title: Interaction of 1,4 dihydropyridine calcium channel antagonists with biological membranes: lipid bilayer partitioning could occur before drug binding to receptors.
abstract: The binding of dihydropyridine calcium channel agonists and antagonists to receptors in cardiac sarcolemmal membranes is a complex reaction that may involve an interaction with the lipid bilayer matrix of the sarcolemma. Membrane/buffer partition coefficients (lambda) for three dihydropyridine calcium channel antagonists were measured directly in the sarcolemma and sarcoplasmic reticulum membranes and found to be in the range of 5,000 to 150,000. These drugs interact primarily with the membrane bilayer component of these membranes but may also bind to non-receptor proteins. The intrinsic forward rate constants for dihydropyridine binding to sarcolemmal calcium channel receptors were apparently not strongly dependent on their membrane partition coefficients. For example, nimodipine (lambda = 6300) had a forward rate constant of 6.8 +/- 0.6 x 10(6)/M/S, whereas the forward rate constant for Bay P 8857 (lambda = 149,000) was 1.4 +/- 0.8 x 10(7)/M/S. Model calculations for this binding reaction demonstrated that since these drugs are highly lipid soluble, the dependence of these rates on lipid solubility would probably not be reflected in the experimental forward rate constants. In addition, the intrinsic forward rate constant for nimodipine binding to sarcolemmal calcium channel receptors was found not to be linearly dependent on the viscosity of the buffer medium over a five-fold range. The rate of nonspecific (non-receptor protein) drug binding to highly purified sarcoplasmic reticulum membranes essentially devoid of specific receptors for these drugs appears to be extremely fast, at least 10(3) times faster than specific drug binding to the receptor in the sarcolemma. Thus, it appears that partitioning into the lipid bilayer matrix of the sarcolemma could be a general property of dihydropyridine calcium channel antagonists and may be a prerequisite for their binding to sarcolemmal membrane receptors.
authors.affiliation: Department of Radiology, University of Connecticut Health Center, Farmington 06032.
authors.forename: L G
authors.initials: LG
authors.lastname: Herbette
authors.forename: Y M
authors.initials: YM
authors.lastname: Vant Erve
authors.forename: D G
authors.initials: DG
authors.lastname: Rhodes
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000378:metabolism*; D015220:Calcium Channels; D004058:Diffusion; D004285:Dogs; D008051:Lipid Bilayers; D009206:Myocardium / Q000378:metabolism; D009543:Nifedipine / Q000031:analogs & derivatives / Q000378:metabolism; D009553:Nimodipine / Q000378:metabolism; D015737:Nisoldipine; D011817:Rabbits; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D008051:Lipid Bilayers; D011978:Receptors, Nicotinic; D015737:Nisoldipine; D009553:Nimodipine; C051102:BAY-P 8857; D009543:Nifedipine