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At least 307 records · Page 17Linked to original sources
PubMed2005

[Influence of pinacidil on the myocardial mitochondrial structure and the respiratory function in scalded rats].

OBJECTIVE: To investigate the influence of pinacidil preconditioning on the protection of the structure and respiratory function of injured myocardial mitochondria in scalded rats. METHODS: Seventy-five healthy Wistar rats, weighed 250 approximately 300 g, were randomly divided into three groups: i.e. control (n = 9, with intraperitoneal injection of 50 microg/kg isotonic saline), scald (n = 33, with 30% TBSA full thickness scald) and pre-conditioning (n = 33, with same extent of scald injury after intraperitoneal injection of 50 microg/kg pinacidil) groups. Mitochondrial ultrastructure was observed by transmission electron microscope. The mitochondrial respiratory function, the MDA content and the superoxide anion level were determined with corresponding methods. RESULTS: The degree of injury to rat myocardial mitochondria in pre-conditioning group was less intensive than that in scald group (P < 0.05 or 0.01). The respiratory control rate in pre-conditioning group was obviously higher than that in scald group (P < 0.05), and the contents of MDA and superoxide anion in pre-conditioning group were markedly lower than those in scald group (P < 0.05 or 0.01), as evidenced by their contents at 3 post scalding hours (0.60 +/- 0.09 micromol/g and 0.127 +/- 0.020) were obviously lower than those in scald group (0.83 +/- 0.07 micromol/g and 0.169 +/- 0.015) (P < 0.01). CONCLUSION: Pinacidil preconditioning was beneficial in the protection of myocardial mitochondria in scalded rats, and it might be related to the pre-opening of potassium channel which was sensitive to mitochondrial ATP.

Animals↗
PubMed1990

Pinacidil antagonism of endothelin-induced contractions of smooth muscle in the lungs: differences between tracheal and pulmonary artery preparations.

Contractions to endothelin and their reversal by pinacidil have been examined in isolated preparations of guinea pig and rat trachea and rat pulmonary artery. Indomethacin attenuated endothelin (less than or equal to 10 nM) on guinea pig trachea, but not on the rat tissues. This indicates that part of the effect of endothelin on guinea pig trachea is indirect and mediated by cyclooxygenase products. Endothelin (direct effects) was more potent on pulmonary artery than on guinea pig or rat trachea (negative log EC50 values: 8.42, 7.71 and 7.76, respectively) and was also a more effective spasmogen on pulmonary artery (maximum was the tissue maximum, i.e., greater than or equal to 80 mM K+) than on trachea (maximum was 60-70% of the tissue maximum to 10 microM carbachol). Pinacidil was less effective preventing (anti-spasmogenic) than reversing (spasmolytic) contractions to endothelin on either tissue type. This is compatible with different mechanisms for the initiation and maintenance of smooth muscle contraction in these tissues. As a spasmolytic against endothelin (0.03 microM), pinacidil was less potent on rat pulmonary artery than on guinea pig or rat trachea (negative log IC50 values: 4.45, 5.65 and 5.49, respectively). This may reflect 1) the greater tone induced by endothelin on pulmonary artery, 2) a smaller receptor reserve for endothelin in trachea and/or 3) a different mechanism whereby endothelin contracts pulmonary vascular smooth muscle compared with tracheal smooth muscle.

Animals↗
PubMed1995

[Potassium channel activators: comparative structural study of pinacidil, diazoxide and cromakalim].

A conformational analysis has been performed with SYBYL starting from the energy optimized (Tripos force field) X-ray conformation of (R,S)-pinacidil. The geometry of four selected low energy conformers has been reoptimized using the AM1 semiempirical Molecular Orbital method (MOPAC 5.0), and the total energy of the optimized conformers has been compared. In spite of an apparent structural dissimilarity, a good analogy has been found between the calculated isopotential map of diazoxide and that of at least one selected low energy conformer of pinacidil. It has been suggested that, unlike cromakalim, the low but observable activity of pinacidil on pancreatic B-cells could be explained by adoption for this compound of a conformation having a diazoxide-like stereoelectronical imprint which could assume a similar interaction on the same biological receptor.

