+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Discontinuous alterations of platelet structure and function by bound ionizable verapamil

Discontinuous alterations of platelet structure and function by bound ionizable verapamil

Journal of Pharmaceutical Sciences 81(1): 49-53

We have investigated several effects of verapamil (5-[(3,4-dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile) on platelet structure and function. At concentrations below a threshold of .apprx.4.2 .times. 107 molecules .cntdot. cell-1, verapamil binds to platelets according to a typical Langmuir adsorption isotherm (i.e., binding is saturable and noncooperative). By extrapolation, we calculate that saturation would occur at 6.8 .times. 107 .+-. 1.9 .times. 107 molecules platelet-1, with one bound verapamil molecule per two membrane phospholipids. Saturation is never achieved, however, because past the threshold surface concentration, the adsorption isotherm becomes discontinuous and further adsorption becomes a linear function of the concentration of drug in solution. We attribute this discontinuity to disorganization of the membrane bilayer which is stretched beyond cohesion by insertion of too many amphiphilic molecules of a length shorter than that of the phospholipid. The partitioning of verapamil between the bulk aqueous phase and the newly created lipid phase would then account for the linear portion of the adsorption isotherm. the discontinuity of binding is accompanied by discontinuities in the verapamil-dependent swelling of platelets and the verapamil-dependent inhibition of both ADP-inducible binding of fibrinogen to, and aggregation of, platelets. In contrast, N-methylverapamil (5-[(3,4-dimethoxyphenyl)-methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile), a hydrophilic quaternary amine derivative of verapamil, neither swells platelts nor inhibits the ADP-dependent processes that we investigated. From this we conclude that deprotonated verapamil is the operative species of the drug. Collectively, these data suggest that verapamil alters platelet structure and function by mechanisms involving disorganization of the platelet plasma membrane.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 007216150

Download citation: RISBibTeXText

PMID: 1619569

DOI: 10.1002/jps.2600810110

Related references

Platelet FcgammaRIIA His131Arg polymorphism and platelet function: antibodies to platelet-bound fibrinogen induce platelet activation. Journal of Thrombosis and Haemostasis 1(2): 355-362, 2003

Effect of platelet function alterations on clot structure formation. Journal of Rheology 22(4): 439, 1978

A guide to murine platelet structure, function, assays, and genetic alterations. Journal of Thrombosis and Haemostasis 5(4): 661-669, 2007

Alterations in platelet membrane structure and function during storage at ambient temperature. Progress in Clinical and Biological Research 28: 113-118, 1978

Evidence that the membrane bound deprotonated form of verapamil inhibits human platelet aggregation. Clinical Research 38(1): 12A, 1990

What are the effects of dietary fatty acid modification on platelet eicosanoid metabolism, platelet-activating factor, and platelet function? How might these metabolic alterations influence thrombosis?. American Journal of Clinical Nutrition 56(4 Suppl): 801s-802s, 1992

Protective effect of verapamil on the cardiac and circulatory alterations induced by platelet-activating factor. Journal of Cardiovascular Pharmacology 9(2): 181-186, 1987

Platelet force development is sensitive to aspirin induced alterations in clot structure and function in patients with coronary artery disease. Anesthesiology (Hagerstown) 77(3A): A540, 1992

Inhibition of human platelet function by verapamil. Thrombosis Research 28(4): 545-556, 1982

Disorders of platelet function caused by verapamil. Arquivos Brasileiros de Cardiologia 30 Suppl 1: 27-30, 1977

Effects of verapamil on doxorubicin induced alterations of cardiac function. Federation Proceedings 45(4): 809, 1986

Mechanism of inhibitory action of verapamil on platelet function. Nihon Ketsueki Gakkai Zasshi 41(5): 881-884, 1978

Effects of verapamil and diltiazem on human platelet function. American Journal of Physiology 250(3 Pt 2): H366-H371, 1986

A new platelet parameter, the mean platelet component, can demonstrate abnormal platelet function and structure in myelodysplasia. Clinical and Laboratory Haematology 25(1): 59-62, 2003