Chapter 23. Calcium Antagonists

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

“…A series of 2-substituted 3-dimethylamino-5,6-methylenedioxyindene hydrochlo rides (MDIs) were synthesized in our labora tories, and their pharmacological, biochemi cal, electrophysiological, toxicological, and chemical-structural profiles have recently been reviewed [17][18][19], An antagonism of the intracellular action and/or availability of cal cium ions has been proposed to play a major part in the mechanisms of action of the three key compounds which were extensively in vestigated: 2-/i-propyl-MDI (pr-MDI), 2-n- butyl-MDI (bu-MDI), and the quaternary ammonium analogue of bu-MDI (2-«-butyl-5,6 -methylenedioxyindene -3 -trimethylammonium iodide; Q-bu-MDI1) ( fig. 1).…”

“…The assignment of a calcium antagonistic mecha nism of action to the tertiary MDIs (pr-MDI and bu-MDI) is based upon their ability to interfere with barium-induced smooth mus cle contraction [15], the reversibility of their smooth muscle relaxant properties by in creasing extracellular calcium [14,15], their ability to inhibit calcium-dependent (but not calcium-independent) evoked adrenomedullary catecholamine secretion without inter fering with cellular calcium uptake [13], their ability to reduce the quantity of calcium re leased from the sarcoplasmic reticulum upon stimulation as evidenced by depression of activation heat in skeletal muscle [1], their inhibitory effect on caffeine-induced contrac ture of skeletal muscle in the presence and in the absence of extracellular calcium [16], their inhibitory' effects on thrombin-induced 1 US patent pending (Application SN 261,008). platelet secretion [9] which is dependent upon intracellular calcium, and their binding characteristics to troponin-C and calmodulin with resultant inhibition of calcium-calmo dulin-dependent processes [11], Electrophysiological studies [ 19], on the other hand, indi cate that pr-MDI, bu-MDI, and Q-bu-MDI may also act as membrane slow calcium channel blockers since they abolish calciumdependent slow response activity in cardiac Purkinje fibers superfused with high potas sium concentrations, tetrodotoxin, and nor epinephrine. It is thus apparent that the MDIs are calcium antagonists with both in tracellular and membrane sites of action [19].…”

“…platelet secretion [9] which is dependent upon intracellular calcium, and their binding characteristics to troponin-C and calmodulin with resultant inhibition of calcium-calmo dulin-dependent processes [11], Electrophysiological studies [ 19], on the other hand, indi cate that pr-MDI, bu-MDI, and Q-bu-MDI may also act as membrane slow calcium channel blockers since they abolish calciumdependent slow response activity in cardiac Purkinje fibers superfused with high potas sium concentrations, tetrodotoxin, and nor epinephrine. It is thus apparent that the MDIs are calcium antagonists with both in tracellular and membrane sites of action [19].…”

Effect of Extra- and Intracellular Calcium Blockers on Histamine and Antigen-Induced Bronchospasms in Guinea Pigs and Rats

“…Calcium antagonists can be broadly classi fied into two groups: agents that block the flux of calcium across biological membranes (calcium channel blockers) and agents that block the intracellular mobilization of cal cium (intracellular calcium blockers) [20,21]. Examples of the calcium channel block ers include verapamil and nifedipine [20,21] and examples of intracellular calcium block ers include TMB-8 and W-7 [2,10,20].…”

“…Examples of the calcium channel block ers include verapamil and nifedipine [20,21] and examples of intracellular calcium block ers include TMB-8 and W-7 [2,10,20]. There are also drugs, such as diazoxide [4,20,21], which appear to have mixed extra-and intracellular calcium blocking activities.…”