SEARCH · PubMed Health

Results for “Pinacidil”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

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

At least 289 records · Page 16Linked to original sources

PubMed1991

Effects of K+ channel agonists cromakalim and pinacidil on rat basilar artery smooth muscle cells are mediated by Ca(++)-activated K+ channels.

Whole-cell and cell-free inside-out patch-clamp recording techniques were used to examine the actions of potassium channel openers pinacidil and cromakalim in enzymatically isolated smooth muscle cells of rat basilar artery. Delayed rectifier and calcium-dependent potassium currents were identified from the whole-cell recordings. Only the calcium-dependent potassium current was increased by cromakalim and pinacidil. Recordings from inside-out membrane patches revealed a large conductance voltage- and calcium-dependent potassium channel, which was blocked by charybdotoxin but unaffected by ATP less than 10 mM. Cromakalim and pinacidil increased the open probability of this channel. On the basis of these results, we suggest that such drugs, acting on cerebral arterial smooth muscle cell potassium channels, may be of some benefit in the treatment of cerebral vasospasm following subarachnoid hemorrhage.

Animals↗

PubMed2000

3-Alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxides structurally related to diazoxide and pinacidil as potassium channel openers acting on vascular smooth muscle cells: design, synthesis, and pharmacological evaluation.

A series of 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides structurally related to diazoxide and pinacidil were synthesized and tested as possible K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. In contrast to previously described 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1, 1-dioxides, most of the new compounds were found to be poorly active on B-cells but exhibited clear vasorelaxant properties. 3-(3, 3-Dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (4d) and 7-chloro-3-(3, 3-dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (5d), two compounds bearing the alkyl side chain of pinacidil, were found to be the most active representatives of their respective series on rat aorta rings. 3-Cycloalkylalkylamino- and 3-aralkylamino-7-chloro-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides also expressed myorelaxant activity on electrically stimulated guinea pig ileum and on oxytocin-induced contractions of the rat uterus. Further biological investigations ((86)Rb efflux measurements, vasodilator potency on 30 and 80 mM KCl-induced contractions in the absence and presence of glibenclamide) revealed that compounds 4d and 5d, but not compound 5f, expressed the pharmacological profile of classical K(ATP) channel openers. In conclusion, by changing the position of the nitrogen atom in the pyridine ring, we now have obtained a family of drugs expressing an opposite tissue selectivity. Taken as a whole, the present findings also suggest that 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides such as 4c, 4d, 5c, and 5d may be considered as new examples of K(ATP) channel openers expressing a pharmacological profile similar to that of pinacidil and diazoxide.

Animals↗

PubMed2002

Diazoxide and pinacidil uncouple pyruvate-malate-induced mitochondrial respiration.

We investigated the effects of K(ATP) channel openers diazoxide and pinacidil on the respiration rate and membrane potential (deltapsi) of rat heart mitochondria, oxidizing pyruvate and malate. Diazoxide and pinacidil (58.8-1348.3 microM) increased the V2 (-ADP) respiration rate accordingly by 13-208% and 30-273% and decreased the deltapsi by 2-17% and 6-55%. These effects were also similar in the respiration medium without K+. Moreover, carboxyatractyloside completely abolished diazoxide- and pinacidil-induced uncoupling, indicating a role for the mitochondrial adenine nucleotide translocase in this process.

Animals↗

PubMed1999

Pharmacodynamics and pharmacokinetics of pinacidil in normotensive volunteers after repeated doses of a new slow-release tablet formulation.

