Background and Purpose: High-fat diet and consequent metabolic syndrome (MS) can lead to elevated risk for cardiac arrhythmias. This preclinical study was to investigate if cicletanine (CIC) could produce cardioprotective effects in conscious rabbits exhibiting the main symptoms of MS.
Methods: NZW rabbits that had undergone an 8-week-long cholesterol-enriched diet (1.5%) were instrumented with a pacemaker electrode and randomly assigned into 3 groups according to the oral treatment of either CIC (50 mg·kg−1) or sotalol (25 mg·kg−1) and their placebo b.i.d. over 5 days. Study groups were subjected to either “arrhythmia challenge” by programmed electrical stimulation in the “Arrhythmogenesis” study (N = 54) or global myocardial ischemia by rapid pacing in the “Ventricular Overdrive Pacing-induced Myocardial Ischemia” study (N = 18). The antiarrhythmic effect was evaluated by the establishment of the incidence of programmed electrical stimulation–induced arrhythmias. Proarrhythmia indicators (eg, QTc, Tpeak–Tend) were also measured to assess the cardiac safety profile of CIC. To evaluate the background of antiarrhythmic effect, cardiac cyclic nucleotide (cyclic 3′,5′-guanosine monophosphate [cGMP], cyclic 3′,5′-adenosine monophosphate [cAMP]) and nitric oxide content were determined. The antiischemic effect was characterized by change of intracavital ST segment.
Results: Cicletanine treatment significantly decreased the incidence of ventricular arrhythmias, increased cardiac cGMP and nitric oxide content and reduced cardiac cAMP level. Cicletanine did not modify significantly QTc and Tpeak–Tend interval. The ST-segment change in response to rapid pacing was reduced significantly by CIC. (P < 0.05).
Conclusions: Cicletanine exerts beneficial cardiac effects in rabbits with symptoms of MS, which may be of influence with regard to the clinical application of the drug.
*Department of Pharmacology and Pharmacotherapy, University of Debrecen Medical, Health, and Science Center
†Pharmapolis Debrecen Ltd
‡Pharmatom Hungaria Ltd, Debrecen, Hungary.
Reprints: László Drimba, MD, H-4032, Debrecen, Nagyerdei Boulevard 98, Hungary (e-mail: firstname.lastname@example.org).
Supported by the Hungarian National Office for Research and Technology (NKFP_07-A2-2008-0260; GOP-1.1.2-07/1-2008-0004; TÁMOP-4.2.2.-08/1-2008-0014, OM-00174/2008, GOP-1.1.1-07/1-2008-0032 and GOP-1.2.1-08-2009-0023) and the Hungarian Scientific Research Fund (OTKA-75965).
Laszlo Drimba, MD, and Csaba Hegedüs are postdoctoral fellows at Gedeon Richter Plc., Hungary.
The authors report no conflicts of interest.
Received June 22, 2012
Accepted April 25, 2012