Effects of azimilide and d,l-sotalol on the heart rate and blood pressure response to isoproterenol in anesthetized rats.
The novel class III antiarrhythmic agent, azimilide, provides antifibrillatory protection in a rat model of ischemia-reperfusion arrhythmias. In other species azimilide's antifibrillatory mechanism is thought to be mediated predominantly through blockade of both the rapid and slow components of the delayed rectifier potassium current in ventricular myocytes. However, the delayed rectifier potassium current does not appear to control cardiac repolarization in the rat. One possible mechanism for antiarrhythmic efficacy in rats is the compound's beta-adrenergic blocking effect, previously seen in isolated guinea pig hearts. The purpose of this study was to evaluate the beta-adrenergic antagonistic effect of azimilide in the rat. Beta-adrenergic blockade was evaluated in the intact anesthetized rat by studying the effects of intravenous azimilide (at or above the antifibrillatory dose) and d,l-sotalol (a known beta-adrenergic antagonist) on heart rate and blood pressure responses to isoproterenol (0.14 Mg/kg i.v.). d,l-Sotalol (6.0 mg/kg) reduced (p < 0.05) the tachycardic response to isoproterenol from 133 +/- 11 to 80 +/- 10 beats/min, and 3.0 mg/kg of d,l-sotalol reduced the hypotensive response from -74 +/- 4 to -43 +/- 5 mmHg. Azimilide (5.0, 10.0, and 20.0 mg/kg) did not have a statistically significant effect on either the heart rate or blood pressure changes caused by isoproterenol. These data demonstrate that azimilide does not have a beta-adrenergic antagonist effect in the rat at antifibrillatory doses. Therefore, the antiarrhythmic effect of azimilide in the rat is mediated through a mechanism other than beta-blockade.
Mittelstadt
S W
SW
Procter & Gamble Pharmaceuticals, Norwich, New York 13815, USA.
Maynard
A E
AE
Benn
D R
DR
Lowe
E R
ER
Kostreva
D R
DR
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy*; D001794:Blood Pressure / Q000187:drug effects*; D004562:Electrocardiography; D006339:Heart Rate / Q000187:drug effects*; D006827:Hydantoins; D007093:Imidazoles / Q000627:therapeutic use*; D048289:Imidazolidines; D007545:Isoproterenol; D008297:Male; D010879:Piperazines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013015:Sotalol / Q000627:therapeutic use*
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; C086123:azimilide; D013015:Sotalol; D007545:Isoproterenol