Abstract
The goal of the present study was to further characterize the effects of the novel cardioprotective agent BMS-180448 on potassium fluxes in cardiac and vascular smooth muscle. Exposure of voltage-clamped guinea pig ventricular myocytes to BMS-180448 (300 μM) produced an inhibition of IK followed by the delayed (5.5 ± 0.5 min) activation of a large time-independent potassium current. At 100 μM, BMS-180448 produced only inhibition of IK. The BMS-180448 activated current was refractory to block by 30 μM, glyburide but was largely inhibited by 100 μM alinidine (84 ± 6% inhibition at + 40 mV). Cromakalim (100 μM)-activated currents were fully inhibited by 3 μM, glyburide and 79 ± 4% blocked by 100 μM alinidine. The current responses to BMS-180448 were unaffected by the inclusion of 10 mM UDP (100 μM, ATP) in the pipette. BMS-180448 also produced a concentrationdependent increase in 86Rb efflux from aortic strips; efflux responses were increased in low calcium medium and fully antagonized by 3 μM, glyburide. Thus, BMS-180448 activates a potassium conductance in both cardiac and smooth muscle. The glyburide sensitivity of the BMS-180448-induced increase in 86Rb efflux from the aortic preparations suggests that this drug activates IKATP in vascular smooth muscle. Moreover, the observation that BMS-180448 (100 μM) partially inhibits the effects of cromakalim in ventricular muscle cells suggests that these drugs interact, directly or indirectly, with a common site in cardiac muscle.
Similar content being viewed by others
References
Atwal KS, Grover GJ, Ahmed SZ, Ferrara FN, Harper TW, Kim KS, Sleph PG, Dzwonczyk S, Russel AD, Moreland S, McCullough JR, Normandin DE (1993) Cardioselective anti-ischemic ATP-sensitive potassium channel openers. J Med Chem 36: 3971–3974
Auchampach JA, Maruyama M, Cavero I, Gross GJ (1991) The new K+ channel opener aprikalim (RP 52891) reduces experimental infarct size in dogs in the absence of hemodynamic changes. J Pharmacol Exp Ther 259:961–967
BoSmith RE, Briggs I, Sturgess NC (1993) Inhibitory actions of ZENECA ZD7288 on whole-cell hyperpolarization activated inward current (If) in guinea-pig dissociated sinoatrial node cells. Br J Pharmacol 110:343–349
Bouman LN, Duivenoorden JJ, Opthof T, Treijtel BW (1984) Electrophysiological effects of alinidine on nodal and atrial fibres in the guinea-pig heart. J Pharmacol Exp Ther 229:551–556
Coldwell MC, Howlett DR (1988) Potassium efflux enhancement by cromakalim (BRL 34915) in rabbit mesenteric artery: an indirect effect independent of calcium? Biochem Pharmacol 37: 4105–4110
D'Alonzo AJ, Darbenzio RB, Sewter JC, Hess TA, Grover GJ, Sleph PG, Normandin DE, Lodge NJ (1995) A comparison between the effects of BMS-180448, a novel K+ channel opener, and cromakalim in rat and dog. Eur J Pharmacol 294:271–280
Fan Z, Nakayama K, Hiraoka M (1990) Multiple actions of pinacidil on adenosine triphosphate-sensitive potassium channels in guinea-pig ventricular myocytes. J Physiol 430:273–295
Findlay I (1992) Inhibition of ATP-sensitive K+ channels in cardiac muscle by the sulphonylurea drug glibenclamide. J Pharmacol Exp Ther 261:540–545
Findlay I (1993) Sulphonylurea drugs no longer inhibit ATP-sensitive K+ channels during metabolic stress in cardiac muscle. J Pharmacol Exp Ther 266:456–476
Grover GJ, McCullough JR, Henry DE, Conder ME, Sleph PG (1989) Anti-ischemic effects of the potassium channel activators pinacidil and cromakalim and the reversal of the effects with the potassium channel blocker glyburide. J Pharmacol Exp Ther 251:98–104
Grover GJ, Dzwonczyk S, Sleph PG (1990) Reduction of ischemic damage in isolated rat hearts by the potassium channel opener, RP 52891. Eur J Pharmacol 191:11–18
Grover GJ, McCullough JR, D'Alonzo AJ, Sargent CA, Atwal KS (1995) Cardioprotective profile of the cardiac-selective ATP-sensitive potassium channel opener BMS-180448. J Cardiovasc Pharm 25:40–50
