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PubMed2000

The molecular basis of the specificity of action of K(ATP) channel openers.

K(ATP) channels incorporate a regulatory subunit of the ATP-binding cassette (ABC) transporter family, the sulfonylurea receptor (SUR), which defines their pharmacology. The therapeutically important K(+) channel openers (e.g. pinacidil, cromakalim, nicorandil) act specifically on the SUR2 muscle isoforms but, except for diazoxide, remain ineffective on the SUR1 neuronal/pancreatic isoform. This SUR1/2 dichotomy underpinned a chimeric strategy designed to identify the structural determinants of opener action, which led to a minimal set of two residues within the last transmembrane helix of SUR. Transfer of either residue from SUR2A to SUR1 conferred opener sensitivity to SUR1, while the reverse operation abolished SUR2A sensitivity. It is therefore likely that these residues form part of the site of interaction of openers with the channel. Thus, openers would target a region that, in other ABC transporters, is known to be tightly involved with the binding of substrates and other ligands. This first glimpse of the site of action of pharmacological openers should permit rapid progress towards understanding the structural determinants of their affinity and specificity.

ATP-Binding Cassette Transporters↗
PubMed2002

Opening of mitochondrial ATP-sensitive potassium channels evokes oxygen radical generation in rabbit heart slices.

The purpose of this study was to determine whether ATP-sensitive potassium channel (K(ATP) channel) activation generates oxygen free radicals in the rabbit heart. We assayed malondialdehyde (MDA) in rabbit heart slices in vitro as an indicator of oxygen free radical generation. The K(ATP) channel openers, pinacidil and cromakalim, significantly increased MDA production in a concentration-dependent manner. MDA formation also increased linearly with incubation time in the presence of K(ATP) channel openers. The K(ATP) channel blockers, glibenclamide and 5-hydroxydecanoate (5-HD), decreased K(ATP) channel opener-induced MDA formation in a concentration-dependent manner. When Fe(2+) was administered to heart slices that had been pretreated with K(ATP) channel openers, a marked elevation in MDA was observed, compared to heart slices that were treated with Fe(2+) alone. A positive linear correlation between Fe(2+) and MDA level was observed. The MDA levels of heart slices subjected to anoxia for 15 min remained unchanged until reperfusion. When the heart slices were reoxygenated for 30 min, a marked increase in MDA formation was observed. However, in the presence of glibenclamide and 5-HD, reperfusion following anoxia did not result in increased MDA. These results suggest that the opening of mitochondrial K(ATP) channels in rabbit heart slices evokes oxygen free radical generation via a Fenton-type reaction.

Adenosine Triphosphate↗
PubMed1996

Analytical studies of spontaneous and vasopressin-induced calcium oscillations in cultured vascular smooth muscle cells.

Spontaneous and vasopressin-induced Ca2+ oscillations in cultured vascular smooth muscle (A7r5) cells were further examined and characterized. Intracellular Ca2+ concentrations ([Ca2+]i) were measured by use of a high-performance laser cytometer. When the oscillatory patterns in [Ca2+]i were analyzed with a power spectrum method, about 80% of cells exhibited spontaneous Ca2+ oscillations with the frequency of 0.02-0.5 Hz. Nifedipine abolished these repetitive spikes, whereas pinacidil partially attenuated their amplitude and frequency. When vasopressin (100 nM) was applied to A7r5 cells, there was an initial rise in [Ca2+]i, followed by a delayed sustained increase in [Ca2+]i. The one-pool, nonoscillatory model was employed to fit this biphasic change, and the difference between the observed response and the simulated response was then analyzed with a power spectral method. About 50% of cells were noted to display oscillatory patterns in [Ca2+]i after sustained increase in [Ca2+]i. The present study indicates that spontaneous Ca2+ oscillations in A7r5 cells are modulated by the activity of ATP-sensitive K+ channels and are not related to pertussis toxin-sensitive GTP-binding protein(s). On the basis of the one-pool, nonoscillatory model, it is suggested that the buffering capacity of internal stores appears to be stronger in the cells with spontaneous Ca2+ oscillations than in those in a quiescent state, and the vasopressin-mediated inhibition of accumulation by internal stores was attenuated when the cells exhibited spontaneous Ca2+ oscillations. The implementation of this minimum kinetic model integrated with a power spectrum method would be an alternative to understand the oscillating behavior in [Ca2+]i.

