Abstract
A dual approach was employed to study β-adrenergic receptor signal transduction in post ischemic (stunned) myocardium, examining physiological interventions in awake, chronically instrumented pigs and biochemical, cellular mechanisms in sarcolemmal preparations from the stunned hearts using the contralateral non-ischemic zone as a control. Ten min of coronary artery occlusion (CAO) and 30 min coronary artery reperfusion (CAR) resulted in depressed posterior wall-thickening (myocardial stunning). Isoproterenol increased transmural wall thickening more in stunned myocardium than in non-ischemic myocardium. In contrast, the responses of wall thickening to forskolin, actually decreased during stunning compared with control. NKH 477, a water soluble forskolin derivative, that does not activate cardiac nerves, increased wall thickening in non-ischemic tissue similarly to the effects on stunned myocardium. Increasing cardiac neural tone reflexly with inferior venal caval occlusion (IVCO) elicited similar results to forskolin, i.e., stunned myocardium responded with less of an increase in wall thickening as compared with non-ischemic myocardium. β-adrenergic receptor density, as determined with 125I-cyanopindolol binding, was significantly increased in stunned subendocardium and subepicardium compared with respective values in non-ischemic myocardium. There were no differences in the response of adenylyl cyclase to isoproterenol in stunned and non-ischemic myocardium. The enhanced responsiveness of the β-adrenergic receptor to isoproterenol stimulation in stunned myocardium corresponded to the increase in β-adrenergic receptor density. The combination of enhanced responses to isoproterenol, and decreased responses to forskolin and to IVCO and preserved responsiveness to NKH 477, suggest that stunned myocardium is characterized by transient sympathetic neural stunning. The enhanced sensitivity to β-adrenergic receptor stimulation has important clinical implications, both in terms of therapy of stunned myocardium and detection of stunned and /or hibernating myocardium, i.e., low dose dobutamine echocardiography.
Similar content being viewed by others
References
Sato S, Sato N, Kudej RK, Uechi M, Asai K, Shen Y-T, Ishikawa Y, Vatner SF, Vatner DE: β-Adrenergic receptor signalling in stunned myocardium of conscious pigs. J Mol Cell Cardiol 29: 1387–1400, 1997
Vatner DE, Sato S, Vatner SF, Stasser RH: Sympathetic signal transduction in myocardial ischemia. In: GR Heyndrickx, SF Vatner, WC Wijns, (eds). Stunning, Hibernation and Preconditioning: Clinical Pathophysiology of Myocardial Ischemia. Lippincott-Raven, Philadelphia, New York, 1997, pp 31–48
Iwase M, Ishikawa Y, Shen Y-T, Shannon RP, Sato N, Ganguly PK, Eki T, Vatner DE, Vatner SF: Neurally mediated cardiac effects of forskolin in conscious dogs. Am J Physiol 271 (Heart Circ Physiol 40): H1473–H1482, 1996
Eckstein RW: Coronary interarterial anastomoses in young pigs, and mongrel dogs. Circ Res 2: 460–465, 1954
Patterson RE, Kirk ES: Analysis of coronary collateral structure, function, and ischemic border zones in pigs. Am J Physiol 244 (Heart Circ Physiol 13): H23–H31, 1983
Shen Y-T, Vatner SF: Differences in myocardial stunning following coronary artery occulsion in conscious dogs, pigs and baboons. Am J Physiol 270: H1312–H1322, 1996
Munson RJ, Rodbard D: LIGAND: A versatile computerized approach for characterization of ligand-binding systems. Anal Biochem 107: 220–239, 1980
Ambrosio G, Jacobus WE, Bergman CA, Weisman HF, Becker LC: Preserved high energy phosphate metabolic reserve in globally 'stunned’ hearts despite reduction of basal ATP content and contractility. J Mol Cell Cardiol 19: 953–964, 1987
Bolli R, Zhu W-X, Myers MD, Hartley CJ, Roberts R: Beta-adrenergic stimulation reverses postischemic myocardial dysfunction without producing subsequent functional deterioration. Am J Cardiol 56: 964–968, 1985
Chiu WC, Kedem J, Scholz PM, Weiss HR: Regional asynchrony of segmental contraction may explain the ‘oxygen consumption paradox’ in stunned myocardium. Basic Res Cardiol 89: 149–162, 1994
Becker LC, Levine JH, DiPaula AF, Guarnieri T, Aversano T: Reversal of dysfunction in postischemic stunned myocardium by epinephrine and postextrasystolic potentiation. J Am Coll Cardiol 7: 580–589, 1986
Gorge G, Papageorgiou I, Lerch R: Epinephrine-stimulated contractile and metabolic reserve in postischemic rat myocardium. Basic Res Cardiol 85: 595–605, 1990
Ciuffo AA, Ouyang P, Becker LC, Levin L, Weisfeldt ML: Reduction of sympathetic inotropic response after ischemia in dogs: Contributor to stunned myocardium. J Clin Invest 75: 1504–1509, 1985