Antihypertensive Agents↗
PubMedDate not supplied

Relaxation by cromakalim and pinacidil of isolated smooth muscle cells from canine coronary artery-multiple sites of action.

Dispersed cells were isolated from the canine coronary artery by enzymatic digestion. Their contraction and relaxation were determined by measuring their length using a video microscaler system. The cells remained structurally intact when examined by Trypan blue exclusion and electron microscopy. The cells showed a concentration-dependent contraction (EC50: 2.3 +/- 0.36 x 10(-12) M) to phenylephrine. The phenylephrine-induced contraction of the intact cells was inhibited by cromakalim (IC50: 1.24 +/- 0.27 x 10(-10) M) and pinacidil (IC50: 6.8 +/- 1.89 x 10(-10) M). The sensitivity of the dispersed cells to cromakalim was approximately 3 orders of magnitude larger than that of the muscle strips (EC50: 1.94 +/- 0.22 x 10(-7) M). Glibenclamide (a selective inhibitor of the ATP-sensitive K+ channel in pancreatic beta-cells) competitively antagonized the cromakalim-induced inhibition of the phenylephrine-contraction in intact cells (pA2:9.12; slope: 1.13) as well as in muscle strips (pA2: 7.84; slope: 0.95). Permeabilized cells were made by a brief exposure of the cells to saponin and were suspended in a buffer medium containing 100 mM KCl and 0.18 microM Ca++. The cells showed a concentration-dependent contraction to phenylephrine (EC50:2.2 +/- 0.40 x 10(-12) M) and inositol 1,4,5-triphosphate (EC50: 5.3 +/- 1.05 x 10(-11) M). These contractions were concentration-dependently inhibited by cromakalim and pinacidil. The inhibition by cromakalim of the inositol-induced contraction was markedly antagonized by apamin and, to a lesser extent, by glibenclamide. Thus, it is suggested that cromakalim and pinacidil exert a potent relaxation by acting on multiple sites: the glibenclamide-sensitive K+ channels of the plasma membrane and the intracellular site sensitive to inositol and apamin.

Animals↗
PubMed1993

Effects of pinacidil and acetylcholine on early afterdepolarization of atrial fibers in mouse heart.

The effects of pinacidil and acetylcholine (Ach) on action potential (AP) and early afterdepolarization (EAD) were investigated in mouse atrial fibers. Under treatment with pinacidil the AP and EAD were affected only with the concentration of 8 x 10(-5) M, which inhibited EAD but did not affect AP except for only a minor reduction of action potential duration (APD). After withdrawal of pinacidil, the inhibitory effect of EAD was enhanced. Under treatment with Ach (2 x 10(-7) M), AP was not changed except the APD, which was significantly reduced, and the EAD was completely abolished. Withdrawal of Ach produced a rebound increase in APD and led to induction of EAD or promoted EAD to more extensive level such as appearance of long second plateau. Atropine (1 x 10(-7) M) abolished the rebound effect caused by withdrawal of Ach. The mechanism of EAD generation induced by removing Ach is discussed.

Acetylcholine↗
PubMed1996

ATP-sensitive potassium channel modulators: both pinacidil and glibenclamide produce antiarrhythmic activity during acute myocardial infarction in conscious rats.

We investigated the effects of pinacidil, an ATP-sensitive potassium channel opener, and of glibenclamide, an ATP-sensitive potassium channel inhibitor, on the incidence of arrhythmias and sudden cardiac death after coronary artery ligation in conscious rats. Occlusion of the left main coronary artery was produced by tightening a previously placed loose silk ligature. In the control group (n = 25) only 40% and 24% of the animals survived for 15 min and 16 hr after coronary artery ligation, respectively. Intravenous pretreatment with 0.1, 0.3 or 1 mg/kg pinacidil increased the survival rate to 67% (n = 15), 70% (n = 20) and 67% (n = 12) in the first 15 min and to 60%, 55% and 67% in the first 16 hr, respectively. Glibenclamide pretreatment (5.0 mg/kg i.p.) improved the survival rate at both time-points to 87% (n = 16). Both types of pretreatment significantly decreased the incidence of life-threatening arrhythmias and increased the number of animals that survived without developing any arrhythmia. In conclusion, the present findings demonstrate that in conscious rats, pretreatment with pinacidil and pretreatment with glibenclamide, although they obviously have different mechanisms of action, may result in a very similar final outcome with respect to arrhythmias and sudden cardiac death during the acute phase of experimental myocardial infarction.