Adenosine Triphosphate↗
PubMed2001

Relaxant effects of 17-beta-estradiol in cerebral arteries through Ca(2+) entry inhibition.

Estrogens account for gender differences in the incidence and outcome of stroke, but it remains unclear to what extent neuroprotective effects of estrogens are because of parenchymal or vascular actions. Because reproductive steroids have vasoactive properties, the authors assessed the effects and mechanisms of action of 17-beta-estradiol in rabbit isolated basilar artery. Cumulative doses of 17-beta-estradiol (0.3 micromol/L to 0.1 mmol/L) induced concentration-dependent relaxation that was larger in basilar than carotid artery, in male than female basilar artery, and in KCl-precontracted than UTP-precontracted male basilar artery. Endothelium removal did not modify relaxation induced by 17-beta-estradiol in basilar artery, whereas relaxation induced by acetylcholine (1 nmol/L to 0.1 mmol/L) was almost abolished. Neither the estrogen receptor antagonist ICI 182,780 (1 micromol/L), nor the protein synthesis inhibitor cycloheximide (1 micromol/L) affected 17-beta-estradiol-induced relaxations. Relaxations induced by the K(+) channel openers NS1619 and pinacidil in the same concentration range were greater and lower, respectively, when compared with relaxation to 17-beta-estradiol, which was not significantly modified by incubation with the K(+) channel blockers charybdotoxin (1 nmol/L and 0.1 micromol/L) or glibenclamide (10 nmol/L and 1 micromol/L). Preincubation with 17-beta-estradiol (3 to 100 micromol/L) produced concentration-dependent inhibition of CaCl(2)-induced contraction, with less potency than the Ca(2+) entry blocker nicardipine (0.01 to 10 nmol/L). The authors conclude that 17-beta-estradiol induces endothelium-independent relaxation of cerebral arteries with tissue and gender selectivity. The relaxant effect is because of inhibition of extracellular Ca(2+) influx to vascular smooth muscle, but activation of estrogen receptors, protein synthesis, or K(+) efflux are not involved. Relatively high pharmacologic concentrations of 17-beta-estradiol causing relaxation preclude acute vascular effects of physiologic circulating levels on the cerebral circulation.

Animals↗
PubMed1995

Differential responsiveness of atrial and ventricular myocytes to potassium channel openers.

We examined the effects of the potassium channel openers (PCOs) pinacidil and lemakalim (BRL 38227) on action potential (AP) configurations and outward currents in atrial and ventricular myocytes isolated from rabbit and guinea pig hearts, using the whole-cell configuration of the patch clamp technique at 33 degrees-35 degrees C. The PCOs known to activate ATP-sensitive K+ current (IKATP) in various tissues, induced this current and decreased AP duration (APD) in rabbit ventricular myocytes. In contrast, in rabbit atrial myocytes, PCOs either had no effect or increased duration and plateau amplitude of the AP. The predominant outward current in rabbit atrial myocytes is a 4-aminopyridine (4-AP)-sensitive transient outward current (Ito). The PCOs caused a decrease in Ito without inducing IKATP in rabbit atria. In identical experimental conditions, PCOs activated IKATP in both guinea pig atrial and ventricular myocytes. Our results suggest that (a) a species as well as cardiac tissue difference exists in responsiveness to PCOs, and (b) the decrease in Ito without concomitant induction of IKATP can lead to changes in AP configuration opposite to that expected from IKATP activation. Different effects of PCOs on distinct parts of the heart could lead to disparity in APD and refractoriness that may contribute to arrhythmogenesis.

Action Potentials↗
PubMed2000

Blockade of cardiac ATP-sensitive K+ channel by cibenzoline targets its pore-forming subunit.