Fan D, Soei LK, Sassen LMA, Krams R, Verdouw PD: Mechanical efficiency of stunned myocardium is modulated by increased afterload dependency. Cardiovasc Res 29: 428–437, 1995
Hashimoto T, Buxton DB, Krivokapick J, Hansen HW, Phelps MD, Schelbert HR: Responses of blood flow, oxygen consumption, and contractile function to inotropic stimulation in stunned canine myocardium. Am Heart J 126: 347–351, 1994
Krams R, Soei LK, McFalls EO, Prins EAW, Sassen LMA, Verdouw PD: End-systolic pressure length relations of stunned right and left ventricles after inotropic stimulation. Am J Physiol 265: H2099–H2109, 1993
Watanabe S, Buffington CW: Electromechanical association in regionally stunned swine myocardium. Anesthesiology 79: 1266–1277, 1993
Zhou Z, Laskey RD, Hegge JO, Bunger R, Mentzer RM: Myocardial stunning: A therapeutic conundrum. J Thorac Cardiovas Surg 110: 1391–1401, 1995
Mercier JC, Lando U, Kanmatsuse K, Ninomiya K, Meerbaum S, Fishbein MD, Swan HJC, Ganz W: Divergent effects of inotropic stimulation on the ischemic and severely depressed reperfused myocardium. Circulation 66: 397–400, 1982
La Canna G, Alfieri O, Giubbini R, Gargano M, Ferrari R, Visioli O: Echocardiography during infusion of dobutamine for identification of reversible dysfunction in patients with chronic coronary artery disease. J Am Coll Cardiol 23: 617–626, 1994
Susanni EE, Manders WT, Knight DR, Vatner DE, Vatner SF, Homcy CJ: One hour of myocardial ischemia decreases the activity of the stimulatory guanine-nucleotide regulatory protein Gs. Circ Res 65(4): 1145–1150, 1989
Vatner DE, Young MA, Knight DR, Vatner SF: Beta-receptors and adenylate cyclase: Comparison of nonischemic, ischemic, and postmortem tissue. Am J Physiol 258: H140–H144, 1990
Vatner DE, Kiuchi K, Manders WT, Vatner SF: Effects of coronary arterial reperfusion on α-adrenergic receptor-adenylyl cyclase coupling. Am J Physiol 264: H196–H204, 1993
Strasser RH, Marquetant R, Kubler W: Adrenergic receptors and sensitization of adenylyl cyclase in acute myocardial ischemia. Circulation 82 (Suppl P):23–29, 1990
Strasser RH, Marquetant R: Supersensitivity of the adenylyl cyclase system in acute myocardial ischemia: Evaluation of three independent mechanisms. Basic Res Cardiol 85 (Suppl 1): 67–78, 1990
Strasser RH, Krimmer J, Braun-Dullaeus R, Marquetant R, Kubler W: Dual sensitization of the adrenergic system in early myocardial ischemia: Independent regulation of the α-adrenergic receptors and adenylyl cyclase. J Mol Cell Cardiol 22(12): 1405–1423, 1990
Strasser RH, Marquetant R, Kubler W: Independent sensitization of beta-adrenoceptors and adenylate cyclase in acute myocardial ischaemia. British J Clin Pharmacol 30 (Suppl 1): 27S–35S, 1990
Gutterman DD, Morgan DA, Miller FJ: Effect of brief myocardial ischemia on sympathetic coronary vasoconstriction. Circ Res 71(4): 960–969, 1992
Hageman GR, Gantenberg NS: Attenuation of baroreflex changes in cardiac sympathetic efferent activities during acute myocardial ischemia. Am Heart J 126: 347–351, 1993
Inoue H, Zipes DP: Time course of denervation of efferent sympathetic and vagal nerves after occlusion of the coronary artery in the canine heart. Circ Res 62(6): 1111–1120, 1988
Neely BH, Hageman GR: Differential cardiac sympathetic activity during acute myocardial ischemia. Am J Physiol 258: H1534–H1541, 1990
Ninomiya I, Matsukawa K, Honda T, Nishiura N, Shirai M: Cardiac sympathetic nerve activity and heart rate during coronary occlusion in awake cats. Am J Physiol 251: H528–H537, 1986
Vatner DE: Characterization of the subfractions from a purified sarcolemma preparation of canine left ventricle. J Mol Cell Cardiol 22: 1349–1357, 1990
Maisel AS, Motulsky HJ, Insel PA: Externalization of α-adrenergic receptors promoted by myocardial ischemia. Science 230: 183–186, 1985
Hartzell HC, Mery P-F, Fischmeister R, Szabo G: Sympathetic regulation of cardiac calcium current is due exclusively to cAMPdependent phosphorylation. Nature 351: 573–576, 1991
Yatani A, Codina J, Imoto Y, Reeves JP, Birnbaumer L, Brown AM: A G protein directly regulates mammalian cardiac calcium channels. Science 238: 1288–1292, 1987
Iwase M, Bishop SP, Uechi M, Vatner DE, Shannon RP, Kudej RK, Wight DC, Wagner TE, Ishikawa Y, Homcy CJ, Vatner SF: Adverse effects of chronic endogenous sympathetic drive induced by cardiac Gs alpha overexpression. Circ Res 78(4): 517–524, 1996
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Vatner, D.E., Vatner, S.F. Physiological and biochemical adrenergic regulation of the stunned myocardium. Mol Cell Biochem 186, 131–137 (1998). https://doi.org/10.1023/A:1006831700336
Issue Date:
DOI: https://doi.org/10.1023/A:1006831700336