Abstract
We studied the effects of pinacidil (3–50 μM) on the membrane currents of canine ventricular myocytes, using the whole-cell variant of the patch-clamp technique, and the modulation of these effects by intracellular environment, using the pipette perfusion technique. The following observations were obtained: (1) pinacidil induced a dosedependent outward shift in current at voltages positive to ±70 mV; (2) the pinacidil-induced current was largely timeindependent at voltages positive to ±50 mV and displayed an increase in current fluctuations at more positive voltages, resembling the kinetic properties of current through the ATP-regulated K+ channels; (3) elevating the extracellular potassium concentration ([K+]o) caused a positive shift in the voltage where the pinacidil-induced current crossed the voltage axis and increased the slope conductance of this current; (4) the pinacidil-induced current was reduced by Ba2+ (0.5–1.5 mM) and abolished by intracellular Cs+ (125 mM); (5) glibenclamide reversibly reduced or abolished the pinacidil-induced current; (6) the action of pinacidil was decreased by elevating [ATP] in the pipette solution (from 1 to 10 mM); (7) the action of pinacidil was augmented by adding isoproterenol (1 μM) to the superfusate or adding cAMP (0.1 mM) to the pipette solution; (8) elevating temperature augmented, and accelerated the onset of, pinacidil's action; (9) pinacidil reversibly decreased the Ca2+ -independent transient outward current (Ito1) but augmented the Ca2+ -dependent transient outward current (Ito2). Based on these observations, we reached the following conclusions: (1) the main effect of pinacidil is to increase an outward current through the ATP-regulated K+ channels; (2) pinacidil's action is modulated by an enzymatic reaction.
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References
Akbarali H, Self DA, Hermsmeyer K (1989) Pinacidil-enhanced potassium currents in vascular smooth muscle are blocked by charybdotoxin. Biophys J 55:198a
Allen DG, Orchard CH (1987) Myocardial contractile function during ischemia and hypoxia. Circ Res 60:153–168
Anderson CS, MacKinnon R, Smith C, Miller C (1988) Charybdotoxin block of single Ca2+-activated K+ channels. Effects of channel gating, voltage, and ionic strength. J Gen Physiol 91:317–333
Arena JP, Kass RS (1989) Enhancement of potassium-sensitive current in heart cells by pinacidil. Evidence for modulation of the ATP-sensitive potassium channel. Circ Res 65:436–445
Ashcroft FM (1988) Adenosine-5′-triphosphate-sensitive potassium channels. Annu Rev Neurosci 11:97–118
Ashcroft FM, Kakei M, Kelly RP (1989) Rubidium and sodium permeability of the ATP-sensitive K+ channel in single rat pancreatic B-cells. J Physiol (Lond) 408:413–430
Belles B, Hescheler J, Trube G (1987) Changes of membrane currents in cardiac cells induced by long whole-cell recordings and tolbutamide. Pflügers Arch 409:582–588
Carmeliet E, Biermans G, Callewaert G, Vereecke J (1987) Potassium current in cardiac cells. Experientia 43:1175–1184
Cook NS (1987) The pharmacology of potassium channels and their therapeutic potential. Trends Pharmacol Sci 9:21–28
Dunne MJ, Illot MC, Petersen OH (1987) Interaction of diazoxide, tolbutamide and ATP4± on nucleotide-dependent K+ channels in an insulin-secreting cell line. J Membr Biol 99:215–224
Escande D, Thuringer D, Leguern S, Cavero I (1988) The potassium channel opener cromakalim (BRL 34915) activates ATP-dependent K+ channels in isolated cardiac myocytes. Biochem Biophys Res Commun 154:620–625
Fabiato A, Fabiato F (1979) Calculator programs for computing the composition of the solutions containing multiple metals and ligands used for experiments in skinned muscle cells. J Physiol (Paris) 75:463–505