Adenosine Triphosphate↗
PubMed1996

Phorbol-12,13-dibutyrate and pinacidil cardioplegia. Novel forms of myoprotection.

BACKGROUND: Activation of either protein kinase C or the ATP-sensitive potassium channel has been shown to induce the preconditioning response. METHODS AND RESULTS: To investigate whether preconditioning activation adjuvant to hypothermic blood cardioplegia enhances postischemic contractile recovery, 23 adult (0.5 to 1.0 year old) sheep were randomized to receive cardioplegia based on the hyperpolarizing ATP-sensitive potassium channel opener pinacidil, the protein kinase C activator 4 beta-phorbol-12, 13-dibutyrate (PDBu), or standard potassium-magnesium (K1/Mg2+). All groups underwent 60 minutes of 10 degrees C antegrade intermittent blood cardioplegia and 30 minutes of reperfusion. Mechanics were assessed on modified right heart bypass by the preload recruitable stroke work relation and the end-systolic pressure-volume relation. Diastolic function was modeled by the exponential time constant of isovolumic left ventricular pressure decay (Tau) and the "stiffness" coefficient (beta) of the end-diastolic pressure volume relation. Recovery rhythm was defined by the first electrical activity seen during reperfusion. Cardioplegic arrest and preconditioning induced by pinacidil provided superior recovery of contractile function compared with PDBu (100% versus 57% recovery, P < .05) or K+/Mg+ (100% versus 56% recovery, P < .05). Active (Tau) and passive (beta) diastolic function was preserved by all three arrest modalities. Hearts treated with pinacidil demonstrated a rapid recovery of a coordinated contraction pattern, which was offset by a reperfusion tachycardia, whereas PDBu arrest was associated with ventricular fibrillation on reperfusion. CONCLUSIONS: Preconditioning during cardioplegic arrest is agent specific, feasible at cold temperatures, and may be superior to the use of standard K+/Mg2+ cardioplegia.

Animals↗
PubMed1988

Effects of food on the bioavailability of sustained-release pinacidil in humans.

The effects of a standard breakfast meal on the bioavailability of a sustained-release tablet formulation of pinacidil [(+/-)-2-cyano-1- (4-pyridyl)-3-(1,2,2-trimethylpropyl)guanidine monohydrate) were investigated in eight healthy volunteers. Concomitant food intake resulted in significantly increased maximum measured serum pinacidil concentrations, Cmax, (172 +/- 21 versus 102 +/- 49 ng/mL, p less than 0.05), and relative bioavailability, measured as AUCo-infinity (904 +/- 189 versus 697 +/- 279 ng.h/mL, p less than 0.05). The time to maximum serum concentration (tmax) was not affected by food (2.3 +/- 1.3 versus 3.3 +/- 1.2 h, p greater than 0.05), and the terminal elimination half-life, (t1/2z) was significantly decreased (4.7 +/- 2.2 versus 2.3 +/- 0.4 h, p less than 0.05).

Adult↗
PubMed2002

Effects of K(ATP) channel openers, P-1075, pinacidil, and diazoxide, on energetics and contractile function in isolated rat hearts.

