Adenosine Triphosphate-sensitive Potassium Channel Opener Research Articles

Nicorandil, a potent adenosine triphosphate–sensitive potassium-channel opener, ameliorates lung allograft reperfusion injury

Background: Lung allograft ischemia-reperfusion injury, characterized by increased pulmonary vascular resistance, pulmonary edema, and hypoxia, is the most frequent cause of early graft failure. Exogenous nitric oxide has been shown to reduce lung allograft reperfusion injury. During hypoxia, the adenosine triphosphate–sensitive potassium channel is an important ionic channel that links the bioenergetic metabolism to membrane excitability. It has been shown to play a critical role in vascular permeability and in activation of neutrophils and their subsequent interaction with vessel wall cellular components. The purpose of this study was to investigate whether nicorandil, a novel nitric oxide generator and adenosine triphosphate–sensitive potassium-channel opener, might enhance lung preservation and prevent allograft reperfusion injury. Materials and methods: Fourteen dogs underwent left lung allotransplantation. Donor lungs were flushed with modified Euro-Collins solution and stored for 21 hours at 1° C. Immediately after transplantation, the contralateral right main pulmonary artery and bronchus were ligated to assess isolated allograft function. Hemodynamics and arterial blood gas analysis (inspired oxygen fraction 1.0) were assessed for 6 hours before the dogs were put to death. After the assessment, activity of allograft myeloperoxidase and protein levels of bronchoalveolar lavage fluid were measured. Control animals (group I, n = 5) received no nicorandil. In group II ( n = 5), the donor lung received nicorandil (24 mg/L) in the flush solution. In addition, recipient animals received nicorandil (0.5 mg/kg, intravenously) just before reperfusion, as well as a continuous infusion (0.74 ± 0.03 mg/kg per hour) during the 6-hour assessment period. In group III ( n = 4), glibenclamide, a selective adenosine triphosphate–sensitive potassium-channel blocker, was administered 15 minutes before nicorandil administration to both donor and recipient. The animals in group III received nicorandil in the same regimen as group II. Result: Superior gas exchange and hemodynamics were observed in lungs receiving only nicorandil. Allograft myeloperoxidase activity and protein levels in bronchoalveolar lavage fluid were significantly reduced in group II. Glibenclamide eliminated the beneficial effects of nicorandil. Conclusions: Nicorandil administration in the flush solution and during the reperfusion period ameliorates lung allograft dysfunction, improves blood flow, and reduces pulmonary vascular resistance and myeloperoxidase activity in the transplanted lung. The present study suggests that nicorandil reduces lung allograft reperfusion injury. The beneficial effects of nicorandil may be attributed to its properties as an adenosine triphosphate–sensitive potassium-channel opener. (J T HORAC C ARDIOVASC S URG 1996;112:1307-14)

Allergic responses reduce the relaxant effect of beta-agonists but not potassium channel openers in guinea-pig isolated trachea

This study was conducted to determine whether the relaxant effect of adenosine triphosphate (ATP)-sensitive potassium channel (KATP) openers on airway smooth muscle are reduced during the hyporesponsiveness of beta-adrenergic receptors. Isometric tension was measured and dose-response curves were constructed for levcromakalim (a KATP opener), Y-26763 (another KATP opener), isoprenaline and theophylline in guinea-pig isolated trachea that was challenged with ovalbumin or pretreated in vitro with either isoprenaline or the KATP openers. Antigen challenge in vitro significantly reduced the potency but not the efficacy of isoprenaline in tracheal strips from actively sensitized guinea-pigs. The concentration of drug that produced a half-maximum inhibition (IC50) was 0.014 +/- 0.004 microM in the challenge group versus 0.006 +/- 0.001 microM in the control group (p < 0.05; n = 9). The IC50 of levcromakalim (1.73 +/- 0.17 microM; n = 6) and of theophylline (110 +/- 3.1 microM; n = 6) were unaffected. Exposure to 4 microM isoprenaline for 30 min evoked beta-adrenergic hyporesponsiveness: the IC50 of isoprenaline rose significantly from 0.010 +/- 0.001 to 0.017 +/- 0.002 microM (p < 0.01; n = 6). No effect was observed on the relaxant actions of levcromakalim and theophylline. In contrast, prior incubation with either levcromakalim or Y-26763 (300 microM for 30 min) significantly reduced the subsequent potency and efficacy of levcromakalim, but did not alter the effects of isoprenaline and theophylline. We conclude that the relaxant effect of the adenosine triphosphate-sensitive potassium channel openers was independent of beta-adrenergic hyporesponsiveness in airway smooth muscle of guinea-pigs.

