CARDIAC IMPLICATIONS OF AMLODIPINE-DANTROLENE COMBINATIONS

Purpose: Cardiac disorders, cardiac arrest and ventricular fibrillatio n in the most severe cases, have been observed after the administratio n of dantrolene to patients treated by verapamil for coronary artery d isease. This study, was designed to examine the interaction of dantrol ene with amlodipine, a dihydropyridine. Methods: In 12 anaesthetized, open-chest pigs, the effects of the interaction have been studied on h eart rate, atrioventricular conduction, monophasic action potential du ration, intraventricular conduction time, left ventricular dP/dt max a nd mean blood pressure. The study was performed with normal coronary c irculation and ischaemia of a large area of the left ventricule, obtai ned by complete occlusion of the left anterior descending coronary art ery near its origin, under pacing at a constant high rate, 180 beats . min(-1). The drugs were injected iv, amlodipine 0.4 mg . kg(-1) first and dantrolene 3.0 mg . kg(-1) 20 min later in six animal and the ord er was reversed in the other animals. Results: Sinus rate and atrioven tricular conduction were not affected by amlodipine, but were slowed b y dantrolene added (145 +/- 9 to 131 +/- 7 beats . min(-1), P < 0.01 a nd 150 +/- 15 to 180 +/- 20 msec, P < 0.01). In contrast, amlodipine o r amlodipine plus dantrolene did not change MAP duration or conduction time in the normal heart Similarly, they did not after the maximal va riations due to ischaemia, but delayed them, while prolonging the time to onset of fibrillation (111 +/- 8 to 343 +/- 33 sec, P < 0001 with amlodipine alone, 289 +/- 11 to 323 +/- 16 sec, P < 0.05 with dantrole ne). Left ventricular dP/dt max was lowered from 1670 +/- 86 to 1532 /- 50 mmHg . sec(-1) (P < 0.001) and mean blood pressure from 79 +/- 3 to 70 +/- 3 mmHg (P < 0.01) by amlodipine, but dantrolene did not enh ance and even counteracted these effects. Finally, potassium plasma co ncentration did not increase above 5.1 +/- 0.2 mmol . L(-1) under the dual influence of amlodpine and dantrolene. Conclusion: In ususal clin ical doses, dantrolene may be safely administered concurrently with am lodipine.