We investigated the metabolic effects of a potent opener of ATP-sensitive K(+) (K(ATP)) channels, P-1075, in perfused rat hearts with the help of(31)P NMR spectroscopy. A 20 min infusion of 5 microm P-1075 depleted phosphocreatine and ATP by approximately 40%, concomitantly with a two-fold increase in inorganic phosphate, while oxygen consumption by the hearts increased by 50%. P-1075 induced a cardiac contracture (left ventricular end diastolic pressure increased from 6 to 60 mmHg) and a cardiac arrest after an infusion of approximately 9 min. The effects were fully reversed by glibenclamide (5 microm), but not by sodium 5-hydroxydecanoate (0.4 m m). A P-1075-related K(ATP) opener, pinacidil (0.3 m m), partially reversed the effects of P-1075, but a structurally unrelated opener, diazoxide (0.5 m m), had no effect. Pinacidil and diazoxide alone did not significantly affect PCr and ATP levels. Bioenergetic and functional effects similar to those of P-1075 were induced by infusion of a classic mitochondrial uncoupler, 2,4-dinitrophenol (50 microm); however, they were not abolished by glibenclamide. In addition, it was shown, using(87)Rb NMR, that both agents, P-1075 and 2,4-dinitrophenol, resulted in a stimulation of Rb(+) efflux from the Rb(+) loaded rat hearts by approximately 130 and 65%, respectively, in a glibenclamide-sensitive manner. An inhibitory effect of P-1075 on ATP synthesis cannot be explained by its well-known action on sarcolemmal K(ATP) channels. We concluded that, unlike an uncoupling effect of 2,4-dinitrophenol, an inhibitory effect of P-1075 is produced by uncoupling of oxidative phosphorylation through the activation of mitochondrial K(ATP) channels.

2,4-Dinitrophenol↗
PubMed1985

Long-term effects of pinacidil in hypertensive dialysis patients.

In an open study, thirteen chronic dialysis patients with nonvolume dependent uncontrolled hypertension were treated with pinacidil for a mean period of 43 weeks. Seven patients were taking concomitant antihypertensive therapy. Twelve patients achieved long-term blood pressure control on a mean dose of 33 mg/day. The baseline supine blood pressure was 184/116 mmHg. After 1 week it had fallen to 161/95 mmHg and blood pressure control was maintained over the study period. Patient weight remained stable. The baseline reading was 61.6 kg and at the end of the study it was 59.7 kg. Pulse rate did not change significantly. For the eight patients not taking beta-blockers the mean change in pulse rate was 7.6 beats/min supine and 6.3 beats/min erect (NS). Pretrial urea and creatinine were 27.6 mmol/l and 1027 mumol/l and after 25 weeks they were 29.6 mmol/l and 1087 mumol/l, respectively (NS). Four patients had ECG evidence of left ventricular hypertrophy before the study and one on completion of the trial. Five patients showed correction of T-waves on their ECG's. Six patients experienced side effects, none of which warranted withdrawal of treatment. These findings suggest that pinacidil is a valuable alternative treatment for hypertensive dialysis patients.

Adolescent↗
PubMed1992

Smooth muscle relaxation and inhibition of responses to pinacidil and cromakalim induced by phentolamine in guinea-pig isolated trachea.

A concentration-dependent relaxant effect of phentolamine was demonstrated in guinea-pig isolated trachea and was probably unrelated to its alpha-adrenoceptor blocking action. The maximal effect of phentolamine against spontaneous tracheal tone was in the 24-100% range. However, phentolamine produced 100% relaxation when the tone was induced by histamine, carbachol, 30 mM K+ or 124 mM K+. Relaxant EC50 values ranged from 8 to 50 microM with the highest potency found against histamine-induced contractions. Phentolamine caused no suppression of contractions elicited by prostaglandin F2 alpha (PGF2 alpha) or leukotriene C4 (LTC4). At a concentration of 100 microM the alpha 2-adrenoceptor blocker, yohimbine, produced minor inhibition of spasmogen-induced tone, whereas the alpha 1-adrenoceptor blocker prazosin (up to 10 microM) had no inhibitory effects in the trachealis. Propranolol (1 microM), prazosin (1 microM), yohimbine (100 microM), tetrodotoxin (3 microM), glibenclamide (10 microM), tetraethylammonium (8 mM), 4-aminopyridine (5 mM), procaine (100 microM), dipyridamole (3 microM) or methylene blue (100 microM) did not influence the relaxant responses to phentolamine. In tracheal preparations contracted by PGF2 alpha or LTC4, phentolamine (1, 10 and 100 microM) antagonized the relaxant action of the K+ channel openers, pinacidil and cromakalim. The concentration-relaxation curves for pinacidil were shifted 30-fold to the right without change in the maximal effects, whereas the maximal cromakalim-induced relaxant responses were markedly suppressed by phentolamine.