Pinacidil (CAS 85371-64-8) is an antihypertensive drug of the class of agents called "potassium channel openers". The pharmacokinetics of were studied after repeated oral administration of a new slow release tablet formulation (Pindac) as compared with the standard slow release capsule formulation in healthy volunteers. Eighteen healthy volunteers (3 males and 15 females), aged from 22 to 48 years, and 49 to 95 kg in weight, were given a 12.5 mg dose of each formulation every 12 h for 7 days on two occasions, in a randomized, cross-over trial with at least two weeks interval between trials. Blood samples were drawn immediately before drug administration on the morning of days 1, 2, 3, 4, 5, 6, and 7 and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 36 h after the last drug administration. Blood pressure, heart rate, and respiratory function were assessed at admission and on the morning of day 0 (baseline), 2 and 7, before drug administration, and at 4, 24 and 36 h after the final administration. Pinacidil plasma levels were determined by an HPLC method. Both formulations elicited similar reductions of systolic and diastolic pressures from 4 h after administration, but did not change heart rate. The main model-independent pharmacokinetic parameters of pinacidil (Cmax, Tmax, AUC, MRT), as well as the absorption and elimination half-lives were similar with the two formulations. During the study there were no complaints of side-effects with either of the formulations. One advantage of the new formulation as compared to the capsules is that the tablets can be cut easily and the dosage adapted to a patient's needs.

Adult↗

PubMed1994

Dilating effect of perivascularly applied potassium channel openers cromakalim and pinacidil in rat and cat pial arteries in situ.

OBJECTIVE: The aim was to test the vasodilator effect of perivascularly applied potassium channel openers cromakalim and pinacidil in pial arteries of cat and rat. METHODS: Using an open cranial window technique the diameter of pial arteries in the parietal cortex of rat and cat was recorded with an image splitting method. Employing micropuncture techniques, test compounds were dissolved in inert cerebrospinal fluid and infused into the perivascular space of individual arteries. RESULTS: Cromakalim (7 x 10(-18)-7 x 10(-13) M) induced concentration dependent dilatation of feline pial arteries with a maximum effect of 26.8(SEM 3.2)% at 7 x 10(-15) M. In rat arteries, cromakalim had a maximum effect of 32.1(4.97)% at 10(-15) M, while pinacidil (10(-10)-10(7) M) exerted a maximum dilatation of 29.5(3.3)% at 10(-8) M. The latter is consistent with previous findings in feline pial arteries. The sulphonylurea glibenclamide (10(-8)-10(-6) M) had no effect on the resting diameter of rat and cat pial arteries, indicating that their resting tone is not influenced by mechanisms involving ATP sensitive potassium channels. However, glibenclamide reduced the dilating effect of cromakalim and pinacidil in rat and cat in a dose dependent manner. CONCLUSIONS: A comparison with previously published data obtained in isolated middle cerebral and basilar arteries showed that potassium channel openers of the benzopyrane and cyanoguanidine type are much more potent in pial arteries than in peripheral arteries in situ or in isolated arteries of the circle of Willis and of peripheral vascular beds.

Animals↗

PubMed1994

Effect of potassium on the action of the KATP modulators cromakalim, pinacidil, or glibenclamide on arrhythmias in isolated perfused rat heart subjected to regional ischaemia.

OBJECTIVE: The ATP sensitive potassium channel openers cromakalim (n = 10) and pinacidil (n = 10), and a blocker of this channel, glibenclamide (n = 10), were studied in isolated perfused rat hearts subjected to regional ischaemia at varying concentrations (2 to 8 mM) of external potassium ([K+]o). METHODS: Hearts were isolated and perfused on a Langendorff apparatus. Vehicle (0.1% DMSO), cromakalim (10 microM), pinacidil (10 microM), or glibenclamide (10 microM) were given 10 min before ischaemia. The left coronary artery was then occluded for 15 min and reperfused for 5 min. RESULTS: No agent caused more than a 10% change in heart rate. Both cromakalim and pinacidil increased (30%), and glibenclamide decreased (30%) coronary flow at 4 and 6 mM [K+]o. In the vehicle group, increases in [K+]o produced concentration dependent reductions in arrhythmia scores by decreasing ventricular fibrillation. No concentration dependent effects of [K+]o on ischaemic ventricular tachycardia was observed. Under ischaemic conditions, potassium channel openers and glibenclamide more markedly reduced ischaemic ventricular tachycardia and fibrillation relative to the effects of increased [K+]o. CONCLUSIONS: Ischaemic ventricular fibrillation was inversely related to changes in [K+]o, whereas effects on ventricular tachycardia were all-or-none. Neither potassium channel openers nor glibenclamide elicited significant proarrhythmic activity despite variations in [K+]o. These data suggest that both potassium channel openers and glibenclamide display potential antiarrhythmic activity through their ability to abolish two distinct arrhythmogenic mechanisms during ischaemia. It is also suggested that the underlying mechanisms of ventricular tachycardia and fibrillation are coupled during ischaemia in the rat.

