The methylenedioxyindenes, a novel class of "intracellular calcium antagonists": effects on contractility and on processes involved in regulating intracellular calcium homeostasis.
The 2-substituted methylenedioxyindenes are a novel class of "calcium antagonists" which have been characterized as acting intracellularly. In the present study, the effect of 2-propyl-methylenedioxyindene (p-MDI) on the contractility of isolated rabbit papillary muscles and aortic rings as well as on several metabolic processes believed to be important in regulating calcium movement within the cell was examined. p-MDI was found to exert a dose-dependent negative inotropic effect in the range of 1.0 X 10(-5) to 1.0 X 10(-3) M (1.0 X 10(-3) M p-MDI produced a total cessation of contractility). At a concentration of 1.0 X 10(-4) M p-MDI, this depressant effect could be partially reversed by increasing the level of calcium in the tissue bath. p-MDI also relaxed aortic rings previously contracted with 50 mM KCl or 10 microM norepinephrine, although the concentration of p-MDI required to relax norepinephrine-contracted rings was 3 times greater than that required to relax KCl-contracted rings. Such selectivity was also observed when the effects of verapamil on norepinephrine- and KCl-contracted rings were examined, but was not observed with papaverine. To determine whether the effects of p-MDI on cardiac and vascular smooth muscle were due to direct interference with any of the metabolic processes which regulate intracellular calcium homeostasis, the effects of p-MDI on isolated cardiac sarcoplasmic reticulum and mitochondria and on the intracellular calcium-binding protein calmodulin were examined. At concentrations which depressed cardiac contractility, p-MDI had no effect on 1) calcium transport, uptake or ethyleneglycol bis(beta-aminoethyl ether)N,N,N',N'-tetraacetic acid-induced calcium release by sarcoplasmic reticulum, 2) calcium uptake by mitochondria or 3) calmodulin. p-MDI did, however, exert a biphasic effect of glutamate-supported mitochondrial respiration; stimulating oxygen consumption at concentrations of 1.0 X 10(-5) and 1.0 X 10(-4) M and inhibiting respiration at 1.0 X 10(-3) M. It is therefore concluded that p-MDI has no apparent direct effect on intracellular calcium movement per se and that the calcium antagonist effect of p-MDI may be due in part to calcium channel blockage. Inhibition of mitochondrial respiration may also contribute to the negative inotropic effect of high concentrations of p-MDI.
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000378:metabolism; D003864:Depression, Chemical; D006706:Homeostasis / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects
D002121:Calcium Channel Blockers; D002147:Calmodulin; D002118:Calcium