TY - JOUR
T1 - OCT2013, AN ISCHAEMIA-ACTIVATED ANTIARRHYTHMIC PRODRUG, DEVOID OF THE SYSTEMIC SIDE EFFECTS OF LIDOCAINE
AU - Hesketh, Louise M.
AU - Sikkel, Markus B.
AU - Mahoney-Sanchez, Laura
AU - Mazzacuva, Francesca
AU - Chowdhury, Rasheda A.
AU - Tzortzis, Konstantinos N
AU - Firth, Jahn
AU - Winter, James
AU - MacLeod, Kenneth T.
AU - Ogrodzinski, Stefan
AU - Wilder, Catherine D.E.
AU - Patterson, Laurence H.
AU - Peters, Nicholas S.
AU - Curtis, Michael
N1 - Funding Information:
No non-author contributions to acknowledge. Funding was supplied by The Academy of Medical Sciences and Medical Research Council.
Publisher Copyright:
© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2022/5
Y1 - 2022/5
N2 - Background and Purpose: Sudden cardiac death (SCD) caused by acute myocardial ischaemia and ventricular fibrillation (VF) is an unmet therapeutic need. Lidocaine suppresses ischaemia‐induced VF, but its utility is limited by side effects and a narrow therapeutic index. Here, we characterise OCT2013, a putative ischaemia‐activated prodrug of lidocaine. Experimental Approach: The rat Langendorff‐perfused isolated heart, anaesthetised rat and rat ventricular myocyte preparations were utilised in a series of blinded and randomised studies to investigate the antiarrhythmic effectiveness, adverse effects and mechanism of action of OCT2013, compared with lidocaine. Key Results: In isolated hearts, OCT2013 and lidocaine prevented ischaemia‐induced VF equi‐effectively, but OCT2013 did not share lidocaine's adverse effects (PR widening, bradycardia and negative inotropy). In anaesthetised rats, i.v. OCT2013 and lidocaine suppressed VF and increased survival equi‐effectively; OCT2013 had no effect on cardiac output even at 64 mg·kg−1 i.v., whereas lidocaine reduced it even at 1 mg·kg−1. In adult rat ventricular myocytes, OCT2013 had no effect on Ca2+ handling, whereas lidocaine impaired it. In paced isolated hearts, lidocaine caused rate‐dependent conduction slowing and block, whereas OCT2013 was inactive. However, during regional ischaemia, OCT2013 and lidocaine equi‐effectively hastened conduction block. Chromatography and MS analysis revealed that OCT2013, detectable in normoxic OCT2013‐perfused hearts, became undetectable during global ischaemia, with lidocaine becoming detectable. Conclusions and Implications: OCT2013 is inactive but is bio‐reduced locally in ischaemic myocardium to lidocaine, acting as an ischaemia‐activated and ischaemia‐selective antiarrhythmic prodrug with a large therapeutic index, mimicking lidocaine's benefit without adversity.
AB - Background and Purpose: Sudden cardiac death (SCD) caused by acute myocardial ischaemia and ventricular fibrillation (VF) is an unmet therapeutic need. Lidocaine suppresses ischaemia‐induced VF, but its utility is limited by side effects and a narrow therapeutic index. Here, we characterise OCT2013, a putative ischaemia‐activated prodrug of lidocaine. Experimental Approach: The rat Langendorff‐perfused isolated heart, anaesthetised rat and rat ventricular myocyte preparations were utilised in a series of blinded and randomised studies to investigate the antiarrhythmic effectiveness, adverse effects and mechanism of action of OCT2013, compared with lidocaine. Key Results: In isolated hearts, OCT2013 and lidocaine prevented ischaemia‐induced VF equi‐effectively, but OCT2013 did not share lidocaine's adverse effects (PR widening, bradycardia and negative inotropy). In anaesthetised rats, i.v. OCT2013 and lidocaine suppressed VF and increased survival equi‐effectively; OCT2013 had no effect on cardiac output even at 64 mg·kg−1 i.v., whereas lidocaine reduced it even at 1 mg·kg−1. In adult rat ventricular myocytes, OCT2013 had no effect on Ca2+ handling, whereas lidocaine impaired it. In paced isolated hearts, lidocaine caused rate‐dependent conduction slowing and block, whereas OCT2013 was inactive. However, during regional ischaemia, OCT2013 and lidocaine equi‐effectively hastened conduction block. Chromatography and MS analysis revealed that OCT2013, detectable in normoxic OCT2013‐perfused hearts, became undetectable during global ischaemia, with lidocaine becoming detectable. Conclusions and Implications: OCT2013 is inactive but is bio‐reduced locally in ischaemic myocardium to lidocaine, acting as an ischaemia‐activated and ischaemia‐selective antiarrhythmic prodrug with a large therapeutic index, mimicking lidocaine's benefit without adversity.
UR - http://www.scopus.com/inward/record.url?scp=85122781753&partnerID=8YFLogxK
U2 - 10.1111/bph.15764
DO - 10.1111/bph.15764
M3 - Article
SN - 0007-1188
VL - 179
SP - 2037
EP - 2053
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 9
ER -