Animals↗
PubMed1996

Inhibition by bertosamil of cardiac responses to pinacidil or Bay k 8644 in isolated dog atria and ventricles.

We investigated the effects of a novel bradycardiac agent, bertosamil (3-isobutyl-7-isopropyl-9,9-pentamethylene-3,7-diazabicyclo[3.3.1] nonane sesquihydrogenfumarate), on the sinus rate and atrial contractile force and the left ventricular contractile force in isolated, blood-perfused dog hearts and the blocking effects of bertosamil on the chronotropic and inotropic responses to pinacidil and Bay k 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- piridine-5-carboxylate). Bertosamil (0.1-100 nmol) caused transient positive, followed by continuous negative, chronotropic responses and positive inotropic responses in atria, and increased the left ventricular contractile force. Neither propranolol nor atropine affected the cardiac responses to bertosamil. Bertosamil (3-100 nmol) dose dependently attenuated the negative chronotropic and inotropic responses to pinacidil but not to acetylcholine. Bertosamil at a high dose attenuated the positive cardiac responses to Bay k 8644, norepinephrine and isoproterenol. These results suggest that bertosamil inhibits negative cardiac responses mediated by an ATP-sensitive K+ channel but not an acetylcholine muscarinic receptor and, at a high dose, attenuates the L-type Ca2+ channel-mediated positive cardiac responses in isolated dog hearts.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Analysis of the potassium channel openers celikalim, pinacidil and cromakalim in platelet models of thrombosis.

The antihypertensive agents pinacidil, cromakalim and celikalim lower blood pressure by opening potassium channels in vascular smooth muscle. The role of these compounds in inhibiting human platelet aggregation and preventing white thrombus formation in a rabbit arteriovenous shunt model was examined. None of these agents (100 microM), substantially inhibited platelet aggregation induced by epinephrine or arachidonic acid. Only celikalim (100 microM) inhibited collagen (45%), ADP (56%), or serotonin (61%) induced platelet aggregation and ADP- (41%) or epinephrine-potentiated (61%) serotonin-induced platelet aggregation. Celikalim inhibited white thrombus formation at i.v. doses of 0.25 mg/kg (46% inhibition) but not 0.1 mg/kg; (14.6%); equihypotensive doses of pinacidil (0.5 mg/kg; 21.7%) and cromakalim (0.2 mg/kg, 7.5%; 0.4 mg/kg, 33%) were less effective. Glyburide (i.v. dose of 0.5 mg/kg) inhibited the antithrombotic activity of celikalim and to a lesser extent cromakalim. The greater antithrombotic activity of celikalim in vivo may be related to beneficial effects on blood rheology and reduced red blood cell deformability.

Animals↗
PubMed1992

Structure-activity studies of potassium channel opening in pinacidil-type cyanoguanidines, nitroethenediamines, thioureas, and ureas.

Potassium channel opening activity for pinacidil-type cyanoguanidines, nitroethenediamines, thioureas, and ureas, has been assessed through simultaneous measurement of spontaneous contractile activity and stimulation of 86Rb+ efflux from rat portal veins loaded with 86Rb+. The good correlation between these two effects suggests that the vasodilator activity of the compounds is directly attributable to an increased opening of potassium channels. The resulting quantitative in vitro data has been used to analyze the structure-activity relationships for potassium channel opening, allowing the biological activity to be rationalized in terms of a pharmacophore involving a hydrogen-bond-acceptor element, a hydrogen-bond-donor element, and a lipophilic binding group. A model for the binding of pinacidil-related compounds to their potassium channel receptor has been developed, and compounds designed to test this model have been synthesized and tested. Prototropic equilibria are implicated as playing a fundamental role in determining the hydrogen-bonding ability of the compounds, and conformational changes in the receptor are invoked to explain disparities in the chiral recognition of lipophilic groups in different compounds.

Animals↗
PubMed1999

Vasorelaxation by new hybrid compounds containing dihydropyridine and pinacidil-like moieties.