Animals↗

PubMed1988

Pinacidil actions on ion channels in vascular muscle.

Electrophysiological and mechanical recordings from isolated single vascular muscle cells and isolated segments of caudal artery showed that pinacidil caused vascular muscle relaxation and hyperpolarization which originates from increased K+ conductance. Voltage-clamp recordings of current flow through single K+ channels strongly suggest that pinacidil increases the specific type of K+ conductance associated with the Ca2+-dependent "big" K+ channel (unit conductance of 200 pS in symmetrical K+ solutions). The increased opening of K+ channels appears certain to be an important cellular mechanism to vasodilation by pinacidil.

Animals↗

PubMed1989

Variable metabolism of pinacidil: lack of correlation with the debrisoquine and trimethylamine C- and N-oxidative polymorphisms.

1. The urinary excretion of pinacidil and its N-oxide in man was found to vary over a five-fold range. 2. Studies in individuals with inherited deficiencies for C-hydroxylation (debrisoquine type) and trimethylamine N-oxidation showed that the N-oxidation of pinacidil did not co-segregate with these oxidative polymorphisms. 3. It is concluded that the variable N-oxidation of pinacidil is most likely to be due to variations in the activity of the P-450 isozymes rather than in the microsomal flavoprotein containing mixed-function amine oxidase of Ziegler which is considered to be responsible for the N-oxidation of trimethylamine.

Adult↗

PubMed1991

Pinacidil inhibits the ryanodine-sensitive outward current and glibenclamide antagonizes its action in cells from the rabbit portal vein.

Pinacidil, a potassium-channel opener, inhibited the ryanodine-sensitive oscillatory outward potassium current induced by Ca released from an intracellular store. Glibenclamide, a blocker of the ATP-sensitive K-channel, prevented the action of pinacidil, suggesting the presence of an additional site (to K channels) for the vasodilator actions of pinacidil at which glibenclamide can act as an antagonist.

Adenosine Triphosphate↗

PubMed1996

Inhibition by P1075 and pinacidil of a calcium-independent chloride conductance in conditionally-immortal renal glomerular mesangial cells.

1. Depolarization of mesangial cells has been shown to occur following an outward movement of chloride ions from the cell. We have shown previously that mesangial cells from the H-2Kb-tsA58 transgenic mouse possess a significant whole-cell chloride conductance and consequently are a suitable preparation for the study of potential chloride channel inhibitors. 2. The effects on the whole-cell chloride conductance of the chloride channel inhibitor, 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) and the potassium channel openers, (KCOs) P1075 and pinacidil were investigated in mesangial cells from the H-2Kb-tsA58 transgenic mouse cultured in permissive conditions (at 33 degrees C in the presence of 50 u ml-1 murine gamma-interferon). 3. In symmetrical solutions of 140 mM tetramethylammonium chloride (TMAC1) the whole-cell chloride conductance was 1.08 +/- 0.05 nS (n = 63) and this could be reversibly inhibited by 5 x 10(-5) M NPPB. 4. Both P1075 and pinacidil inhibited the whole-cell chloride conductance. This inhibition was not reversible after drug washout and was demonstrated only when drugs were applied to the extracellular surface of the cells. Very low concentrations of the drugs were found to reduce the chloride conductance after 16 h incubation but under no circumstances studied was the conductance totally inhibited, leaving a mean residual current of 0.33 +/- 0.03 nS (n = 12). 5. The effects of different peptide calcium concentrations on the magnitude of the residual current in the presence of the drugs were investigated. The residual current was reduced with 10(-8) M calcium in the pipette and increased with 10(-3) M pipette calcium. Therefore, these data suggest that P1075 and pinacidil selectively inhibit a calcium-independent chloride conductance in mesangial cells from the H-2Kb-tsA58 transgenic mouse.

