Circulation Research, Vol 71, 673-688, Copyright © 1992 by American Heart Association

ARTICLES

Mechanisms for the positive inotropic effect of alpha 1-adrenoceptor stimulation in rat cardiac myocytes [published erratum appears in Circ Res 1993 Feb;72(2):489]

D Fedida and RA Bouchard
Department of Physiology, Queen's University, Kingston, Canada.

alpha 1-Adrenoceptor activation can enhance myocardial contractility, and two possible inotropic mechanisms are an increase in myofilament Ca2+ sensitivity and action potential prolongation, which can increase net Ca2+ entry into cells. In adult rat ventricular myocytes (bath Ca2+, 1 mM; stimulated at 0.2-0.5 Hz), the drug 4-aminopyridine and the whole-cell voltage clamp have been used to control Ca2+ entry and differentiate between the two mechanisms. At 22-23 degrees C the specific alpha 1-adrenoceptor agonist methoxamine (100 microM) prolonged action potential duration at 50% repolarization from 55 +/- 2 to 81 +/- 5 msec, delayed time to peak contraction, and increased shortening amplitude from 5.3 +/- 0.6 to 7.8 +/- 1 microns (n = 18). Reduction of the transient outward current and other K+ currents by methoxamine was the major cause of action potential prolongation in rat myocytes with little change in the L-type calcium current. Block of the transient outward current with 2 mM 4-aminopyridine prolonged action potential duration from 52 +/- 6 to 98 +/- 12 msec and increased unloaded cell shortening from 2.9 +/- 0.4 to 6.6 +/- 0.6 microns (n = 4). Subsequently, methoxamine no longer increased cell shortening, although significant potentiation of twitch amplitude was still seen after a brief rest interval. In voltage-clamp experiments, with 70-500- msec pulses, although membrane currents were reduced, methoxamine had no positive inotropic effect and reduced cell shortening from 5.3 +/- 0.7 to 4.97 +/- 0.8 microns at pulse potentials positive to -40 mV. Similar alpha 1-adrenoceptor responses were observed at 35 degrees C during action potential and voltage-clamp experiments, which could be blocked by 10 microM prazosin. In myocytes loaded with the Ca2+ indicator indo-1, alpha 1-adrenoceptor stimulation or 4-aminopyridine both increased cell contraction and intracellular Ca2+ transients by similar amounts. As in unloaded cells, prior exposure to 4- aminopyridine prevented any inotropic effect of methoxamine without changing the systolic intracellular Ca2+ transient. The results indicated that under our experimental conditions positive inotropy in rat cardiomyocytes on exposure to alpha 1-adrenoceptor agonists was strongly correlated with the action potential prolongation that accompanied K+ current reduction. In addition, modulation of K+ channels could occur independent of changes in contractility and/or [Ca2+]i.

This article has been cited by other articles:

				C. Putzke, K. Wemhoner, F. B. Sachse, S. Rinne, G. Schlichthorl, X. T. Li, L. Jae, I. Eckhardt, E. Wischmeyer, H. Wulf, et al. The acid-sensitive potassium channel TASK-1 in rat cardiac muscle Cardiovasc Res, July 1, 2007; 75(1): 59 - 68. [Abstract] [Full Text] [PDF]

				J. O-Uchi, K. Komukai, Y. Kusakari, T. Obata, K. Hongo, H. Sasaki, and S. Kurihara {alpha}1-Adrenoceptor stimulation potentiates L-type Ca2+ current through Ca2+/calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes PNAS, June 28, 2005; 102(26): 9400 - 9405. [Abstract] [Full Text] [PDF]

				C. Zobel, Z. Kassiri, T.-T. T. Nguyen, Y. Meng, and P. H. Backx Prevention of Hypertrophy by Overexpression of Kv4.2 in Cultured Neonatal Cardiomyocytes Circulation, October 29, 2002; 106(18): 2385 - 2391. [Abstract] [Full Text] [PDF]

				S. S. Po, R. C. Wu, G. J. Juang, W. Kong, and G. F. Tomaselli Mechanism of alpha -adrenergic regulation of expressed hKv4.3 currents Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2518 - H2527. [Abstract] [Full Text] [PDF]

				A. Descorps-Declere, M. P. Sauviat, K. Samii, and Y. Lecarpentier Mechanical and electrophysiological effects of thiopental on rat cardiac left ventricular papillary muscle Br. J. Anaesth., January 1, 2001; 86(1): 103 - 109. [Abstract] [Full Text] [PDF]