The synthesis and pharmacological properties of a novel type of vasorelaxant hybrid compounds are described. The investigated compounds originate from fluorinated 4-aryl-1,4-dihydropyridines, which are known calcium channel blockers, and/or from fluorinated analogues of pinacidil, which is an opener of ATP-sensitive potassium channels. In particular, we studied the most potent hybrid, 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-difluoromethoxy-5-N-(N' '-cyano-N'-1,2,2-trimethyl-propylguanidyl)-phenyl)-1, 4-dihydropyridine (4a), together with its parent compounds, the dihydropyridine 1b and the pinacidil analogue 3. In isolated rat mesenteric arteries, micromolar concentrations of 4a relaxed contractions exerted by K(+)-depolarization or by norepinephrine. The latter effect was sensitive to the potassium channel blocker glibenclamide. Micromolar 4a also inhibited [(3)H](+)-isradipine and [(3)H]P1075 binding to rat cardiac membranes, and it blocked L-type calcium channels expressed in a mammalian cell line. The respective parent compounds 1b and 3 were always more potent and more selective regarding calcium channel or potassium channel interaction, respectively. In contrast, 4a combined both effects within the same concentration range, indicating that it may represent a lead structure for a novel class of pharmacological hybrid compounds.

Animals↗
PubMed1999

Gene delivery of Kir6.2/SUR2A in conjunction with pinacidil handles intracellular Ca2+ homeostasis under metabolic stress.

Metabolic injury is a complex process affecting various tissues, with intracellular Ca2+ loading recognized as a common precipitating event leading to cell death. We have recently observed that cells overexpressing recombinant ATP-sensitive K+ (KATP) channel subunits may acquire resistance against metabolic stress. To examine whether, under metabolic challenge, intracellular Ca2+ homeostasis can be maintained by an activator of channel proteins, we delivered Kir6.2 and SUR2A genes, which encode KATP channel subunits, into a somatic cell line lacking native KATP channels. Hypoxia-reoxygenation was simulated by application and removal of the mitochondrial poison 2,4 dinitrophenol. Under such metabolic stress, Ca2+ loading was induced by Ca2+ influx during hypoxia and release of Ca2+ from intracellular stores during reoxygenation. Delivery of Kir6.2/SUR2A genes, in conjunction with the KATP channel activator pinacidil, prevented intracellular Ca2+ loading irrespective of whether the channel opener was applied throughout the duration of hypoxia-reoxygenation or transiently during the hypoxic or reoxygenation stage. In all stages of injury, the effect of pinacidil was inhibited by the selective antagonist of KATP channel, 5-hydroxydecanoate. The present study provides evidence that combined use of gene delivery and pharmacological targeting of recombinant proteins can handle intracellular Ca2+ homeostasis under hypoxia-reoxygenation irrespective of the stage of the metabolic insult.

Animals↗
PubMed1986

Aggressive long-term antihypertensive therapy with pinacidil does not cause regression of cardiovascular hypertrophy in the spontaneously hypertensive rat.

After dosage titration from the age of 1 month to the age of 3 months, spontaneously hypertensive rats (SHR) were treated with pinacidil 10 mg/kg daily until the age of 6 or 12 months. Morphometric data were obtained from the treated SHR as well as from untreated age-matched SHR and normotensive Wistar-Kyoto rats (WKY) at these two developmental stages. Heart:body weight ratios and media:lumen ratios for resistance vessels were determined. Vessels obtained from the mesenteric region were investigated on a myograph. Vessels from heart, kidney and lung were investigated by morphometric analysis of histological sections, only specimens from 12-month-old rats were used. In SHR no effects of either ageing or treatment were detectable, although their blood pressure had been effectively held at normotensive levels throughout the life of the treated animals from the age of 3 months. With the exception of the media index of the pulmonary vessels, which was not statistically different from treated or control SHR, the WKY morphological parameters were significantly lower. In conclusion, pinacidil normalized blood pressure without complications, but this did not affect SHR cardiovascular structure. It is suggested that development of this strain-specific enlargement can only be modified if blood pressure is kept at hypotensive levels, or if the effect of a hitherto unidentified causative factor is antagonized by more-specific pharmacological treatment.

Animals↗