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OCT2013, an ischaemia‐activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine
Author(s) -
Hesketh Louise M.,
Sikkel Markus B.,
MahoneySanchez Laura,
Mazzacuva Francesca,
Chowdhury Rasheda A.,
Tzortzis Konstantinos N.,
Firth Jahn,
Winter James,
MacLeod Kenneth T.,
Ogrodzinski Stefan,
Wilder Catherine D. E.,
Patterson Laurence H.,
Peters Nicholas S.,
Curtis Michael J.
Publication year - 2022
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15764
Subject(s) - lidocaine , medicine , anesthesia , antiarrhythmic agent , ventricular fibrillation , ischemia , pharmacology , asystole , anti arrhythmia agents , bradycardia , adverse effect , cardiology , heart rate , atrial fibrillation , heart disease , blood pressure
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 Ca 2+ 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.