. Methylene blue inhibited the relaxation caused by nitroprusside-Na but not that due to cromakalim. The different modes of action of the two components of relaxation caused by nicorandil were studied in agonist-agonist interaction experiments. The interaction between nicorandil and nitroprusside-Na or 3-morpholino-sydnonimine (SIN-1) was overadditive in the absence of glibenclamide but additive, i.e. competitive, in the presence of glibenclamide. The interaction of nicorandil with cromakalim or pinacidil was overadditive in the absence of methylene blue but additive, i.e. competitive, in the presence of methylene blue. The results show that nicorandil relaxes smooth muscle through two independent mechanisms: ATP-dependent activation of K+ channels and stimulation of guanylyl cyclase resulting in increases in cGMP.

Animals↗

PubMed1994

Effects of K+ channel openers on the vascular actions of human gamma globulin.

The aim of this study was to determine if the stimulatory action of human gamma globulin on the spontaneous activity of the rat mesenteric portal vein is due to decreased K+ conductance. Glibenclamide potentiated the action of human gamma-globulin on the portal vein by 45% and on its own had a concentration- and time-dependent biphasic (increase followed by a decrease) effect on the spontaneous activity of the portal vein. Diazoxide and pinacidil both inhibited the action of human gamma-globulin on the rat mesenteric portal vein. Levcromakalim (BRL 38227) potentiated the stimulatory action of human gamma-globulin on the integrated force of the spontaneous contractions of the rat mesenteric portal vein by 40% and 49% at concentrations of 0.5 and 5 microM, respectively. These studies suggest that human gamma-globulin can act by directly modulating a K+ channel.

Animals↗

PubMed1995

K+ channel openers delay intestinal transit and have antidiarrheal activity.

The effect of pinacidil and cromakalim, two KATP channel openers, on intestinal transit and castor oil-induced diarrhea was studied in mice. Both drugs, administered orally, dose dependently inhibited the intestinal propulsion of charcoal, and castor oil-induced diarrhea, comparing favorably with morphine. These results may suggest a new approach for the symptomatic treatment of diarrhea.

Animals↗

PubMed1996

The effects of pharmacological modulation of KATP on the guinea-pig isolated diaphragm.

The purpose of the present study was to investigate the functional consequences of KATP modulation in the normal and the metabolically inhibited guinea-pig isolated diaphragm using the K+ channel openers cromakalim, pinacidil, RP49356 (N-methyl-2-(3-pyridil)-tetrahydrothiopyran-2-carbothiami de-1-oxide) and ZM260384 (2-(2,2-bis(difluoromethyl)-6-nitro-3,4-dihydro-2H-1,4-benzoxazine -4-yl)pyridine-N-oxide) and the K+ channel inhibitors glibenclamide, phentolamine and ciclazindol. All K+ channel openers accelerated the decline in function induced by intermittent tetanic contractions following metabolic inhibition and delayed the development of contracture. Cromakalim also improved the recovery of twitch tension following 10 min intermittent tetanic stimulation in the hypoxic guinea-pig diaphragm preparation. Of the K+ channel inhibitors tested, only ciclazindol, at the highest concentration tested (10 microM), significantly delayed the decline in tetanic tension following metabolic inhibition in the guinea-pig isolated diaphragm. None of the inhibitors significantly accelerated the development of contracture. All inhibitors however, antagonised the actions of the K+ channel opener, cromakalim. The results indicate that opening of KATP can accelerate the decline in function following metabolic inhibition in the guinea-pig isolated diaphragm. In the absence of K+ channel openers however, KATP does not appear to contribute to this decline under the conditions of the present study.

Adenosine Triphosphate↗

PubMed1996

Modulation of vascular KATP channels in hypothyroidism.