Animals↗

PubMed1992

Influence of osmolarity of solutions used for K+ contraction on relaxant responses to pinacidil, verapamil, theophylline and terbutaline in isolated airway smooth muscle.

Concentration-relaxation profiles for pinacidil, verapamil, terbutaline and theophylline were studied in guinea-pig trachealis contracted by two commonly applied techniques for K+ depolarization. All drugs were much less effective on contractions induced by hyperosmolar 124 mMn K+ solution (added KCl) than on contractions elicited by an isoosmolar 124 mM K+ Krebs solution (substituted KCl). The maximal relaxant responses were (isoosmolar K+/hyperosmolar K+): pinacidil 100%/40%, verapamil 100%/60%, theophylline 100%/0%, terbutaline 50%/0%. Addition of mannitol to establish the same hyperosmolarity as with 124 mM KCl also produced contraction of guinea-pig trachealis. Concentration-relaxation curves for the drugs on mannitol-induced contractions had close resemblance to those obtained in hyperosmolar 124 mM K+ solution. When contraction was elicited by 30 mM K+, pinacidil showed seven times higher relaxant potency in hyperosmolar compared to isoosmolar solution, whereas the relaxant responses to verapamil, theophylline and terbutaline were not influenced by osmolarity. When K+ depolarization is used as a tool for evaluation of drug action in airway smooth muscle, the two different techniques produce dissimilar results. The influence of hyperosmolarity per se appears to be an important and unwanted feature when K+ depolarization is produced by addition of KCl.

Animals↗

PubMed1993

Contraction induced either by iso-osmolar or hyper-osmolar potassium-rich solutions influences relaxant responses to pinacidil and verapamil in rat isolated aorta.

Relaxant responses of pinacidil and verapamil were studied in rat isolated aorta contracted by either iso-osmolar or hyper-osmolar potassium-rich solutions. Relaxant response profiles of pinacidil and verapamil in rat isolated aorta contracted by 124 mM K+ hyper-osmolar Krebs solutions showed marked reductions in inhibiting Emax values and substantial increases in corresponding IC50 values in comparison with results obtained at iso-osmolar conditions. Changes in the slopes of the fitted log concentration-relaxation curves were also observed, whereas pinacidil relaxation curves obtained after initial contraction induced by 30 mM K+ Krebs solutions were only slightly influenced by osmolarity, a definite decrease in Emax occurred for verapamil at hyper-osmolar conditions. Initial tension development was much slower and maximal tension lower when induced by 124 mM K+ in hyper-osmolar compared with iso-osmolar Krebs solutions. After incubation in Ca(2+)-deprived EGTA-containing Krebs solutions the maximal tension produced by 124 mM K+ iso-osmolar Krebs solution in rat aorta was nearly 95% reduced, whereas it was only reduced by 50% at hyper-osmolar conditions. Hyper-osmolarity as established by direct addition of potassium chloride to Krebs solutions in order to induce contraction in vascular smooth muscle could influence the in-vitro action profile, potency and intrinsic activity of the two vascular relaxant drugs.

Animals↗

PubMed1991

Cromakalim and pinacidil dilate small mesenteric arteries but not small cerebral arteries.