Guillemare E, Lazdunski M, Honore E (1995) Gilbenclamide opens ATP-sensitive potassium channels in Xenopus oocyte follicular cells during metabolic stress. Mol Pharmacol 47:588–594
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high resolution current recording from cells and cell-free membrane patches. Pflügers Arch 395:85–100
Ibbotson T, Edwards G, Noack Th, Weston AH (1993) Effects of P1060 and aprikalim on whole-cell currents in rat portal vein; inhibition by glybenclamide and phentolamine. Br J Pharmacol 108:991–998
Jonas JC, Plant TD, Henquin JC (1992) Imidazoline antagonists of alpha 2-adrenoceptors increase insulin release in vitro by inhibiting ATP-sensitive K+ channels in pancreatic beta cells. Br J Pharmacol 107:8–14
Kameyama MF, Hofman F, Trautwein W (1985) On the mechanism of β-adrenergic regulation of the Ca channel in the guinea pig heart. Pflügers Arch 405:285–293
Kamigaki M, Ichihara K, Abiko Y (1994) Enhancement of ischemic myocardial metabolic derangement by glybenclamide. Jpn J Pharmacol 65:121–129
Lederer WJ, Nichols CG (1989) Nucleotide modulation of the activity of rat heart ATP-sensitive K+ channels in isolated membrane patches. J Physiol 419:193–211
Lee K, Groh WJ, Blair TA, Maylie JG, Adelman JP (1995) Imidazoline compounds inhibit KATP channels in guinea pig ventricular myocytes. Eur J Pharmacol 285:309–312
Lodge NJ, Halaka N (1993) 8-(Diethlamino)-Octl-3,4,5-Trimethoxybenzoate inhibits cromakalim-induced 86Rb efflux from the rat aorta. J Pharmacol Exp Ther 265:1399–1405
Lodge NJ, Cohen RB, Havens CN, Colatsky TJ (1991) The effects of the putative potassium channel activator WAY-120,491 on 86Rb efflux from the rabbit aorta. J Pharmacol Exp Ther 256:639–644
Lodge NJ, Colatsky TJ, Cullinan CA, Follmer CH (1992) Electromechanical effects of the putative potassium channel activator celikalim (WAY-120,491) on feline atrial and ventricular muscle. J Pharmacol Exp Ther 261:1153–1159
Notsu T, Tanaka I, Takano M, Noma A (1992) Blockade of the ATP-sensitive K+ channels by 5-hydroxydecanoate in guinea pig ventricular myocytes. J Pharmacol Exp Ther 260:702–708
Okabe K, Kajioka S, Nakao K, Kitamura K, Kuriyama H, Weston AH (1990) Actions of cromakalim on ionic currents recorded from single smooth muscle cells of the rat portal vein. J Pharmacol Exp Ther 252:832–839
Post JM, Smith JM, Jones AW (1989) BRL 34915 (cromakalim) stimulation of 42K efflux from rabbit arteries is modulated by calcium. J Pharmacol Exp Ther 250:591–597
Sakuta H, Okamoto K (1994) Inhibition by imidazoline derivatives of glibenclamide-sensitive K+ currents in Xenopus oocytes. Eur J Pharmacol 259:223–231
Sanguinetti MC, Jurkiewicz NK (1990) Two components of cardiac delayed rectifier K+ current. J Gen Physiol 96:195–215
Terzic A, Jahangir A, Kurachi Y (1994) HOE-234, a second generation K+ opener, antagonizes the ATP-dependent gating of cardiac ATP-sensitive K+ channels. J Pharmacol Exp Ther 268:818–825
Tung RT, Kurachi Y (1991) On the mechanism of nucleotide diphosphate activation of the ATP-sensitive K+ channel in ventricular cell of guinea-pig. J Physiol 437:239–256
Yao Z, Gross GJ (1994a) Effects of the KATP channel opener bimakalim on coronary blood flow, monophasic action potential duration, and infarct size in dogs. Circulation 89:1769–1775
Yao Z, Gross GJ (1994b) Activation of ATP-sensitive potassium channels lowers threshold for ischemic preconditioning in dogs. Am J Physiol 267:H1888-H1894
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lodge, N.J., Smith, M.A. The novel cardioprotective agent BMS-180448 activates a potassium conductance in cardiac and vascular smooth muscle. Naunyn-Schmiedeberg's Arch Pharmacol 354, 444–451 (1996). https://doi.org/10.1007/BF00168435
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00168435