The role of vascular KATP channels in hypothyroidism-induced decrease in myogenic activity of rat portal vein was examined by using pharmacologically relevant concentrations of K+ channel ligands. As compared to controls, a significant decrease in the myogenic tone and noradrenaline (10(-9)-10(-5) M)-induced contractions was observed in portal veins from hypothyroid rats. In both euthyroid and hypothyroid states, pinacidil (10(-9)-10(-5) M) and cromakalim (10(-9)-10(-5) M) caused concentration-related inhibition of the myogenic tone (frequency and amplitude). However, hypothyroidism caused a leftward shift in the concentration-response curves of the K+ channel openers with a corresponding decrease in their IC50 values both in the absence and presence of the KATP channel blocker, glibenclamide (10(-7) M). Further, concentration-dependent increase in the frequency of myogenic tone by glibenclamide (10(-8)-3 x 10(-6) M) was greater in tissues from hypothyroid rats (EC50 = 2.07 x 10(-7) M; 95% CL, 1.06-4.05 x 10(-7) M) in comparison to controls (EC50 = 8.07 x 10(-7) M; 95% CL, 0.53-1.22 x 10(-6) M). These results suggest that a decrease in the myogenic tone of rat portal vein may possibly be related to an enhanced opening of the KATP channels in hypothyroidism.

Animals↗

PubMed1989

Influence of ATP-sensitive potassium channel modulators on ischemia-induced fibrillation in isolated rat hearts.

We have confirmed the findings of Kantor and colleagues that ischemia-induced fibrillation in isolated Langendorff-perfused rat hearts can be prevented by glyburide, a blocker of ATP-dependent K channels. These data suggest that block of ATP-dependent K current [IK(ATP)] is a novel antiarrhythmic mechanism. This hypothesis was further tested by evaluating the effects of another sulfonylurea IK(ATP) blocker, tolbutamide (1 mM) and two agents known to activate these channels in cardiac tissue, BRL 34915 (10 microM) and pinacidil (30 microM). Similar to glyburide, tolbutamide was also effective in preventing fibrillation in this isolated rat heart model. The IK(ATP) activators enhanced the rate of tachycardia and shortened the time required for the hearts to develop fibrillation. Coadministration of glyburide with either IK(ATP) activator prevented their effects. It is concluded that activation of IK(ATP) during global ischemia contributes to the development of fibrillation in the perfused rat heart model.

Adenosine Triphosphate↗

PubMed1995

Effect of four potassium channel agonists on bupivacaine-induced toxicity in mice.

The influence of four potassium channel agonists i.e. diazoxide (D), levcromakalim (L), nicorandil (N) and pinacidil (P) on bupivacaine-induced acute toxicity was evaluated by measuring the convulsant activity, the time of latency to convulse and the mortality rate. Four different dosages (i.e. 0.1, 1, 10 and 100 mg/kg/i.p. for D, N and P and 0.01, 0.1, 1 and 5 mg/kg/i.p. for L) were injected to a total of 200 male NMRI adult mice: 16 groups of 10 mice each were previously treated by a single i.p. dose of each potassium channel agonist while controls (n = 40) received saline injection. Thus, 15 minutes later, all groups were injected with a 50 mg/kg/i.p. single dose of bupivacaine. The convulsant activity of bupivacaine was significantly modified by only high doses of L in a dose-dependent manner. Compared to the controls, the period of latency was significantly increased for most of the doses of P, N, D and L in a dose dependent manner for L and P. The anesthetic-induced mortality (47.5% for controls) was not significantly modified by D, but decreased by N and increased by high doses of L and P which is probably related to a delayed mortality.

Animals↗

PubMed1995

Opening of brain potassium-channels inhibits the ACTH-induced behavioral syndrome in the male rat.

In adult male rats, the intracerebroventricular (i.c.v.) injection of pinacidil, a potassium channel opener, at the doses of 100, 200 or 300 micrograms/rat, dose-dependently reduced the display of the most typical behavioral symptoms (excessive grooming, stretching, yawning, penile erections) induced by the i.c.v. administration of ACTH-(1-24) (4 micrograms/rat). These data indicate that the complex mechanism of the melanocortin-induced behavioral syndrome involves closure of potassium channels in target neurons, and provide further experimental support to the idea that melanocortins are functional antagonists of opioids.

