BACKGROUND: This study investigated the effects of the K+ channel opener, pinacidil on hypoxic pulmonary vasoconstriction in isolated perfused rabbit lungs. In order to evaluate the vasodilatation mechanism of K+ channel opener, we also studied the effects of two K+ channel blocker, tetraethylammonium (TEA), a Ca2+ activated K+ channel blocker and glibenclamide (GLB), an ATP-sensitive K+ channel blocker. METHODS: Isolated lungs from white rabbits were ventilated with a normoxic gas (21%O2-5%CO2-74%N2) and a hypoxic gas (3%O2- 5%CO2-92%N2) alternatively, and then perfused with blood-containing perfusate solution. After a hypoxic pressor response (HPR) had been obtained, various drugs were added to the perfusate reservoir to achieve the predetermined circulating concentration, and the influences of the drugs on HPR were then tested. RESULTS: Pinacidil (0.3-6.0 mcM) produced a dose-dependent pulmonary vasodilation on hypoxic ventilation challenge. TEA (1 mM) caused pulmonary vasoconstriction in normoxic ventilation and potentiated a hypoxic pressor response. When the hypoxic pressor response was potentiated by TEA, pinacidil (1.0, 3.0 mcM) reduced the contraction, but GLB did not cause pulmonary vasoconstriction under normoxic ventilation, potentiate a hypoxic pressor response. CONCLUSIONS: Piacidil is capable of opposing the pulmonary responses of acute hypoxia. Moreover the effects of TEA and GLB suggest that HPV might be mediated through Ca2+ activated K+ channels, not through ATP-sensitive K+ channels.
Anoxia ; Glyburide* ; Lung* ; Pinacidil* ; Potassium Channels, Calcium-Activated ; Rabbits ; Tea ; Tetraethylammonium ; Vasoconstriction* ; Vasodilation ; Ventilation

PURPOSE: Currently available K+-channel openers are exclusively KATP channel openers. Among the KATP channel openers, minoxidil and diazoxide have been already used as antihypertensive agents clinically but their erectogenic activities have not been demonstrated. We performed this study to identify the effects of intracavernosal minoxidil and diazoxide on feline penile erection and also to compare that of pinacidil, relatively well-demonstrated K+-channel opener. MATERIALS AND METHODS: Using a feline model, the magnitude of penile erection caused by pinacidil was compared with that caused by minoxidil and diazoxide. With control erectile responses of intracavernosal PGE1 and papaverine, synergistic effects of erectogenic agents with KATP channel openers were also investigated in twenty-eight male cats in vivo. RESULTS: Intracavernosal injection of pinacidil increased intracavernosal pressure (ICP) in a dose-dependent fashion but minoxidil and diazoxide did not affect ICP significantly. Furthermore, pinacidil (10-5M/ml) enhanced the increase of ICP by PGE1 or papaverine but minoxidil and diazoxide did not. Noteworthy, pinacidil induced cavernous relaxation to the following erectogenic agents even in refractory cases to higher concentration (10-1M/ml) of erectogenic agent alone (n=7, p<0.01). CONCLUSIONS: These result suggests that minoxidil and diazoxide, which have been used as antihypertensive agents clinically, do not affect intracavernosal pressure. Among the KATP channel openers, pinacidil seems to be promising in producing penile erection as an alternate component of previous intracavernous injection. Also, pinacidil may be useful clinically because of the potential therapeutic effects as an intracavernosal agents in combination with PGE1 or papaverine.
Alprostadil ; Animals ; Antihypertensive Agents ; Cats ; Diazoxide* ; Humans ; Male ; Minoxidil* ; Papaverine ; Penile Erection* ; Pinacidil* ; Relaxation

To investigate whether hydrogen peroxide (H2O2) affects intestinal motility, pacemaker currents and membrane potential were recorded in cultured interstitial cells of Cajal (ICC) from murine small intestine by using a whole-cell patch clamp. In whole cell patch technique at 30 degress C, ICC generated spontaneous pacemaker potential under current clamp mode (I=0) and inward currents (pacemaker currents) under voltage clamp mode at a holding potential of -70 mV. When ICC were treated with H2O2 in ICC, H2O2 hyperpolarized the membrane potential under currents clamp mode and decreased both the frequency and amplitude of pacemaker currents and increased the resting currents in outward direction under voltage clamp mode. Also, H2O2 inhibited the pacemaker currents in a dose-dependent manner. Because the properties of H2O2 action on pacemaker currents were same as the effects of pinacidil (ATP-sensitive K+ channels opener), we tested the effects of glibenclamide (ATP-sensitive K+ channels blocker) on H2O2 action in ICC, and found that the effects of H2O2 on pacemaker currents were blocked by co- or pre-treatment of glibenclamide. These results suggest that H2O2 inhibits pacemaker currents of ICC by activating ATP-sensitive K(+) channels.
Gastrointestinal Motility ; Glyburide ; Hydrogen Peroxide* ; Hydrogen* ; Interstitial Cells of Cajal* ; Intestine, Small ; Membrane Potentials ; Pinacidil