Small elevations in external K+ hyperpolarize and dilate small cerebral arteries. The hyperpolarization and dilation to K+ are blocked by barium (less than 0.1 mM). Since membrane hyperpolarization appears to be an important mechanism for dilation of these small cerebral arteries, we investigated the effects of the hyperpolarizing vasodilators, cromakalim and pinacidil, on isolated pressurized rat cerebral arteries (diameter of 158 +/- 5 microns at 50% of the systolic blood pressure). Cromakalim and pinacidil, which are potent relaxants of a variety of muscle types, were without effect on posterior cerebral arteries at concentrations that completely dilate similarly sized rat mesenteric arteries (diameter 134 +/- 6 microns at 50% of the systolic blood pressure). The mesenteric artery dilation to cromakalim and pinacidil was reversed by glibenclamide. However, unlike the cerebral arteries, mesenteric arteries did not exhibit a barium-sensitive dilation to external K+. Thus it appears that there may be differences in the types of K+ channels that are activated by dilating mechanisms in small cerebral and mesenteric arteries.

Animals↗

PubMed1990

Relaxation response to pinacidil and diazoxide in the mouse isolated distal colon.

Pinacidil and diazoxide induced concentration-related relaxations of the longitudinal muscle of the mouse distal colon. The relaxing effects of pinacidil and diazoxide were unaffected by tetraethylammonium, but were antagonized by tolbutamide and glibenclamide. Relaxations provoked by nifedipine were not counteracted by the two hypoglycaemic sulfonylureas. It is tempting to suggest that the relaxation response to pinacidil and diazoxide could reflect the ability of both compounds to interfere with membrane K+ channels sharing common pharmacological properties with the K+ATP channels recently described in other tissues.

Animals↗

PubMed1991

Effect of three novel K+ channel openers, cromakalim, pinacidil and nicorandil on allergic reaction and experimental asthma.

The anti-allergic and anti-asthmatic activities of three potassium (K+) channel openers, cromakalim, pinacidil, and nicorandil, were investigated. 1) Forty-eight-hour homologous passive cutaneous anaphylaxis (PCA) in mice was not affected by cromakalim, pinacidil, or nicorandil. Ketotifen significantly inhibited the reaction. 2) Antigen-induced histamine release from sensitized guinea pig lung tissue was not affected by cromakalim, pinacidil or nicorandil (except for 10(-4) M nicorandil). Salbutamol inhibited the release of histamine. 3) Histamine, serotonin and LTC4-induced vasculitis in rat back skin was not affected by any of these three K+ channel openers. 4) Antigen-induced constriction of isolated sensitized guinea pig tracheal muscle was relaxed by each of the K+ channel openers. 5) Constrictions of isolated guinea pig tracheal muscle caused by high potassium, histamine, LTC4, or U-46619 were clearly relaxed by each of the three K+ channel openers. 6) Increases of airway resistance caused by histamine, LTD4, or U-46619 in guinea pigs in vivo were inhibited by administration of each of the three K+ channel openers. 7) Experimental asthma caused by the IgE antibody and antigen system in guinea pigs was inhibited by each of the three K+ channel openers.

Airway Resistance↗

PubMed2004

Hypotonic stress increases efficacy of rilmakalim, but not pinacidil, to activate ATP-sensitive K(+) current in guinea pig ventricular myocytes.

The aim of this study was to investigate the influence of hypotonic challenge on the effects of potassium channel openers (PCO), rilmakalim and pinacidil, on activation of the ATP-sensitive K(+) current. The whole cell configuration of the patch-clamp technique was applied to guinea pig ventricular myocytes exposed to isotonic and hypotonic solutions. Difference in osmolarity was about 100 mOsm due to different mannitol concentrations. Rilmakalim, a second generation PCO [(3S,4R)-3-hydroxy-2,2-dimethyl-4-(2-oxo-l-pyrrolidinyl)-6-phenylsulfonylchromanhemihydrate], activated time-independent K(+) current in the isotonic solution with pD2 (-log EC(50)) = 6.42 +/- 0.12 and E(max) = 19.74 +/- 2,16 pA/pF, n = 7, at 0 mV. The effects of the cyanoguanidine compound pinacidil were similar to those of rilmakalim, but the action appeared slower and with about 600-fold less potency than the former. Efficacy of rilmakalim, but not pinacidil, was enhanced in hypotonic solution, with E(max) = 30.87 +/- 5.40 pA/pF (P<0.05, n = 7), and the current was completely inhibited by glibenclamide. Additionally, rilmakalim concentration-effects correlation coefficient (R) decreased from 0.96 to 0.86 and Hill's coefficient increased from 1.21 to 1.45. Pretreatment with phalloidin (20 microM), a cytoskeleton stabilizer, prevented an intensification of the effects of rilmakalim in hypotonic solution and returned R and Hill's coefficients to the control values. We conclude that osmotic stress increases efficacy of rilmakalim to activate K(ATP) channels in guinea pig ventricular myocytes due to the specific interaction with actin filaments.