Animals↗

PubMed1993

Comparative electrophysiological and mechanical actions of ATP-sensitive potassium channel openers in canine Purkinje fibers.

1. Electrophysiological and mechanical effects of ATP-dependent potassium channel openers on canine Purkinje fibers were examined. 2. Cromakalim and pinacidil (0.3-10 microM) and nicorandil (0.3-1 mM) shortened the action potential duration (APD), and reduced the contractile force, in a concentration-dependent manner. Other action potential parameters were unaffected. The effects were reversible. 3. Effects of the openers were antagonized by tetraethylammonium (a non-specific potassium channel blocker) and more potently by glibenclamide (a blocker of ATP-sensitive K+ channel). 4. The APD shortening and the negative inotropic effect induced by a switch of stimulation frequency (from 0.5 to 3 Hz) were potentiated by the openers. At high Ca2+ (5.4 and 10.8 mM), the effects of the openers on the APD and contractile force were unaffected. 5. In the spontaneously beating preparations, the openers hyperpolarized the maximum diastolic potential, and an arrest occurred. 6. Under the calcium overload condition, the K+ openers abolished a delayed after depolarization, and enhanced the depressed post-rest potentiation. 7. These results suggest that the K+ channel openers increase the K+ conductance and might decrease the cellular Ca2+ level in calcium overloading cells, and that nicorandil might also act directly ATP-sensitive K+ channels.

Action Potentials↗

PubMed1995

Diverse actions of calcitonin gene-related peptide on intracellular free Ca2+ concentrations in UMR 106 osteoblastic cells.

Calcitonin gene-related peptide (CGRP) was examined for its effects on intracellular free Ca2+ concentration ([Ca2+]i) in UMR 106 osteoblast-like cells. Cells loaded with the Ca2+ dye FURA-2 dose-dependently responded to CGRP (1-100 nM) with transient two-fold increases in [Ca2+]i. An intracellular source for this Ca2+ transient was suggested by the failure of membrane depolarization with high extracellular K+ or acute depletion of extracellular Ca2+ ([Ca2+]e) with EGTA to attenuate this response. After cells were incubated for 45 min with 0.1 mM extracellular Ca2+ to deplete intracellular Ca2+ stores, CGRP produced a 25-30% decrease in [Ca2+]i rather than a transient increase. This calcium decrease was mimicked by membrane depolarization or by pinacidil, a specific activator of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, and blocked by glybenclamide, a specific blocker of KATP channels. Our data suggest that CGRP has diverse Ca2+ regulatory effects in UMR 106 cells, mobilizing Ca2+ from intracellular stores via classical signaling while possibly promoting cellular Ca2+ efflux or inhibiting uptake through voltage-dependent Ca2+ channels via KATP-mediated hyperpolarization.

Adenosine Triphosphate↗

PubMed2004

Evaluation of antipruritic effects of several agents on scratching behavior by NC/Nga mice.

We investigated the effects of several agents on the established itching model in NC/Nga mice, model of atopic dermatitis-like disease, to elucidate related characteristics. The number of spontaneous scratching behaviors (the duration time is over 1.5 s) by NC/Nga mice with severe skin lesions was measured before and after administration of agents for 24 h. The scratching behavior by NC/Nga mice was significantly suppressed by administration of dexamethasone or tacrolimus, but not by chlorpheniramine maleate or cyproheptadine hydrochloride. These results suggest that this method shows a good correlation with the effectiveness of drugs prescribed for itching in humans with atopic dermatitis, and histamine and serotonin do not play an important role in causing the scratching behavior seen by NC/Nga mice. The scratching behavior was also significantly suppressed by naloxone hydrochloride, dibucaine or capsaicin. These results suggest that the scratching behavior seen in this model is caused by itching signal transmission through neural system. Furthermore, we found that theophylline, pinacidil or limaprost had scratching suppression effects in this model.

Alprostadil↗

PubMed2006

Differences in arrhythmogenicity between the canine right ventricular outflow tract and anteroinferior right ventricle in a model of Brugada syndrome.