OBJECTIVEOn the basis that pinacidil can produce an "all or none" repolarization in right ventricular wall of canine, to observe the effects of quinidine on the marked transmural dispersion of repolarization. Recent studies have shown that ventricular myocardium is composed of at least 3 electrophysiological distinct cell types: epicardial, endocardial, and midcardial cells. Differences in the response of the 3 cell types to pharmacologic agents and/or pathophysiological states often result in amplification of intrinsic electrical heterogeneities, thus providing a substrate as well as a trigger for the development of arrhythmias. The study was designed to observe the right ventricular transmural heterogeneity in vitro canine heart tissue preparation level.

METHODSThe strips were isolated from the anterior wall of the right ventricular of canine. The preparations perfused with oxygenated (95%O(2)/5%CO(2)) Tyrode's solution. The tissues were stimulated at basic cycle lengths of 1000 ms. Standard microelectrode techniques were used. Transmembrane action potentials were recorded from epicardial, midcardial and endocardial cells respectively from right ventricular free wall of canine on different conditions [perusing with Tyrode's solution (Control), pinacidil (2.5 micromol/L), and quinidine (5 micromol/L) in turn].

RESULTSCompared with that of endocardial cells, the action potentials of canine ventricular epicardial and midcardial cells had more obvious spike and dome morphology. Pinacidil (2.5 micromol/L) caused a loss of the dome of transmembrane action potentials and a marked abbreviation of the action potential duration (APD) in right ventricular epicardial and midcardial cells, especially in epicardial cells, but not in endocardial cells (n = 10). With pinacidil (2.5 micromol/L), in epicardial cells, phase 2 amplitude of action potentials decreased from (117.7 +/- 9.3) mV to (71.3 +/- 6.4) mV (P < 0.01), and 90% of the APD(90) decreased from (198.2 +/- 20.8) ms to (103.9 +/- 13.5) ms (P < 0.01). The transmural dispersion of action potential duration increased from (48.5 +/- 9.2) ms to (128.7 +/- 13.5) ms (P < 0.01). Quinidine (5 micromol/L) effectively prolonged the APD abbreviated by pinacidil, restored or partly restored the dome of transmembrane action potentials of epicardial and midcardial cells but not of endocardial cells (n = 10). In epicardial cells phase 2 amplitude increased from (71.3 +/- 6.4) mV to (106.6 +/- 7.7) mV (P < 0.01), and 90% of the APD(90) increased from (103.9 +/- 13.5) ms to (185.9 +/- 15.7) ms (P < 0.01). The transmural dispersion of action potential duration significantly decreased from (128.7 +/- 13.5) ms to (54.3 +/- 10.8) ms (P < 0.01). Quinidine reduced pinacidil-induced transmural dispersion of phase 2 amplitude and the APD in right ventricular wall of canine.

CONCLUSIONBy restoring the dome and the APD of the epicardial and midcardial cells action potentials, quinidine (5 micromol/L) could reduce the marked transmural dispersion of repolarization caused by pinacidil.

Action Potentials ; drug effects ; Animals ; Dogs ; Heart Ventricles ; drug effects ; physiopathology ; Pinacidil ; pharmacology ; Quinidine ; pharmacology

