The effect of isoproterenol on the class III effect of azimilide in humans.
BACKGROUND
Many class III antiarrhythmic agents lose efficacy under beta-adrenergic stimulation and at high heart rates (reverse rate dependence). This effect is thought to be due to selective blockade of the rapidly (I(Kr)), but not the slowly (I(Ks)), activating component of the delayed inward rectifier potassium current. Azimilide is an investigational class III antiarrhythmic agent that blocks both IKr and IKs.


METHODS
We investigated the electrophysiologic effect of azimilide with and without beta-adrenergic stimulation in humans. Right ventricular effective refractory period at cycle lengths of 600 and 400 milliseconds and monophasic right ventricular action potential duration at 90% repolarization at cycle lengths of 250, 300, 400, 500 and 600 milliseconds were measured in 13 patients at baseline. Isoproterenol was then infused to increase the heart rate to 125% of baseline, and the pacing protocol was repeated. Patients then received, in a single-blind randomized manner, azimilide dihydrochloride (4.5 mg/kg intravenous loading dose followed by 0.625 mg/kg/h) plus either isoproterenol at the previous dose, or saline. After measurements were taken, treatment groups were crossed over, the azimilide infusion was continued and the procedure repeated.


RESULTS
Azimilide significantly (P < 0.05) prolonged monophasic action potential duration compared to baseline at all cycle lengths except for the 250 millisecond cycle length. In the presence of isoproterenol, azimilide maintained its class III effect, prolonging the action potential duration at 90% repolarization by a mean of 8.7 +/- 3.9 milliseconds, (3.7 +/- 1.7%), whereas isoproterenol alone shortened the action potential duration at 90% repolarization by -2.6 +/- 3.2 milliseconds (-1.2 +/- 1.4%) (P = 0.0051). Isoproterenol alone shortened the right ventricular effective refractory period by -13.6 +/- 3.4 milliseconds, whereas with isoproterenol in the presence of azimilide, the right ventricular effective refractory period was essentially unaffected (-1.4 +/- 3.4 milliseconds, P = 0.0085).


CONCLUSIONS
Azimilide maintained its class III effect in the presence of isoproterenol and at increased heart rates, suggesting that IKs block may be of particular benefit in these circumstances.
Dorian
Paul
P
Department of Medicine, St. Michael's Hospital, Toronto, Canada.
Dunnmon
Preston
P
Elstun
Laura
L
Newman
David
D
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D048289:Imidazolidines; D007545:Isoproterenol / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D016037:Single-Blind Method; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000503:physiopathology; D016278:Ventricular Function, Right / Q000187:drug effects* / Q000502:physiology
D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; C086123:azimilide; D007545:Isoproterenol