Several antiarrhythmic agents with Na-channel blocking action have been shown to inhibit cardiac K(ATP) channels. We used cibenzoline to examine its precise target site using patch-clamp techniques and receptor binding assays in guinea-pig ventricular myocytes. Exposure of myocytes to a glucose-free perfusate containing 1 mM cyanide produced a time-dependent shortening of the action potential duration (APD) in the current-clamp mode. Cibenzoline (30 microM) slowed the development of APD shortening (APD90 to approximately 91% vs. approximately 55% control 16 min after metabolic inhibition) at pHo 7.4, but not at pHo 6.4 (to approximately 60%). The pinacidil (30 microM)-induced K(ATP) currents were inhibited by cibenzoline in a pHo-dependent manner: the higher the pHo, the stronger the blocking effect of cibenzoline. The binding of [3H]-labeled cibenzoline was prevented by cibenzoline, but not by glibenclamide. Alkalinization produces a higher concentration of the uncharged form of cibenzoline, which can more easily permeate the cell membrane than the charged form. In NIH3T3 cells stably expressing Kir6.1, a putative pore-forming subunit of K(ATP) channel, cibenzoline but not glibenclamide inhibited the K conductance. Thus cibenzoline interacts with the channel pore-forming subunit of the K(ATP) channel (Kir6.2), but not the sulfonylurea receptor, from the cytosolic side after it permeates into the cell interior via the membrane lipid bilayer.

Action Potentials↗
PubMed2004

ATP-sensitive potassium channels are involved in adenosine-induced reduction of blood pressure variability in spontaneously hypertensive rats.

With a computerized analysis system, blood pressure was recorded continuously in conscious unrestrained spontaneously hypertensive rats. The effects of different adenosine receptor agonists and ATP-sensitive potassium channel opener and blocker on blood pressure variability in spontaneously hypertensive rats were studied. It was found that adenosine, 5'-N-cyclopropyl-carboxamidoadenosine (CPCA, a selective adenosine A2-receptor agonist) and pinacidil (a nonselective ATP-sensitive potassium channel opener) decreased blood pressure variability when one of them was used alone, whereas N -cyclopentyladenosine (CPA, a selective adenosine A1-receptor agonist) had no significant effects on blood pressure variability. When pretreated with glibenclamide (a nonselective ATP-sensitive potassium channel blocker), the inhibitory effects of adenosine and CPCA on blood pressure variability were significantly prevented. By itself, however, glibenclamide had no influence on blood pressure variability. These results suggest that the effect of adenosine on blood pressure variability in spontaneously hypertensive rats is due to activation of ATP-sensitive potassium channels mediated by adenosine A2-receptor.

Adenosine↗
PubMed2003

Cerebrovascular vasodilation to extraluminal acidosis occurs via combined activation of ATP-sensitive and Ca2+-activated potassium channels.

Albeit controversial, it has been suggested by several authors that nitric oxide (NO) serves as a permissive factor in the cerebral blood flow response to systemic hypercapnia. Potassium channels are important regulators of cerebrovascular tone and may be modulated by a basal perivascular NO level. To elucidate the functional targets of the proposed NO modulation during hypercapnia-induced vasodilation, the authors performed experiments in isolated, cannulated, and pressurized rat middle cerebral arteries (MCA). Extracellular pH was reduced from 7.4 to 7.0 in the extraluminal bath to induce NO dependent vasodilation. Acidosis increased vessel diameter by 35 +/- 10%. In separate experiments, ATP-sensitive potassium channels (KATP) were blocked by extraluminal application of glibenclamide (Glib), Ca2+-activated potassium channels (KCa) by tetraethylammonium (TEA), voltage-gated potassium channels (Kv) by 4-aminopyridine, and inward rectifier potassium channels (KIR) by BaCl2. Na+-K+-ATP-ase was inhibited by ouabain. Application of TEA slightly constricted the arteries at pH 7.4 and slightly but significantly attenuated the vasodilation to acidosis. Inhibition of the other potassium channels or Na+-K+-ATP-ase had no effect. Combined blockade of KATP and KCa channels further reduced resting diameter, and abolished acidosis induced vasodilation. The authors conclude that mainly KCa channels are active under resting conditions. KATP and KCa channels are responsible for vasodilation to acidosis. Activity of one of these potassium channel families is sufficient for vasodilation to acidosis, and only combined inhibition completely abolishes vasodilation. During NO synthase inhibition, dilation to the KATP channel opener pinacidil or the KCa channel opener NS1619 was attenuated or abolished, respectively. The authors suggest that a basal perivascular NO level is necessary for physiologic KATP and KCa channel function in rat MCA. Future studies have to elucidate whether this NO dependent effect on KATP and KCa channel function is a principle mechanism of NO induced modulation of cerebrovascular reactivity and whether the variability of findings in the literature concerning a modulatory role of NO can be explained by different levels of vascular NO/cGMP concentrations within the cerebrovascular tree.

