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

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.

Experimental Pharmacology of the Methylenedioxyindenes

“…In agreement with the results in cardiac tissue (89), the tertiary, but not the quaternary, MDIs inhibited contractions of the rat aortic strip induced by potassium (1 75), norepinephrine (46), or U44069 (45).…”

“…It is evident that the tertiary MDIs act principally on cardiac muscle and not on nodal tissue, as evidenced by our repeated observation that these agents had no effect on heart rate in vitro in the isolated rabbit (125) and guinea pig (90) hearts and in the spontaneously beating isolated guinea pig right atrium (89), and in vivo in dogs (87,88,123) and in rats (88). This is a decisive difference between the MDIs and verapamil, and explains why AV block occurs with verapamil but not with the MDIs (88).…”

“…(e) Saturation that yielded the trans forms resulted in significant loss of potency ( 175). N-methylation (quaternarization) of the saturated or unsaturated tertiary MDIs resulted in loss of in vitro activity (45,89,175). …”

“…A major problem associated with the use of some calcium channel blockers is their ability to suppress nodal tissue (verapamil, diltiazem) and cause atrioventricular block. On the other hand, it is evident that the MDIs act principally on cardiac muscle in the heart and not on nodal tissue in vitro (89,90,125) and in vivo (87,88,123). This is a decisive difference between the MDIs and the calcium channel blockers, and explains why AV block occurs with the latter agents but not with the MDIs (88).…”