BACKGROUND: The Brugada syndrome is characterized by ST-segment elevation on the ECG, especially in the right precordial leads sensitive to the right ventricular outflow tract (RVOT). OBJECTIVES: The purpose of this study was to evaluate the hypothesis that right ventricular electrophysiologic heterogeneity caused arrhythmogenicity in the Brugada syndrome. METHODS: Action potentials (APs) were mapped on the epicardium of 14 RVOT preparations and on the transmural surfaces of 15 pairs of RVOT and right ventricular anteroinferior (RVAI) preparations isolated from canine hearts. Brugada ECG and arrhythmias were induced with pilsicainide (2.5-12.5 micromol/L), pinacidil (1.25-12.5 micromol/L), and terfenadine (2.0 micromol/L). RESULTS: Low doses of drugs elevated the J-ST segment and induced APs with both short and long action potential durations (APDs) in contiguous RVOT epicardial regions. In addition, APs in the RVOT had a larger phase 1 notch and longer APD than in RVAI. The longest APDs were in the epicardium in RVOT but in the endocardium in RVAI regions. High doses of drugs eliminated the phase 2 dome of the AP and abbreviated APDs in the epicardium but not in endocardium and reduced the epicardial heterogeneity of APs but increased the transmural gradient of APD in 14 (93%) of the RVOT preparations. In contrast, abbreviations of epicardial APDs occurred in only 4 (27%) of the RVAI preparations. Ventricular tachycardia occurred more frequently in the RVOT (47%) than in paired RVAI preparations (7%). Blocking the transient outward current reduced the heterogeneity of APs and eliminated arrhythmogenicity in all preparations. CONCLUSION: Compared with the RVAI region, the RVOT has greater electrophysiologic heterogeneity that contributes to arrhythmogenicity in this model of Brugada syndrome.

Action Potentials↗

PubMed2006

Hypotonic stress enhances slope conductivity of ATP-sensitive K+ channels activated pharmacologically.

The aim of this paper was to find out the effects of hypotonic stress on the slope conductivity of ATP-sensitive K(+) channels. Using patch clamp technique, rilmakalim and pinacidil as the activators and glibenclamide as an inhibitor of mentioned channels, we have demonstrated that short hypotonic challenge doubled slope conductivity of exploring channels by augmentation of their open probability.

Adenosine Triphosphate↗

PubMed2006

Cellular basis for trigger and maintenance of ventricular fibrillation in the Brugada syndrome model: high-resolution optical mapping study.

OBJECTIVES: We examined how repolarization and depolarization abnormalities contribute to the development of extrasystoles and subsequent ventricular fibrillation (VF) in a model of the Brugada syndrome. BACKGROUND: Repolarization and depolarization abnormalities have been considered to be mechanisms of the coved-type ST-segment elevation (Brugada-electrocardiogram [ECG]) and development of VF in the Brugada syndrome. METHODS: We used high-resolution (256 x 256) optical mapping techniques to study arterially perfused canine right ventricular wedges (n = 20) in baseline and in the Brugada-ECG produced by administration of terfenadine (5 micromol/l), pinacidil (2 micromol/l), and pilsicainide (5 micromol/l). We recorded spontaneous episodes of phase 2 re-entrant (P2R)-extrasystoles and subsequent self-terminating polymorphic ventricular tachycardia (PVT) or VF under the Brugada-ECG condition and analyzed the epicardial conduction velocity and action potential duration (APD) restitutions in each condition. RESULTS: Forty-one episodes of spontaneous P2R-extrasystoles in the Brugada-ECG were successfully mapped in 9 of 10 preparations, and 33 of them were originated from the maximum gradient of repolarization (GR(max): 176 +/- 54 ms/mm) area in the epicardium, leading to PVT (n = 12) or VF (n = 5). The epicardial GR(max) was not different between PVT and VF. Wave-break during the first P2R-extrasystole produced multiple wavelets in all VF cases, whereas no wave-break or wave-break followed by wave collision and termination occurred in PVT cases. Moreover, conduction velocity restitution was shifted lower and APD restitution was more variable in VF cases than in PVT cases. CONCLUSIONS: Steep repolarization gradient in the epicardium but not endocardium develops P2R-extrasystoles in the Brugada-ECG condition, which might degenerate into VF by further depolarization and repolarization abnormalities.

