Downloaded from https://journals.lww.com/anesthesia-analgesia by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3ltH2fbMApE1PlBTIOXwTzcPwiyoHUTorfZ7oLvXrPRk= on 11/03/2018 Myocyte Endothelin Exposure During Cardioplegic Arrest Exacerbates Contractile Dysfunction After Reperfusion B. Hugh Dorman, MD, PhD*, R. Brent New, MD†, Brian R. Bond, PhD*, Rupak Mukherjee, PhD†, Y. V. Mukhin, PhD‡, James H. McElmurray, BS†, and Francis G. Spinale, MD, PhD† Departments of *Anesthesia & Perioperative Medicine, †Cardiothoracic Surgery, and ‡Medicine, Medical University of South Carolina, Charleston, South Carolina Transient left ventricular (LV) dysfunction can occur after cardioplegic arrest. The contributory mecha- nisms for this phenomenon are not completely un- derstood. We tested the hypothesis that exposure of LV myocytes to endothelin (ET) during simulated cardioplegic arrest would have direct effects on con- tractile processes with subsequent reperfusion. LV porcine myocytes were randomly assigned to three groups: 1) Control: normothermic (37°C) cell media (n = 204); 2) Cardioplegia: simulated cardioplegic ar- rest (K + 24 mEq/L, 4°C  2 h) followed by reperfu- sion and rewarming with cell media (n = 164); and 3) Cardioplegia/ET: simulated cardioplegic arrest in the presence of ET (200 pM) followed by reperfusion with cell media containing ET (n = 171). Myocyte contractility was measured by computer-assisted video microscopy. In a subset of experiments, myo- cyte intracellular calcium was determined after Fluo-3 (Molecular Probes, Eugene, OR) loading by digital fluorescence image analysis. Myocyte short- ening velocity was reduced after cardioplegic arrest compared with controls (52  2 vs 84  3 m/s, re- spectively; P  0.05) and was further reduced with cardioplegic arrest and ET exposure (43  2 m/s, P  0.05). Intracellular calcium was significantly in- creased in myocytes exposed to cardioplegia com- pared with normothermic control myocytes and was further augmented by cardioplegia with ET supple- mentation (P  0.05). Exposure of the LV myocyte to ET during cardioplegic arrest directly contributed to contractile dysfunction after reperfusion. Moreover, alterations in intracellular calcium may play a role in potentiatiing the myocyte contractile dysfunction as- sociated with ET exposure during cardioplegic ar- rest. (Anesth Analg 2000;90:1080 –5) H ypothermic, hyperkalemic cardioplegic arrest is a common means of providing a quiescent heart during cardiac surgery. Although transient left ventricular (LV) dysfunction can occur after cardiople- gic arrest, the contributory mechanisms for this phe- nomenon are not completely understood. A number of hemodynamic and neurohormonal changes occur during cardioplegic arrest and after separation from cardiopulmonary bypass (CPB) which can in turn in- fluence LV pump function (1–3). Specifically, the in- duction of cardioplegic arrest and institution of CPB has been associated with increased levels of the potent vasoactive peptide, endothelin (ET) (3,4). ET causes increased vascular resistance and has been implicated in influencing LV myocyte contractility (5– 8). For ex- ample, several studies have demonstrated that ET caused a negative inotropic effect in animal models of chronic LV pump failure (8). However, whether and to what degree changes in ET levels can specifically in- fluence myocyte contractile properties in the setting of cardioplegic arrest has not been defined. Therefore, we tested the central hypothesis that exposure of LV myocytes to ET during simulated cardioplegic arrest would result in negative effects on contractile perfor- mance with subsequent reperfusion and rewarming. The early reperfusion and rewarming period after car- dioplegic arrest is associated with changes in LV loading conditions and neurohormonal system activation (1–3). These multiple systemic effects, which are operative in vivo, preclude the ability to specifically identify how ET may influence LV myocardial contractility in the setting of cardioplegic arrest. This laboratory has previously described an isolated LV myocyte system which simu- lates cardioplegic arrest and rewarming (9). This in vitro system of cardioplegic arrest is well suited to define specific mechanisms that may contribute to LV myocyte Supported by a National American Heart Association Grant-in- Aid and National Institute of Health Grants HL-56603 and HL- 45024. FGS is an Established Investigator of the AHA. Accepted for publication January 31, 2000. Address correspondence and reprint requests to B. Hugh Dorman, MD, PhD, Department of Anesthesia & Perioperative Medicine, Medical University of South Carolina, 165 Ashley Ave., Suite 525, PO Box 250912, Charleston, SC 29425. Address e-mail to dormanhb@musc.edu. ©2000 by the International Anesthesia Research Society 1080 Anesth Analg 2000;90:1080–5 0003-2999/00