Myocardial protection with potassium-channel openers is as effective as St. Thomas' solution in the rabbit heart

Previous work from our laboratory has demonstrated the advantage of adenosine triphosphate-sensitive potassium-channel openers as cardioplegic agents when compared with hyperkalemic (20 mmol/L KCl) Krebs-Henseleit solution. However, Krebs-Henseleit with 20 mmol/L KCl is not an ideal hyperkalemic cardioplegia. Therefore, we investigated the hypothesis that hyperpolarized arrest with pinacidil and aprikalim could provide equal or superior myocardial protection to hyperkalemic arrest with the widely accepted St. Thomas' solution. Myocardial protection was compared in the blood-perfused isolated parabiotic rabbit heart Langendorff model. Twenty-four hearts were protected with a 50-mL infusion of cardioplegia for a 30-minute global normothermic ischemic period followed by 30 minutes of reperfusion. Systolic function (percent recovery of developed pressure) and the diastolic properties of the left ventricle were measured. Coronary blood flow was measured throughout each experiment. The percent recovery of developed pressure (mean +/- standard error of the mean) for St. Thomas' solution, pinacidil, and aprikalim was 53.1% +/- 5.4%, 64.0% +/- 3.0%, and 62.4% +/- 3.2%, respectively. The time (minutes) until mechanical and electrical arrest was significantly longer in the pinacidil (4.82 +/- 0.10 and 12.06 +/- 1.07) and aprikalim (3.33 +/- 0.28 and 11.12 +/- 0.94) groups when compared with the St. Thomas group (1.84 +/- 0.74, and 3.17 +/- 1.44). Coronary blood flow upon reperfusion was significantly greater in the pinacidil (16.4 +/- 2.1 mL/min) and aprikalim (19.4 +/- 2.8 mL/min) groups compared with the St. Thomas' solution group (8.0 +/- 1.0 mL/min), and this returned to baseline after 15 minutes of reperfusion. Myocardial protection with pinacidil and aprikalim is comparable with that of St. Thomas' solution in the blood-perfused isolated rabbit heart despite prolonged mechanical and electrical activity during ischemia.

Myocardial protection with pinacidil cardioplegia in the blood-perfused heart

Adenosine triphosphate-sensitive potassium-channel openers are potent vasodilators that have been found to be cardioprotective during myocardial ischemia. The potassium-channel opener pinacidil was investigated to determine its efficacy as a cardioplegic agent. A blood-perfused, parabiotic, isolated rabbit heart Langendorff preparation was used. Fifty-six hearts underwent 30 minutes of global normothermic ischemia after a 50-mL infusion of cardioplegia, followed by 60 minutes of reperfusion. The cardioplegia consisted of Krebs-Henseleit solution with either vehicle alone (control), 20 mmol KCl, or pinacidil (10, 50, 100, 150, or 200 mumol/L). The developed pressure was measured at baseline and after reperfusion. Coronary blood flow was measured with an in-line ultrasonic probe. Pinacidil (50 mumol/L), as opposed to potassium cardioplegia, provided significantly better postischemic percentage recovery of developed pressure compared with controls (68.3% +/- 4.0% versus 44.6% +/- 5.5%; p < 0.05). The time until electrical arrest was significantly shorter in the hyperkalemic group than in all other groups. Linear end-diastolic pressure-volume relationships revealed an increase in slope after ischemia in all groups. Coronary flow after 5 minutes of reperfusion was significantly higher in both the 50-mumol/L and 100-mumol/L pinacidil groups compared with traditional hyperkalemic arrest, and this returned to baseline after 15 minutes. The potassium channel opener pinacidil provided dose-dependent myocardial protection during global ischemia in the blood-perfused rabbit heart model. Potassium-channel openers are a promising class of drugs that may provide an alternative to traditional hyperkalemic cardioplegia.

Is there an alternative to potassium arrest?

Mounting clinical and experimental evidence suggests that postoperative myocardial dysfunction is a frequent consequence of surgical global ischemia and reperfusion, despite our modern techniques of myocardial protection. The ubiquitous use of hyperkalemic depolarizing solutions in all forms of cardioplegia may be partly responsible for this phenomenon because of the known ongoing metabolic processes and damaging transmembrane ionic fluxes that occur at depolarized membrane potentials. Cardiac arrest at hyperpolarized potentials, the natural resting state of the heart, may avoid the shortcomings of depolarized arrest and provide an alternative means of myocardial protection. An adenosine triphosphate-sensitive potassium channel opener, aprikalim, was used to induce hyperpolarized arrest. Aprikalim was able to produce sustained and reproducible electromechanical arrest that was reversible by reperfusion. In isolated heart models, when compared with depolarized hyperkalemic arrest, hyperpolarized arrest afforded better protection from global normothermic ischemia and resulted in better postischemic recovery of function upon reperfusion. Preliminary studies in a porcine cardiopulmonary bypass model also have revealed that hyperpolarized arrest can be achieved in a model more closely approximating the clinical setting, and can effectively protect the heart during normothermic surgical global ischemia. Hyperpolarized cardiac arrest may offer an effective alternative to traditional potassium arrest.