Acidosis↗
PubMed1997

Hyperpolarization of isolated capillaries from guinea-pig heart induced by K+ channel openers and glucose deprivation.

1. The present study was designed to test if microvascular coronary endothelial cells express ATP-sensitive K+ channels (KATP channels). We performed microfluorometric measurements of the membrane potential of freshly isolated guinea-pig coronary capillaries equilibrated with the voltage-sensitive dye bis-oxonol (bis-[1,3-dibutylbarbituric acid] trimethineoxonol, [DiBAC4(3)]). 2. The resting membrane potential of capillaries in physiological salt solution was -46 +/- 4.2 mV (n = 8) at room temperature (22 degrees C) as determined after calibration of the fluorescence using the Na(+)-K+ ionophore gramicidin in the presence of different K+ concentrations. Spontaneous membrane potential fluctuations of 10-20 mV amplitude were often observed. 3. A reversible, sustained hyperpolarization to a new membrane potential close to the K+ equilibrium potential (EK) could be induced by application of the K+ channel openers HOE 234 (100 nM to 1 microM), diazoxide (10 PM to 100 nM) or pinacidil (100 nM). Subsequent addition of glibenclamide (200 nM to 2 microM) reversed this hyperpolarization. 4. A glibenclamide-sensitive hyperpolarization of coronary capillaries to values near EK was also observed upon omission of D-glucose (10 mM) from the superfusing solution or by substituting L-glucose for D-glucose. Maximum hyperpolarization was reached in less than 10 min. 5. Our results suggest that microvascular coronary endothelial cells express KATP channels which may be activated during hypoglycaemia.

Adenosine Triphosphate↗
PubMed1998

Anoxia differentially modulates multiple K+ currents and depolarizes neonatal rat adrenal chromaffin cells.

1. Using perforated-patch, whole cell recording, we investigated the membrane mechanisms underlying O2 chemosensitivity in neonatal rat adrenomedullary chromaffin cells (AMC) bathed in extracellular solution containing tetrodotoxin (TTX; 0.5-1 microM), with or without blockers of calcium entry. 2. Under voltage clamp, low PO2 (0-15 mmHg) caused a graded and reversible suppression in macroscopic outward K+ current. The suppression during anoxia (PO2 = 0 mmHg) was approximately 35% (voltage step from -60 to +30 mV) and was due to a combination of several factors: (i) suppression of a cadmium-sensitive, Ca2+-dependent K+ current, IK(CaO2); (ii) suppression of a Ca2+-insensitive, delayed rectifier type K+ current, IK(VO2); (iii) activation of a glibenclamide- (and Ca2+)-sensitive current, IK(ATP). 3. During normoxia (PO2 = 150 mmHg), application of pinacidil (100 microM), an ATP-sensitive potassium channel (KATP) activator, increased outward current density by 45.0 +/- 7.0 pA pF-1 (step from -60 to + 30 mV), whereas the KATP blocker glibenclamide (50 microM) caused only a small suppression by 6.3 +/- 4.0 pA pF-1. In contrast, during anoxia the presence of glibenclamide resulted in a substantial reduction in outward current density by 24.9 +/- 7.9 pA pF-1, which far exceeded that seen in its absence. Thus, activation of IK(ATP) by anoxia appears to reduce the overall K+ current suppression attributable to the combined effects of IK(CaO2) and IK(VO2). 4. Pharmacological tests revealed that IK(CaO2) was carried predominantly by maxi-K+ or BK potassium channels, sensitive to 50-100 nM iberiotoxin; this current also accounted for the major portion (approximately 60%) of the anoxic suppression of outward current. Tetraethylammonium (TEA; 10-20 mM) blocked all of the anoxia-sensitive K+ currents recorded under voltage clamp, i.e. IK(CaO2), IK(VO2) and IK(ATP). 5. Under current clamp, anoxia depolarized neonatal AMC by 10-15 mV from a resting potential of approximately -55 mV. At least part of this depolarization persisted in the presence of either TEA, Cd2+, 4-aminopyridine or charybdotoxin, suggesting the presence of anoxia-sensitive mechanisms additionalto those revealed under voltage clamp. In Na+/Ca2+-free solutions, the membrane hyperpolarized, though at least a portion of the anoxia-induced depolarization persisted. 6. In the presence of glibenclamide, the anoxia-induced depolarization increased significantly to approximately 25 mV, suggesting that activation of KATP channels may function to attenuate the anoxia-induced depolarization or receptor potential.