Findlay I (1987) ATP-sensitive K+ channels in rat ventricular myocytes are blocked and inactivated by internal divalent cations. Pflügers Arch 410:313–320
Fosset M, De Weille JR, Green RD, Schmid-Antomarchi H, Lazdunski M (1988) Antidiabetic sulfonylureas control action potential properties in heart cells via high affinity receptors that are linked to ATP-dependent K+ channels. J Biol Chem 263:7933–7936
Gelband CH, van Breemen C (1989) Reconstituted aortic Ca2+-activated K+ channels: selectivity and pharmacological modulation by cromakalim (BRL 34915) and pinacidil. Biophys J 55: 545a
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth J (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch 391:85–100
Hirano Y, Hiraoka M (1988) Barium-induced automatic activity in isolated ventricular myocytes from guinea-pig hearts. J Physiol (Lond) 395:455–472
Horie M, Irisawa H, Noma A (1987) Voltage-dependent magnesium block of adenosine-triphosphate-sensitive potassium channel in guinea-pig ventricular cells. J Physiol (Lond) 387:251–272
Hunter M, Giebisch G (1988) Calcium-activated K-channels of Amphiuma early distal tubule: inhibition by ATP. Pflügers Arch 412:331–333
Imanishi S, Arita M, Aomine M, Kiyosue T (1984) Antiarrhythmic effects of nicorandil on canine cardiac Purkinje fibers. J Cardiovasc Pharmacol 6:772–779
Josephson IR, Sanchez-Chapula J, Brown AM (1984) Early outward current in rat single ventricular cells. Circ Res 54:157–162
Kakei M, Noma A, Shibasaki T (1985) Properties of adenosinetriphosphate-regulated potassium channels in guinea-pig ventricular cells. J Physiol (Lond) 363:441–462
Kakei M, Yoshinaga M, Saito K, Tanaka H (1986) The potassium current activated by 2-nicotinamideoethyl nitrate (nicorandil) in single ventricular cells of guinea pigs. Proc R Soc Lond [Biol] 229:331–343
Kerr MJ, Wilson R, Shanks RG (1985) Suppression of ventricular arrhythmias after coronary artery ligation by pinacidil, a vasodilator drug. J Cardiovasc Pharmacol 7:875–883
Kohlhardt M, Krause H, Kubler M, Herdey A (1973) Kinetics of inactivation and recovery of the slow inward current in the mammalian ventricular myocardium. Pflügers Arch 355:1–17
Latorre R, Miller C (1983) Conductance and selectivity in potassium channels. J Membr Biol 71:11–30
Marban E, Tsien RW (1982) Effects of nystatin-mediated intracellular ion substitution on membrane currents in calf Purkinje fibres. J Physiol (Lond) 329:569–587
Matsuda H, Noma A (1984) Isolation of calcium current and its sensitivity to monovalent cations in dialysed ventricular cells of guinea-pig. J Physiol (Lond) 357:553–573
Nakayama T, Palfrey C, Fozzard HA (1988) Modulation of the cardiac transient outward current by catecholamines. Circ Res 62:162–172
Noma A, Shibasaki T (1985) Membrane current through adenosinetriphosphate-regulated potassium channels in guinea pig ventricular cells. J Physiol (Lond) 363:463–480
Osterrieder W (1988) Modification of K+ conductance of heart cell membrane by BRL 34915. Naunyn-Schmiedeberg's Arch Pharmacol 337:93–97
Osterrieder W, Yang Q-F, Trautwein W (1982) Effects of barium on the membrane currents in the rabbit S-A node. Pflügers Arch 394:78–84
Powell T, Twist VW (1976) A rapid technique for the isolation and purification of adult cardiac cells having respiratory control and tolerance to calcium. Biochem Biophys Res Commun 72:327–333
Quast U, Cook NS (1989) In vitro and in vivo comparison of two K+ channel openers, diazoxide and cromakalim, and their inhibition by glibenclamide. J Pharmacol Exp Therap 250:261–271
Quast U, Scholtysik G, Weir SW, Cook NS (1988) Pertussis toxin treatment does not inhibit the effects of the potassium channel opener BRL 34915 on rat isolated vascular and cardiac tissues. Naunyn-Schmiedeberg's Arch Pharmacol 337:98–104
Ribalet B, Eddlestone GT, Ciani S (1988) Metabolic regulation of the K(ATP) and a maxi-K(V) channel in the insulin-secreting RINm5F cell. J Gen Physiol 92:219–237
