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  • Title: The comparative antiarrhythmic and proarrhythmic activity of a 3,7-diheterobicyclo[3.3.1]nonane, BRB-I-28, and lidocaine in the 1-4-day-old infarcted dog heart.
    Author: Fazekas T, Scherlag BJ, Mabo P, Berlin KD, Garrison GL, Chen CL, Sangiah S, Patterson E, Lazzara R.
    Journal: Acta Physiol Hung; 1993; 81(3):289-99. PubMed ID: 8197884.
    Abstract:
    We compared the electrophysiological effects and quantified the antiarrhythmic/proarrhythmic potential of the 3,7-diheterobicyclo[3.3.1]nonane-derivative, BRB-I-28 and lidocaine in 15 consecutive postinfarction dogs. Electrophysiologic studies were performed in anesthetized animals, 1-4 days (mean +/- SE = 2.47 +/- 0.36) after the two-stage ligation of the left anterior descending coronary artery. Inducibility of sustained monomorphic ventricular tachycardia (SMVT) was compared in the pre-drug state, and after i.v. lidocaine (3 and 6 mg/kg) and BRB-I-28 (3 and 6 mg/kg) administration. During the control state, SMVT was inducible in 6/15 dogs (40%). After the administration of lidocaine, the rate of the inducible SMVT slowed (353 +/- 91 to 272 +/- 96 beat/min; p < 0.01), but due to the proarrhythmic action of the drug, SMVT became inducible in 13/15 dogs (87%). Sustained reentry was induced after 3 mg/kg lidocaine in 3 dogs and after 6 mg/kg in 4. The mean aortic blood pressure in these SMVTs was 36 +/- 8 mm Hg. After administration of BRB-I-28 (6 mg/kg) SMVT was not inducible in 2/6 and in 4 the SMVT rate was slowed (380 +/- 104 to 208 +/- 105 beat/min; p < 0.005) before termination in 3. In 2 dogs SMVT was induced after BRB-I-28 was given whereas they were non-inducible in the control state (proarrhythmic effect: 13%). Furthermore the hemodynamic state during the SMVTs was more stable after BRB-I-28 (mean aortic blood pressure = 65 +/- 7 mm Hg; post-BRB-I-28 vs post-lidocaine, p < 0.001). During sinus rhythm, lidocaine caused a transient lowering of the MBP (105 +/- 17 to 84 +/- 18 mm Hg; p < 0.001), whereas, BRB-I-28, induced a consistent but short-lasting pressor response (98 +/- 18 to 120 +/- 29 mm Hg; p < 0.001) after its bolus injection. The low proarrhythmic activity and the lack of a cardiodepressant action makes this new chemical class of antiarrhythmics worthy of further development.
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