Animals↗
PubMed1999

Specificity of synergistic coronary flow enhancement by adenosine and pulsatile perfusion in the dog.

1. Coronary flow elevation from enhanced perfusion pulsatility is synergistically amplified by adenosine. This study determined the specificity of this interaction and its potential mechanisms. 2. Mean and phasic coronary flow responses to increasing pulsatile perfusion were assessed in anaesthetized dogs, with the anterior descending coronary artery servoperfused to regulate real-time physiological flow pulsatility at constant mean pressure. Pulsatility was varied between 40 and 100 mmHg. Hearts ejected into the native aorta whilst maintaining stable loading. 3. Increasing pulsatility elevated mean coronary flow +11.5 +/- 1.7 % under basal conditions. Co-infusion of adenosine sufficient to raise baseline flow 66 % markedly amplified this pulsatile perfusion response (+82. 6 +/- 14.3 % increase in mean flow above adenosine baseline), due to a leftward shift of the adenosine-coronary flow response curve at higher pulsatility. Flow augmentation with pulsatility was not linked to higher regional oxygen consumption, supporting direct rather than metabolically driven mechanisms. 4. Neither bradykinin, acetylcholine nor verapamil reproduced the synergistic amplification of mean flow by adenosine and higher pulsatility, despite being administered at doses matching basal flow change with adenosine. 5. ATP-sensitive potassium (KATP) activation (pinacidil) amplified the pulse-flow response 3-fold, although this remained significantly less than with adenosine. Co-administration of the phospholipase A2 inhibitor quinacrine virtually eliminated adenosine-induced vasodilatation, yet synergistic interaction between adenosine and pulse perfusion persisted, albeit at a reduced level. 6. Thus, adenosine and perfusion pulsatility specifically interact to enhance coronary flow. This synergy is partially explained by KATP agonist action and additional non-flow-dependent mechanisms, and may be important for modulating flow reserve during exercise or other high output states where increased flow demand and higher perfusion pulsatility typically co-exist.

Adenosine↗
PubMed1991

The binding site for [3H]glibenclamide in the rat cerebral cortex does not recognize K-channel agonists or antagonists other than sulphonylureas.

The binding of the potent oral antidiabetic sulphonylurea [3H]glibenclamide was studied in rat cerebral cortex membranes. A single population of high affinity and saturable binding sites with equilibrium constants, Kd = 0.2 +/- 0.06 nM and Bmax = 58.6 +/- 6.2 fmol/mg protein was found. Specific [3H]glibenclamide binding to rat cerebral cortex membranes was inhibited by glibenclamide and other sulphonylureas, glibenclamide being the most potent drug and the sulphonylurea of the second generation chlorpropamide the least potent. This observation suggests that this site may be related to the hypoglycaemic properties of sulphonylureas and possibly to their interaction with ATP-sensitive K(+)-channel. Nevertheless, other non-selective K(+)-channel antagonists such as TEA, 4-aminopyridine, quinine, quinidine or apamin failed to interact with this site (IC50 greater than 100 microM). Similarly, both non-selective K(+)-channel agonists such as cromakalim, pinacidil or minoxidil as well as the pancreatic ATP-sensitive K(+)-channel agonist diazoxide failed to interact with this site. It may thus be concluded that this site, under the present experimental conditions, represents a drug specific recognition site which may be coupled to the hypoglycaemic activity of sulphonylureas, possibly on a particulate ATP-dependent K(+)-channel.

Animals↗
PubMed1992

Characteristics of the contractile response of rabbit aorta produced by cromakalim in calcium-free solution.

