Association of calmodulin inhibition, erythrocyte membrane stabilization and pharmacological effects of drugs.
The present study was designed to determine whether there is an association of drug-induced inhibition of calmodulin functions, drug-induced membrane stabilization (protection against osmotic lysis), and pharmacological effects of drugs. First, data on drugs which have been studied for both calmodulin inhibition and membrane antihemolysis were collected from the literature and an association of the two properties was established. Second, ten additional drugs were selected for study of all three properties. Four drugs, with known antihemolytic effects, were studied for calmodulin inhibition. One drug, which was a known calmodulin inhibitor, was studied for antihemolysis. Our results show that membrane-stabilizing drugs are usually calmodulin inhibitors, and vice versa; that drugs in certain therapeutic classes inhibit calmodulin-activated functions and protect against osmotic lysis; and finally, that there is a significant correlation (P less than 0.01) in terms of potency between these two actions of drugs. Data from the literature which bear on these mechanisms of drug actions suggest that the interactions between drugs and calmodulin, and drugs and the membrane, appear to be hydrophobic in nature. At this point, we do not know whether there is some causal relationship between calmodulin inhibition and the antihemolytic effect of drugs, or whether the two are simply a result of hydrophobic properties of drugs. Similarly, the roles of calmodulin inhibition and/or membrane antihemolysis in producing therapeutic efficacy are unknown.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000097:blood*; D014150:Antipsychotic Agents / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors*; D000252:Calcium-Transporting ATPases / Q000097:blood*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D004910:Erythrocyte Membrane / Q000502:physiology*; D004912:Erythrocytes / Q000502:physiology*; D006220:Haloperidol / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D010600:Pharmacology; D010640:Phenothiazines; D015032:Zinc / Q000494:pharmacology
D014150:Antipsychotic Agents; D002135:Calcium-Binding Proteins; D002147:Calmodulin; D010640:Phenothiazines; D008238:Lysergic Acid Diethylamide; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000252:Calcium-Transporting ATPases; D015032:Zinc; D006220:Haloperidol; D007099:Imipramine