ATP-Binding Cassette Transporters↗

PubMed1988

Effects of pinacidil on bladder muscle.

Infravesical outflow obstruction and bladder hypertrophy are often associated with bladder hyperactivity causing frequency, urge and urinary incontinence. This hyperactivity may be due to a supersensitivity to depolarising stimuli. Drugs that inhibit smooth muscle activity by opening K+ channels, resulting in hyperpolarisation, would therefore seem to be an attractive therapeutic principle. Pinacidil is an effective vasodilator classified as a K+ channel opener. The drug has been shown to effectively depress spontaneous contractile activity, the contractions induced by low (less than 40 mmol/L) concentrations of K+, carbachol and by electrical stimulation of nerves in isolated normal human bladder tissue and also in normal and hypertrophied rat bladder. The effect was more pronounced in hypertrophied detrusor. Pinacidil in concentrations inhibiting muscle activity also increased the efflux of 86Rb in bladder tissue. In vivo pinacidil suppressed spontaneous contractile activity in rats with infravesical bladder obstruction and detrusor hypertrophy. The findings make K+ channel openers an interesting, potentially useful therapeutic principle in hyperactivity associated with bladder hypertrophy.

Animals↗

PubMed2003

[Effect of pinacidil on rat myocardial calcium regulation].

OBJECTIVE: To understand the effect of pinacidil on rat myocardial Ca(2+)regulation. METHODS: After baseline measurement and a period of equilibrium, myocytes were randomly allocated to one of 4 treatment groups: Control group (8 myocytes): incubation in Lactate Ringer's solution at 24 degrees C for 2 hours; K group (8 myocytes): incubation in Lactate Ringer's solution containing 16 mmol/L potassium at 24 degrees C for 2 hours; K+P group (8 myocytes): incubation in Lactate Ringer's solution containing potassium 16 mmol/L and pinacidil 50 micromol/L at 24 degrees C for 2 hours; K+P+G group (8 myocytes): incubation in Lactate Ringer's solution containing potassium 16 mmol/L, pinacidil 50 micromol/L and glibenclamide 10 micromol/L at 24 degrees C for 2 hours. After each incubation, myocytes were resuspended in cell culture media at the same temperature and intracellular [Ca(2+)](i) and SR Ca(2+) release were measured. RESULTS: The amplitude percent of [Ca(2+)](i) transient evoked by electrical stimulation in the K group was significantly decreased to 67.05% - 80.11% compared to 90.27% - 95.57% in the K+P group during reperfusion after ischemia (P<0.01). The percent amplitude of the [Ca(2+)](i) transient evoked by the rapid application of 10 mmol caffeine in the K group myocyte was approximately 112.00%+/-16.93% compared with that of the [Ca(2+)](i) transient evoked by electrical stimulation. However, in the K+P group myocyte the peak amplitude of the caffeine induced Ca(2+) release was 173.15%+/-26.01% compared with electrical stimulation (P<0.01). The duration of transient evoked by caffeine in K+P group (3.20+/-0.71 ms was significantly shorter than that in K group (3.93+/-0.46) ms (P<0.05). CONCLUSION: Cardioplegic arrest with simultaneous activation of KATP channels preserves rat myocardial Ca2+ by inducing sarcoplasmic reticulum Ca(2+) release and by alteration of Na(+)-Ca(2+) exchanger to better maintain [Ca(2+)](i) homeostasis.

Animals↗