The effect of pinacidil, a K+ channel opener, on the contraction of rabbit carotid artery was investigated by using muscle contraction and Ca2= uptake experiments. Pinacidil reduced phenylephrine-induced contraction by dose dependent manner, which was antagonized by glibenclamide, a blocker of the ATP sensitive K+ channel. Phenylephrine-induced tonic contraction was more reduced by pinacidil than its phasic contraction. In the effect of pinacidil on the Ca2+ uptake of rabbit carotid artery, pinacidil decreased it at the resting state of tissue, dose-dependently. Phenylephrine-induced stimulation of Ca2+ uptake was also reduced by pinacidil. Pinacidil 10micrometer reduced high potassium-induced contraction, which was not reversed by glybenclamide 10micrometer. Threshold concentration of K+ increased by pinacidil pretreatment. Phorbol 12, 13-dibutyrate, an activator of protein kinase C, induced sustained contraction of rabbit carotid artery, which was reduced by pinacidil but not antagonized by glibenclamide. In Ca2+-free buffer, pinacidil also decreased phorbol 12, 13-dibutyrate-induced contraction. These results indicate that pinacidil reduces Ca2+ uptake of vascular smooth muscle by stimulation of K+ channel which could be antagonized by glibenclamide, and another mechanism of vasorelaxation which could not be antagonized by glibenclamide. It was indecated that pinacidil affects the contaction of smooth muscle by the inhibition of protein kinase C.
Adenosine Triphosphate ; Carotid Arteries* ; Glyburide ; Muscle Contraction ; Muscle, Smooth ; Muscle, Smooth, Vascular ; Pinacidil* ; Protein Kinase C ; Vasodilation

PURPOSE: Thallium behaves similarly to potassium in vivo. Potassium channel opener (K-opener) opens ATP-sensitive K+/-channel located at cell membrane, resulting in potassium efflux from cytosol. We have previously reported that K-opener can alter biokinetics of Tl-201 in cultured cells and in vivo. Malignant tumor cells have high Na-K ATPase activity due to increased metabolic activities and dedifferentiation, and differential delineation of malignant tumor can be possible with Tl-201 imaging. K-opener may affect tumoral uptake of Tl-201 in vivo. To investigate the effects of pinacidil (one of the potent K-openers) on the localization of the tumor with Tl-201 chloride, we evaluated the changes in biodistribution of Tl-201 with pinacidil treatment in tumor-bearing mice. MATERAL AND METHODS: Balb/c mice received subcutaneous implantation of murine breast cancer cells in the thigh and were used for biodistribution study 3 weeks later. 100 microgram of pinacidil dissolved in 200 microliter DMSO/PBS solution was injected intravenously via tail vein at 10 min after 185 KBq (5 microcurie) Tl-201 injection. Percentage organ uptake and whole body retention ratio of Tl-201 were measured at various periods after injection, and values were compared between control and pinacidil-treated mice. RESULTS: Pinacidil treatment resulted in mild decrease in blood levels of Tl-201, but renal uptakes were markedly decreased at 30-min, 1- and 2-hour, compared to control group. Hepatic, intestinal and muscular uptake were not different. Absolute percentage uptake and tumor to blood ratios of Tl-201 were lower in pinacidil treated mice than in the control group at all time points measured. Whole body retention ratio of Tl-201 was lower in pinacidil treated mice (58+/-4%), than in the control group (67+/-3%) at 24 hours after with injection of 100 microgram pinacidil. CONCLUSION: K-opener did not enhance, but rather decreased absolute tumoral uptake and tumor-to-blood ratios of Tl-201. Decreased whole body retention ratio and renal uptake were observed with pinacidil treatment in tumor-bearing mice.
Adenosine Triphosphatases ; Animals ; Breast Neoplasms ; Cell Membrane ; Cells, Cultured ; Cytosol ; Mice* ; Pinacidil* ; Potassium ; Potassium Channels ; Thallium ; Thigh ; Veins