Action Potentials↗

PubMed2006

Identification of two types of ATP-sensitive K+ channels in rat ventricular myocytes.

The ATP-sensitive K(+) (K(ATP)) channels are known to provide a functional linkage between the electrical activity of the cell membrane and metabolism. Two types of inwardly rectifying K(+) channel subunits (i.e., Kir6.1 and Kir6.2) with which sulfonylurea receptors are associated were reported to constitute the K(ATP) channels. In this study, we provide evidence to show two types of K(ATP) channels with different biophysical properties functionally expressed in isolated rat ventricular myocytes. Using patch-clamp technique, we found that single-channel conductance for the different two types of K(ATP) channels in these cells was 57 and 21 pS. The kinetic properties, including mean open time and bursting kinetics, did not differ between these two types of K(ATP) channels. Diazoxide only activated the small-conductance K(ATP) channel, while pinacidil and dinitrophenol stimulated both channels. Both of these K(ATP) channels were sensitive to block by glibenclamide. Additionally, western blotting, immunochemistry, and RT-PCR revealed two types of Kir6.X channels, i.e., Kir6.1 and Kir6.2, in rat ventricular myocytes. Single-cell Ca(2+) imaging also revealed that similar to dinitrophenol, diazoxide reduced the concentration of intracellular Ca(2+). The present results suggest that these two types of K(ATP) channels may functionally be related to the activity of heart cells.

Animals↗

PubMed2006

ATP-sensitive potassium channels expressed by human monocytes play a role in stasis-induced thrombogenesis via tissue factor pathway.

Blood stasis is one of the key risk factors in deep vein thrombosis. Localized blood oxygen and glucose depletion are main characteristics observed during stasis. However, the causal chain leading to clot formation is still obscure. According to our hypothesis, energy depletion causes opening of K(ATP) channels present on monocytes, facilitating influx of calcium and triggering tissue factor-(TF)-dependent procoagulatory activity and eventually clot formation. Using Reverse-Transcript-PCR (RT-PCR) in magnetically enriched human monocytes, mRNA transcription of the K(ATP)-channel subunits Kir6.1 and Kir6.2 could be confirmed. Membrane potential and cytosolic calcium were recorded by time-resolved flow cytometry. The specific K(ATP)-channel opener pinacidil caused a glibenclamide-sensitive hyperpolarization of monocytes and a prolongation of cytosolic calcium transients triggered by purinergic stimulation. TF-initiated whole blood clotting time (TiFaCT) was accelerated comparing 2 and 8 h of simulated in vitro blood stasis using blood of male healthy volunteers. Both with and without activation of the monocytes with 100 ng/ml LPS, the K(ATP)-channel blocker glibenclamide resulted in a significantly (p<0.001) prolonged clotting time after 8 h of stasis compared to vehicle control and LPS, respectively. In the course of stasis, flow cytometry showed an increase in monocytes expressing TF (0.1% and 1.3% after 2 and 8 h, respectively). LPS (100 ng/ml) increased the amount of TF expression significantly to 36%, whereas 30 microM glibenclamide partly reversed this increase down to 24%. Phosphatidylserine-exposure (PSE) on monocytes increased strongly during stasis by 11.2 times, a process which glibenclamide attenuated by 23%. LPS increased PSE further by 65%, which glibenclamide reduced by 50%. In conclusion, presence of integral subunits of K(ATP)-channels is demonstrated in human monocytes. These channels are able to enhance Ca(2+)-dependent intracellular signalling and can increase TF-activity and phosphatidylserine exposure thereby accelerating clot formation during stasis by monocytes.

Adenosine Triphosphate↗