Novel monohydroxamate drugs attenuate myocardial reperfusion-induced arrhythmias.
The novel monohydroxamates N-methyl hexanoylhydroxamic acid, N-methyl acetohydroxamic acid, and N-methyl butyrohydroxamic acid have antioxidant and iron chelating properties. They attenuated reperfusion-induced contractile dysfunction following long periods of ischaemia (50 min) in the isolated rat heart. Here we compare their effects and that of the trihydroxamate desferrioxamine on reperfusion-induced arrhythmias following short duration ischaemia (10 min). Isolated rat hearts were perfused by the Langendorff method, subjected to regional ischaemia and reperfusion. Arrhythmias induced during the first 5 min of reperfusion were quantified. Drugs (all at 150 microM) were introduced during the last 2 min of ischaemia and remained throughout reperfusion. Although the monohydroxamate- and desferrioxamine-treated hearts showed a reduction in the incidence of ventricular tachycardia and fibrillation, only the reduction in the incidence of sustained fibrillation ( > 3 min duration) in N-methyl acetohydroxamic acid--(27%), N-methyl hexanoylhydroxamic acid--(27%) and desferrioxamine-treated hearts (20%) was statistically significant (p < 0.05 vs control 73%; n = 15). There was a reduction in the severity of the arrhythmias, manifest as a significant increase in the duration of sinus rhythm in all the monohydroxamate-treated hearts, and a significant reduction (vs control 218 +/- 29 s; mean +/- SEM) in the duration of ventricular fibrillation in hearts treated with N-methyl acetohydroxamic acid (101 +/- 31 s) and desferrioxamine (112 +/- 30 s). This improvement was offset by an increase in the duration of ventricular tachycardia, in hearts treated with N-methyl acetohydroxamic acid, N-methyl butyrohydroxamic acid and desferrioxamine. These results suggest that these novel monohydroxamates, particularly N-methyl acetohydroxamic acid, attenuate reperfusion-induced arrhythmias in this model when introduced during the ischaemic period.
Collis
C S
CS
Division of Biochemistry and Molecular Biology, UMDS Guy's Hospital, London, UK.
Rice-Evans
C
C
Davies
M J
MJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004562:Electrocardiography / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006877:Hydroxamic Acids / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D014693:Ventricular Fibrillation / Q000188:drug therapy
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D006877:Hydroxamic Acids; C082752:N-methyl acetohydroxamic acid; C082751:N-methyl butyrohydroxamic acid; C082082:N-methyl hexanoylhydroxamic acid