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J Thorac Cardiovasc Surg 1998;115:190-199
© 1998 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

Downstream defects in ß-adrenergic signaling and relation to myocyte contractility after cardioplegic arrest

From the Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, S.C.

Address for reprints: Francis G. Spinale, MD, PhD, CardiothoracicSurgery, Room 418 CSB, Medical University of South Carolina, Charleston, SC29425.

Abstract

Objective: Transientleft ventricular dysfunction can occur after hypothermic, hyperkalemic cardioplegicarrest and is associated with decreased ß-adrenergic receptor responsiveness.Occupancy of the ß-adrenergic receptor activates adenylate cyclase, whichphosphorylates the L-type Ca²⁺ channel–enhancing myocytecontractility. The goal of this study was to identify potential mechanismsthat contribute to the defects in the ß-adrenergic receptor signalingcascade after cardioplegic arrest.
Methods:Isolated left ventricular porcine myocytes were assigned to one of two treatmentgroups: (1) cardioplegic arrest (24 mEq/L K⁺, 4° C x2 hours, then 5 minutes in 37° C cell media; n =130) or (2) normothermic control (cell media, 37° C x 2 hours; n = 222). Myocyte contractility was assessed atbaseline and after either ß-adrenergic receptor occupancy (25 nmol/Lisoproterenol [INN: isoprenaline]), activation of adenylate cyclase (0.5 µmolforskolin), or direct activation of the L-type Ca²⁺-channel (10nmol/L or 100 nmol/L (–)BayK 8644).
Results:Myocyte velocity of shortening (µm/sec) was increased with ß-adrenergicreceptor occupancy or direct adenylate cyclase stimulation compared with baselinein the normothermic group (187.3 ± 6.9, 181.7 ± 10.2,and 73.9 ± 2.9, respectively; p <0.0001) and after cardioplegic arrest (128.6 ± 8.9, 124.3 ±9.4, and 46.1 ± 2.6, respectively; p <0.0001). However, the response after cardioplegic arrest was significantlyreduced compared with normothermic values under all conditions (p = 0.012). Direct activation of the L-type Ca²-channel, which eliminates ß-adrenergic receptor–dependentevents, increased myocyte contractility in the normothermic group (161.90 ±12.0, p < 0.0001) and after cardioplegicarrest (92.78  ± 6.8, p <0.0001), but the positive inotropic response appeared reduced compared withnormothermic control values (p = 0.003).
Conclusion: These findings suggest that contributorymechanisms for the reduced ß-adrenergic receptor–mediated responseafter hypothermic, hyperkalemic cardioplegic arrest lie downstream from thesespecific components of the transduction pathway and likely include defectsin Ca²⁺ homeostasis, myofilament Ca²⁺ sensitivity, orboth.

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