1 The effect of potassium channel opening compounds has been investigated in the smooth muscle of rabbit aorta under Ca-free conditions. Examination of the characteristics of the response has been performed using cromakalim as the prototype compound. 2 In order of potency, Ro 31-6930, cromakalim, minoxidil sulphate and pinacidil each produced a contraction in rabbit aortic strips bathed in Ca-free MOPS-buffered physiological salt solution (PSS). In contrast, forskolin, glyceryl trinitrate and nifedipine each failed to increase tension under identical conditions. Cromakalim also evoked contraction of bovine trachealis muscle bathed in Ca-free PSS. 3. The contractile response to cromakalim in rabbit aortic strips was of delayed onset (15-20 min) and reached a plateau after approximately 120 min (1.8 g maximum with 1 microM cromakalim). No cromakalim-induced tension changes were observed in either 1 mM or 2.5 mM Ca-containing PSS. 4. Raising the [KCl] of the Ca-free PSS to 65.9 mM fully inhibited the cromakalim-induced contraction in rabbit aortic strips. In addition, pretreatment of aortic strips with the sulphonylurea glibenclamide antagonized the subsequent mechanical response to cromakalim. 5. In Ca-free PSS, cromakalim (1 microM) stimulated 42K-efflux with a time-course corresponding to the contractile event. Glibenclamide (1 microM) inhibited this cromakalim-induced 42K-efflux. 6. In sharp microelectrode studies in bovine trachealis, cromakalim (10 microM) produced a sustained membrane hyperpolarization in normal PSS. In contrast, the cromakalim-induced hyperpolarization in Ca-free PSS was not sustained. The fading of the hyperpolarization was temporally correlated with the increase in tension under these experimental conditions. 7. It is concluded that the K-channel opener-induced smooth muscle contractile response revealed in Ca-free PSS is the consequence of K-channel opening. The nature of the detailed mechanism which underlies this contractile phenomenon remains to be determined.

Animals↗
PubMed1993

Effects of beraprost on the transmembrane potentials of guinea-pig ventricular muscles during normoxia and hypoxia-reoxygenation.

1. The present study was performed to determine whether beraprost, a new stable analogue of prostacyclin, may exert beneficial effects on the transmembrane action potentials during normoxia and hypoxia-reoxygenation in isolated right ventricular muscles of the guinea-pig. 2. Under normal oxygenation, beraprost (0.01-100 mumol-1) had no effects on the electrophysiological parameters. 3. Hypoxic conditions induced a decrease in action potential duration (APD) without affecting other action potential parameters. Beraprost inhibited this hypoxia-induced decrease in APD. However, beraprost had no effect on the decrease in contractile force induced by hypoxia, whereas it significantly improved the recovery of contractile force after reoxygenation. 4. Pinacidil-induced shortening of APD was not antagonized by beraprost. 5. Hypoxia significantly decreased the myocardial adenosine triphosphate (ATP) level, which was also prevented by beraprost. 6. These results suggested that beraprost may inhibit the hypoxia-induced shortening of APD by some mechanisms which contribute to the maintenance of muscle ATP level.

Action Potentials↗
PubMed1994

Reversibility of electrophysiological abnormalities in subacute ischemia.

Twenty-four hours after occlusion of the left anterior descending coronary artery in the dog, ventricular tachycardia is the predominant rhythm. At this time, records of transmembrane potentials from the subendocardial Purkinje fibers adjacent to the infarct show a low maximum diastolic potential, prominent phase 4 depolarization, and slow response action potentials. Exposure of the fibers to pinacidil, 25-100 microM, increases resting potential to the estimated value of EK, abolishes the phase 4 depolarization, and restores action potential amplitude and Vmax toward normal. Perfusion of the bed of the occluded coronary artery with Tyrode's solution prior to isolation of the subendocardial tissues results in similar normalization of transmembrane potentials. These findings indicate: (a) that the major cause of the abnormal transmembrane potentials of the subendocardial tissues is the loss of resting potential; and (b) that abnormalities of the transmembrane potentials are caused by some substance that can be washed out by perfusion and not by a direct effect of ischemia.

Action Potentials↗
PubMed1992

Clinical pharmacology of potassium channel openers.