PURPOSE: Intracavernous injection of PGE1 or papaverine is widely used in the diagnosis and treatment of erectile dysfunction. However, these drugs have several side effects such as pain, priapism, and fibrotic lesions. In this study, we assessed the effects of pinacidil (a K+ -ATP - channel opener) as an alternative for inducing penile erection. METHODS: Using a feline model, the magnitude of penile erection caused by pinacicil was compared with that caused by other drugs, namely acetylcholine, PGE1 and L-arginine. The effects of K+ -channel blockers(4-aminopyridine, glibenclamide, and tetraethylammonium; TEA) and pinacidil on the induced erections were investigated. RESULTS: Intra-arterial injection of pinacicil increased the intracavernous pressure (ICP) in a dose-dependent fashion, and the increase in ICP induced by pinacicil plus acetylcholine, PGE1 or L-arginine was more pronounced than that induced by any of these drugs alone. Furthermore, pinacicil (10(-3)M/mL) effectively reversed the inhibitory effects of the K+-channel blockers on cavernous relaxation induced by acetylcholine, PGE1 or L-arginine (P<0.01). Notably, pinacidil induced cavernous relaxation even in cases refractory to a higher concentration <10(-1) M/mL) of erectics (n = 11; p<0.01). CONCLUSIONS: These results suggest that pinacidil is effective in relaxing feline erectile tissue in vivo, probably via increased K+ permeability and subsequent hyperpolarization. Further comparative studies with human erectile tissue and clinical testing are required to show whether K+-channel openers can be used in the diagnosis and treatment of erectile dysfunction.
Acetylcholine ; Alprostadil ; Arginine ; Diagnosis ; Erectile Dysfunction* ; Glyburide ; Humans ; Injections, Intra-Arterial ; Male ; Papaverine ; Penile Erection ; Permeability ; Pinacidil ; Priapism ; Relaxation ; Tetraethylammonium

PURPOSE: Intracavernous injection of PGE1 or papaverine is widely used in the diagnosis and treatment of erectile dysfunction. However, these drugs have several side effects such as pain, priapism, and fibrotic lesions. In this study, we assessed the effects of pinacidil (a K+ -ATP - channel opener) as an alternative for inducing penile erection. METHODS: Using a feline model, the magnitude of penile erection caused by pinacicil was compared with that caused by other drugs, namely acetylcholine, PGE1 and L-arginine. The effects of K+ -channel blockers(4-aminopyridine, glibenclamide, and tetraethylammonium; TEA) and pinacidil on the induced erections were investigated. RESULTS: Intra-arterial injection of pinacicil increased the intracavernous pressure (ICP) in a dose-dependent fashion, and the increase in ICP induced by pinacicil plus acetylcholine, PGE1 or L-arginine was more pronounced than that induced by any of these drugs alone. Furthermore, pinacicil (10(-3)M/mL) effectively reversed the inhibitory effects of the K+-channel blockers on cavernous relaxation induced by acetylcholine, PGE1 or L-arginine (P<0.01). Notably, pinacidil induced cavernous relaxation even in cases refractory to a higher concentration <10(-1) M/mL) of erectics (n = 11; p<0.01). CONCLUSIONS: These results suggest that pinacidil is effective in relaxing feline erectile tissue in vivo, probably via increased K+ permeability and subsequent hyperpolarization. Further comparative studies with human erectile tissue and clinical testing are required to show whether K+-channel openers can be used in the diagnosis and treatment of erectile dysfunction.
Acetylcholine ; Alprostadil ; Arginine ; Diagnosis ; Erectile Dysfunction* ; Glyburide ; Humans ; Injections, Intra-Arterial ; Male ; Papaverine ; Penile Erection ; Permeability ; Pinacidil ; Priapism ; Relaxation ; Tetraethylammonium

PURPOSE: Intracavernous injection of prostaglandin (PG) E1 or papaverine (PA) is widely used in the diagnosis and treatment of erectile dysfunction. Because these drugs are sometimes associated with insufficient erection in and side effects such as priapism, corporal fibrosis, and pain, there has been increasing interest in finding effective and safe alternatives. Recent studies demonstrated that pinacidil (PI) relaxes the smooth muscle. This study was performed to examine the efficacy of PI as an alternative or supplement to drugs such as PG, PA, or phentolamine (PT). MATERIALS AND METHODS: In 28 adult male cats, the maximal intracavernous pressure (ICPmax), time to ICPmax (T1/2) and duration of increased ICP (time) in response to intracavernous injection of PG, PA, or mixture of vasoactive drugs (PA + PT, PA + PG + PT) were compared with the responses to mixtures containing PI (PI + PA, PI + PA + PT,
Adult ; Animals ; Cats ; Diagnosis ; Erectile Dysfunction ; Fibrosis ; Humans ; Male ; Muscle, Smooth ; Papaverine ; Penile Erection ; Penis ; Phentolamine ; Pinacidil* ; Potassium Channels ; Priapism

OBJECTIVETo understand the effect of pinacidil on rat myocardial Ca(2+)regulation.

METHODSAfter 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.

RESULTSThe 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).

CONCLUSIONCardioplegic 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 ; Calcium ; metabolism ; Female ; Heart ; drug effects ; Male ; Myocardium ; metabolism ; Pinacidil ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Sodium ; metabolism