				K. Hu, D. Mochly-Rosen, and M. Boutjdir Evidence for functional role of epsilon PKC isozyme in the regulation of cardiac Ca2+ channels Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2658 - H2664. [Abstract] [Full Text] [PDF]

				S. Doi, D. S. Damron, K. Ogawa, S. Tanaka, M. Horibe, and P. A. Murray K+ channel inhibition, calcium signaling, and vasomotor tone in canine pulmonary artery smooth muscle Am J Physiol Lung Cell Mol Physiol, August 1, 2000; 279(2): L242 - L251. [Abstract] [Full Text] [PDF]

				B. M. Palmer, M. C. Olsson, J. M. Lynch, L. C. Mace, S. M. Snyder, S. Valent, and R. L. Moore Chronic run training suppresses alpha -adrenergic response of rat cardiomyocytes and isovolumic left ventricle Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2136 - H2144. [Abstract] [Full Text] [PDF]

				T. Volk, T. H.-D. Nguyen, J.-H. Schultz, and H. Ehmke Relationship between transient outward K+ current and Ca2+ influx in rat cardiac myocytes of endo- and epicardial origin J. Physiol., September 15, 1999; 519(3): 841 - 850. [Abstract] [Full Text] [PDF]

				W. Kong, S. Po, T. Yamagishi, M. D. Ashen, G. Stetten, and G. F. Tomaselli Isolation and characterization of the human gene encoding Ito: further diversity by alternative mRNA splicing Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H1963 - H1970. [Abstract] [Full Text] [PDF]

				W. H. duBell, S. T. Gaa, W. J. Lederer, and T. B. Rogers Independent inhibition of calcineurin and K+ currents by the immunosuppressant FK-506 in rat ventricle Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2041 - H2052. [Abstract] [Full Text] [PDF]

				O. Zolk, M. Flesch, G. Nickenig, P. Schnabel, and M. Bohm Alteration of intracellular Ca2+-handling and receptor regulation in hypertensive cardiac hypertrophy: insights from Ren2-transgenic rats Cardiovasc Res, July 1, 1998; 39(1): 242 - 256. [Abstract] [Full Text] [PDF]

				S. J. Liu and R. H. Kennedy alpha 1-Adrenergic activation of L-type Ca current in rat ventricular myocytes: perforated patch-clamp recordings Am J Physiol Heart Circ Physiol, June 1, 1998; 274(6): H2203 - H2207. [Abstract] [Full Text] [PDF]

				M. Stengl, K. Mubagwa, E. Carmeliet, and W. Flameng Phenylephrine-induced stimulation of Na+/Ca2+ exchange in rat ventricular myocytes Cardiovasc Res, June 1, 1998; 38(3): 703 - 710. [Abstract] [Full Text] [PDF]

				A. D Wickenden, R. Kaprielian, Z. Kassiri, J. N Tsoporis, R. Tsushima, G. I Fishman, and P. H Backx The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure Cardiovasc Res, February 1, 1998; 37(2): 312 - 323. [Abstract] [Full Text] [PDF]

				Z.-H. Zhang, J. A. Johnson, L. Chen, N. El-Sherif, D. Mochly-Rosen, and M. Boutjdir C2 Region–Derived Peptides of ß-Protein Kinase C Regulate Cardiac Ca2+ Channels Circ. Res., May 19, 1997; 80(5): 720 - 729. [Abstract] [Full Text]

				G.-R. Li, J. Feng, Z. Wang, B. Fermini, and S. Nattel Adrenergic Modulation of Ultrarapid Delayed Rectifier K+ Current in Human Atrial Myocytes Circ. Res., May 1, 1996; 78(5): 903 - 915. [Abstract] [Full Text]

				K. T. Strang and R. L. Moss {alpha}1-Adrenergic Receptor Stimulation Decreases Maximum Shortening Velocity of Skinned Single Ventricular Myocytes From Rats Circ. Res., July 1, 1995; 77(1): 114 - 120. [Abstract] [Full Text]

				R. A. Bouchard, R. B. Clark, and W. R. Giles Effects of Action Potential Duration on Excitation-Contraction Coupling in Rat Ventricular Myocytes : Action Potential Voltage-Clamp Measurements Circ. Res., May 1, 1995; 76(5): 790 - 801. [Abstract] [Full Text]

				W. H. duBell, M. S. Gigena, S. Guatimosim, X. Long, W. J. Lederer, and T. B. Rogers Effects of PP1/PP2A inhibitor calyculin A on the E-C coupling cascade in murine ventricular myocytes Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H38 - H48. [Abstract] [Full Text] [PDF]