Opening of K+ channels in cell membranes with resulting increase in K+ conductance, shifts the membrane potential in a hyperpolarizing direction towards the K+ equilibrium potential. Hyperpolarization reduces the opening probability of ion channels involved in membrane depolarization and excitation is reduced. K+ channel openers are believed to hyperpolarize smooth muscle cells by a direct action on the cell membrane. The best known members of the group are cromakalim, nicorandil and pinacidil, but several new compounds are being evaluated. In addition, it has recently been shown that also clinically well-known drugs like, e.g. diazoxide and minoxidil exhibit K+ channel opening properties. Nicorandil and new compounds containing nitro groups have a dual mechanism of action, also activating guanylate cyclase, an effect that contributes to their cardiovascular effect profile. K+ channel openers have a wide range of effects. Some of their properties and actions are summarized, and their present applications and/or potential for future application, in e.g. hypertension, angina pectoris, asthma, bladder instability, and several other disorders are discussed. It is concluded that K+ channel openning represents an interesting pharmacological principle with many potential clinical applications. However, most available drugs do not seem to have a sufficient tissue selectivity to be useful therapeutic alternatives. Before the potential of the new members of the group on clinical trials can be properly evaluated, clinical experiences are needed.

Antihypertensive Agents↗
PubMed2005

Alteration of binding sites for [3H]P1075 and [3H]glibenclamide in renovascular hypertensive rat aorta.

AIM: The alterations of the binding sites for ATP-sensitive K+ channel (K(ATP)) openers and blockers in aortic strips were investigated in hypertensive rats. METHODS: Radioligand binding techniques were used to compare the specific binding properties of [3H]P1075 and [3H]glibenclamide (Gli) in normotensive (NWR) and reno-vascular hypertensive rat (RVHR) aortic strips. RESULTS: The KD values of [3H]P1075 binding were increased by 1.5-fold, while the Bmax values were unchanged in RVHR. The IC50 values of P1075 and pinacidil (Pin) for displacing the [3H]P1075 binding in RVHR were increased by 1.8- and 1.7-fold, respectively. The kinetic processes of association and dissociation of [3H]P1075 binding were slower in RVHR. Glibenclamide pretreatment slowed down the kinetic processes of the association and dissociation of [3H]P1075 binding in NWR, but failed to alter the kinetic processes of [3H]P1075 binding in RVHR. The IC50 values of Gli for displacing the [3H]Gli binding at high-affinity sites were increased by 3-fold, while those at low-affinity sites remained to be unchanged in RVHR. The kinetic processes of association of [3H]Gli binding were decreased and those of the dissociation were accelerated in RVHR. The treatment with Pin slowed down the association kinetic processes but accelerated the process of the dissociation of [3H]Gli binding in NWR, but did not alter the kinetics of [3H]Gli binding in RVHR. CONCLUSION: The affinity of binding sites for [3H]P1075 and of high-affinity binding sites for [3H]Gli are decreased, and the negative allosteric interactions between the two binding sites are impaired in RVHR aorta.

Animals↗
PubMed1991

Metabolic correlates to pacemaker activity in the smooth muscle of guinea-pig mesotubarium.

Oxygen consumption (FO2) and lactate production (Flac) were measured during spontaneous activity in the guinea-pig mesotubarium. During spontaneous contractions FO2 increased to maximally 0.270 +/- 0.025 mumol min-1g-1 (n = 23), followed by a rapid fall immediately upon relaxation. In the relaxed period (5-15 min) between spontaneous contractions FO2 continued to slowly decrease by about 25% towards a final value of 0.150 +/- 0.01 mumol min-1g-1. Flac showed no consistent variation during the relaxed period. Ouabain (10(-6)M) produced a contracture, which was abolished by the Ca2(+)-antagonist felodipine (10(-6)M). In the presence of felodipine, addition of ouabain caused depolarization and a decrease of oxygen consumption by 21% and of lactate production by 31%. Exchange of glucose in the physiological Krebs solution for beta-hydroxybutyrate did not influence spontaneous activity, while subsequent addition of cyanide (2 mM) abolished contractions and caused a hyperpolarization of 15 mV. Blockade of ATP-dependent K+ channels by addition of glibenclamide (10(-7)M) to the relaxed muscle in this situation caused spontaneous contractile activity to reappear. In glucose-containing Krebs solution glibenclamide had no effect on the spontaneous contractile and electrical activity and contractions persisted after addition of cyanide. The relaxing and hyperpolarizing effect of pinacidil could be counteracted by addition of glibenclamide. The results suggest that a decrease in electrogenic Na+/K(+)-pump activity in the course of the relaxed period between contractions could contribute to the pacemaker behaviour. ATP-dependent K+ channels, while having little influence on the spontaneous contractile activity under normal metabolic conditions, could be activated during blockade of aerobic and anaerobic metabolism, leading to inhibition of pacemaker activity.

Adenosine Triphosphate↗