Pretreatment with the adenosine triphosphate-sensitive potassium channel opener nicorandil and improved myocardial protection during high-potassium ca rdioplegic hypoxia

We hypothesized that pretreatment with the potassium channel opener nicorandil might enhance myocardial protection achieved by cold (20 degrees C) high-potassium (16 mmol/L) cardioplegia (5 ml/min) during long-duration (120 minutes) myocardial hypoxia (average oxygen content 5.4 ml/dl). We tested a 15-minute infusion of nicorandil (1 mmol/L) given only before (group A, n = 8) or before and during cardioplegia (group B, n = 8) in guinea pig papillary muscle preparations contracting isometrically while stimulated (4 mA, 2 msec) at 1600 msec cycle length. Nicorandil was significantly negative inotropic before cardioplegia and shortened significantly action potential duration. During cardioplegia, time to arrest of contraction was shortened from 145 +/- 28 seconds (mean +/- standard error) in the vehicle group (dimethyl sulfoxide 1:100; n = 8) to 56 +/- 10 seconds (p < 0.02) and 68 +/- 5 seconds (p < 0.05) in groups A and B, respectively. Recovery of developed tension at 60 minutes of normothermic reoxygenation (expressed as percent of prehypoxia basal value) was ameliorated from 54% +/- 6% (vehicle group) to 92% +/- 4% (group A, p < 0.01) and to 119% +/- 19% (group B, p < 0.01). The specific potassium channel blocker glibenclamide (glib: 1 mumol/L, n = 8) prolonged action potential duration and was without effect on time to arrest. On reoxygenation, the glib group had prolonged time to half relaxation (versus group A, p < 0.02) and the worst percent developed tension at 60 minutes (40% +/- 4%). In the overall study, time to arrest and percent developed tension at 60 minutes were inversely correlated (r = -0.45, p < 0.01). Arrhythmias were never observed. Multivariate analysis showed that pretreatment with nicorandil (with or without drug adjunct to cardioplegic solution) was a significant factor (r2 = 0.65, p = 0.0001) to influence reoxygenation-mediated recovery of mechanical function. Neither the negative inotropic effect of nicorandil before cardioplegia nor its abbreviating action on time to arrest during cardioplegia was contributory to explain recovery of function on reoxygenation. In subgroup analysis, negative inotropism and the shortening of action potential duration were contributory factors. These data suggest that nicorandil pretreatment activates potassium channels and enhances the myocardial protection provided by cold cardioplegia an effect, which is evident after a long hypoxic period, late on reoxygenation.

Elective cardiac arrest with a hyperpolarizing adenosine triphosphate–sensitive potassium channel opener: A novel form of myocardial protection?

