Effects of Tertiary and Quaternary Derivatives of Aminomethylenedioxyindenes on the Mechanical and Electrical Activity of Isolated Guinea Pig Atria

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Abstract
The 2-n-propyl- and 2-n-butyl-3-dimethylamino-5,6-methylenedioxyindenes (pr-MDI and bu-MDI, respectively) have been characterized as calcium antagonists with coronary dilating and antiarrhythmic properties. The quaternary 2-n-butyl-3-trimethylamino MDI (Q-bu-MDI) has been demonstrated to possess very potent antiarrhythmic activity in several model systems. In this investigation, the effects of pr-MDI, bu-MDI and Q-bu-MDI on the mechanical and electrical behavior of isolated guinea pig atria were investigated. The tertiary pr- and bu-MDIs caused marked, concentration-dependent decreases in contractile force of stimulated left atria, while the Q-bu-MDI caused only a slight peak reduction in contractile force which was partially reversed at high concentrations. At a concentration of 3 × 10-4M, the pr- and bu-MDIs significantly depressed the frequency-force profile of stimulated left atria, and significantly decreased membrane excitability (as reflected by a significant increase in threshold voltage), while the Q-bu-MDI did not significantly alter either parameter. Spontaneous right atrial rate was only slightly depressed by the three MDI analogues at concentrations of 3 × 10-5 M or less. At higher concentrations, the tertiary pr- and bu-MDIs were much more potent than the quaternary analogue in reducing atrial rate. These results indicate that Q-bu-MDI, the most potent antiarrhythmic analogue in the MDI series, exhibits significantly lesser deleterious effects on cardiac function than the tertiary MDIs.