Ribalet B, Ciani S, Eddlestone GT (1989) Modulation of ATP-sensitive K channels in RINm5F cells by phosphorylation and G proteins. Biophys J 55:587a
Saigusa A, Matsuda H (1988) Outward currents through the inwardly rectifying potassium channel of guinea-pig ventricular cells. Jpn J Physiol 38:77–91
Sakmann B, Trube G (1984) Conductance properties of single inwardly rectifying potassium channels in ventricular cells from guinea-pig heart. J Physiol (Lond) 347:641–657
Sanguinetti MC, Scott AL, Zingaro GJ, Siegl PKS (1988) BRL 34915 (cromakalim) activates ATP-sensitive K+ current in cardiac muscle. Proc Natl Acad Sci USA 85:8360–8364
Schmid-Antomarchi H, De Weille J, Fosset M, Lazdunski M (1987) The receptor for antidiabetic sulfonylureas controls the activity of the ATP-modulated K+ channel in insulin-secreting cells. J Biol Chem 262:15840–15844
Shibasaki T (1987) Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart. J Physiol (Lond) 387:227–250
Smallwood JK, Steinberg MI (1988) Cardiac electrophysiological effects of pinacidil and related pyridylcyanoguanidines: relationship to antihypertensive activity. J Cardiovasc Pharmacol 12:102–109
Soejima M, Noma A (1984) Mode of regulation of the ACh-sensitive K channel by the muscarinic receptor in rabbit atrial cells. Pflügers Arch 400:424–431
Spruce AE, Standen NB, Stanfield PR (1987) Studies of the unitary properties of adenosine-triphosphate-regulated potassium channels of frog skeletal muscle. J Physiol (Lond) 382:213–236
Standen NB, Quayle JM, Davies NW, Brayden JE, Huang Y, Nelson MT (1989) Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science 245:177–180
Sturgess NC, Kozlowski RZ, Carrington CA, Hales CN, Ashford MLJ (1988) Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide-sensitive channels in an insulin-secreting cell line. Br J Pharmacol 95:83–94
Tseng G-N (1988) Calcium current restitution in mammalian ventricular myocytes is modulated by intracellular calcium. Circ Res 63:468–482
Tseng G-N, Hoffman BF (1989) Two components of transient outward current in canine ventricular myocytes. Circ Res 64:633–647
Tseng G-N, Robinson RB, Hoffman BF (1987) Passive properties and membrane currents of canine ventricular myocytes. J Gen Physiol 90:671–701
Walsh KB, Begenisich TB, Kass RS (1988) B-adrenergic modulation in the heart. Independent regulation of K and Ca channels. Pflügers Arch 411:232–234
Walsh JV, Singer JJ (1983) Ca++ -activated K+ channels in vertebrate smooth muscle cells. Cell Calcium 4:321–330
Williams DL Jr, Katz GM, Roy-Contancin L; Reuben JP (1988) Guanosine 5′-monophosphate modulates gating of high conductance Ca2+ -activated K+ channels in vascular smooth muscle cells. Proc Natl Acad Sci USA 85:9360–9364
Winquist RJ, Heaney LA, Wallace AA, Baskin EP, Stein RB, Garcia ML, Kaczorowski GJ (1989) Glyburide blocks the relaxation response to BRL 34915 (cromakalim), minoxidil sulfate and diazoxide in vascular smooth muscle. J Pharmacol Exp Ther 248:149–156
Yue DT, Marban E (1988) A novel cardiac potassium channel that is active and conductive at depolarized potentials. Pflügers Arch 413:127–133
Zunkler BJ, Lenzen S, Manner K, Panten U, Trube G (1988) Concentration-dependent effects of tolbutamide, meglitinide, glipizede, glibenclamide and diazoxide on ATP-regulated K+ currents in pancreatic B-cells. Naunyn-Schmiedeberg's Arch Pharmacol 337:225–230
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Tseng, G.N., Hoffman, B.F. Actions of pinacidil on membrane currents in canine ventricular myocytes and their modulation by intracellular ATP and cAMP. Pflügers Arch 415, 414–424 (1990). https://doi.org/10.1007/BF00373618
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DOI: https://doi.org/10.1007/BF00373618