Hyperkalemic depolarized cardiac arrest has been the cornerstone of myocardial protection during cardiac surgery for more than 30 years. Many of the advances in myocardial protection seek to minimize the cellular damage and to reduce the ongoing metabolic processes occurring as a direct consequence of the depolarized state. Ideally, cardiac arrest at hyperpolarized cellular membrane potentials--the natural resting state of the heart--will meet all the requirements of modern cardioplegia, namely, electromechanical asystole and cardiac relaxation, while preserving the vital integrity of the heart itself. To determine whether activation of adenosine triphosphate-sensitive potassium channels by pharmacologic agents could produce hyperpolarized cardiac arrest, we tested the ability of aprikalim, a known adenosine triphosphate-sensitive potassium channel opener, to arrest the intact beating heart. In a normothermic (37 degrees C) isolated rabbit heart preparation, aprikalim was found to rapidly shorten the action potential duration and produce cardiac asystole that was maintained during 20 minutes of "no-flow" global ischemia without a rise in end-diastolic pressure. Cardiac rhythm and function were fully restored by reperfusion alone (developed pressure was 100.6% +/- 7.9% of prearrest value after 30 minutes of reperfusion). In contrast, 20 minutes of unprotected normothermic global ischemia resulted in a 2.7 +/- 0.55 mmHg rise in end-diastolic pressure and only 58.2% +/- 3.8% recovery of developed pressure after 30 minutes of reperfusion. By way of comparison, 20 minutes of standard hyperkalemic depolarized normothermic rest was accompanied by a 1.2 +/- 0.6 mmHg rise in end-diastolic pressure and only 80.8% +/- 2.6% recovery of developed pressure after 30 minutes of reperfusion. To directly compare hyperkalemic depolarized cardiac arrest to hyperpolarized cardiac arrest induced by potassium channel openers and to better define the characteristics of such hyperpolarized arrest, we studied a fixed (4 mmHg rise in end-diastolic pressure--contracture) ischemic injury model. The time to development of the contracture was prolonged by hyperkalemic arrest (35.8 +/- 1.7 minutes) and significantly more so by hyperpolarized arrest (47.0 +/- 3.3 minutes) when compared with that of unprotected hearts (24.0 +/- 1.2 minutes). Moreover, aprikalim resulted in significantly better postischemic recovery of function (developed pressure was 69.0% +/- 6.7% of prearrest value after 30 minutes of reperfusion) than after no cardioplegia (45.4% +/- 7.5%) or standard hyperkalemic cardioplegia (44.3% +/- 5.7%). Pharmacologic activation of adenosine triphosphate-sensitive potassium channels can result in predictable and sustainable hyperpolarized cardiac arrest that is reversible by reperfusion. This method of myocardial protection was found to fully preserve cardiac electromechanical function after a 20-minute period of global normothermic ischemia. Furthermore, hyperpolarized arrest induced by potassium channel openers significantly prolonged the period to the development of contracture and afforded a significantly better postischemic recovery of function than obtained in either hearts protected with hyperkalemic depolarized arrest or those not protected by any form of cardioplegia.

Myocardial hypoxia and reoxygenation: electrophysiologic and mechanical correlates.

ARTICLESMyocardial hypoxia and reoxygenation: electrophysiologic and mechanical correlatesWW Brooks, B Sturckow, and OH BingWW Brooks, B Sturckow, and OH BingPublished Online:01 Mar 1974https://doi.org/10.1152/ajplegacy.1974.226.3.523MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformationCited ByHemodynamic Responses to Hypoxia and Hypercapnia during Acute Normovolemic Hemodilution in Anesthetized Cats.The Japanese Journal of Physiology, Vol. 50, No. 2Felodipine protects human atrial muscle from hypoxia–reoxygenation dysfunction: a force–frequency relationship study in an in vitro model of stunningInternational Journal of Cardiology, Vol. 62, No. 2The risk of myocardial stunning is decreased concentration-dependently by KATP channel activation with nicorandil before high K+ cardioplegiaInternational Journal of Cardiology, Vol. 48, No. 1Pretreatment with the adenosine triphosphate-sensitive potassium channel opener nicorandil and improved myocardial protection during high-potassium ca rdioplegic hypoxiaThe Journal of Thoracic and Cardiovascular Surgery, Vol. 108, No. 3Hypoxia-induced changes in electrophysiological responses and associated calcium movements of flounder (Platichthys flesus) heart and gutComparative Biochemistry and Physiology Part A: Physiology, Vol. 101, No. 4A cellular mechanism for impaired posthypoxic relaxation in isolated cardiac myocytes. Altered myofilament relaxation kinetics at reoxygenation.Circulation Research, Vol. 69, No. 1Relative roles of Ca2(+)-dependent and Ca2(+)-independent mechanisms in hypoxic contractile dysfunction.Circulation, Vol. 82, No. 2Progressive hypoxemia limits left ventricular oxygen consumption and contractility.Circulation Research, Vol. 63, No. 5The Ventricular Intracardiac Unipolar Paced-Evoked Potential in an Isolated Animal Heart30 June 2006 | Pacing and Clinical Electrophysiology, Vol. 11, No. 2PathophysioSogy of Myocardial ReperfusionCardiology Clinics, Vol. 5, No. 1Influence of strong static magnetic fields on heart muscle contraction6 December 2000 | Physics in Medicine and Biology, Vol. 31, No. 7Features of cardiac myocytes in culture: characterisation of the failing cellTime Course of Changes in Action Potential Duration and Ejection Shortening During Regional Transient Ischaemia of PIG Ventricle In SituVentricular contracture and compliance changes with global ischemia and reperfusion, and their effect on coronary resistance in the rat.Circulation Research, Vol. 41, No. 2 More from this issue > Volume 226Issue 3March 1974Pages 523-527 Copyright & PermissionsCopyright © 1974 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1974.226.3.523PubMed4817403History Published online 1 March 1974 Published in print 1 March 1974 Metrics