William B. Lacefield

Dipyridamole directly inhibits vascular smooth muscle cell proliferation in vitro and in vivo : implications in the treatment of restenosis after angioplasty

OBJECTIVES The effect of dipyridamole on smooth muscle cell proliferation and prevention of intimal thickening after arterial injury was investigated. BACKGROUND In addition to antiplatelet activity, dipyridamole also inhibits cell proliferation. We examined whether the antiproliferative action of dipyridamole on smooth muscle cells, as demonstrated here, has a direct effect on intimal thickening after vascular injury. METHODS Cell proliferation was determined by measuring deoxyribonucleic acid (DNA) synthesis and by cell counting. The in vivo effect of locally delivered dipyridamole was determined in a rabbit model with carotid or femoral artery injury. RESULTS Dipyridamole produced a dose-dependent inhibition of smooth muscle cell proliferation, producing 50% inhibition at 7 micrograms/ml. Structural analogues SH-869 and mopamidol were 10 to 100 times less effective than dipyridamole, suggesting that cell growth inhibition may be unrelated to the antiplatelet activity of dipyridamole. Inhibition of cell proliferation by dipyridamole was attenuated by increasing the serum concentration in the culture medium. Bypassing serum by local delivery of dipyridamole at the periadventitial site produced 63% inhibition (p < 0.05) of cell replication in balloon-injured arteries. Locally delivered dipyridamole also inhibited intimal thickening (20%, p < 0.05) after balloon injury. CONCLUSIONS Dipyridamole inhibited smooth muscle cell proliferation in vitro. This activity was attenuated by serum proteins. Locally delivered dipyridamole inhibited cell replication in arteries and intimal thickening after balloon injury. These results suggest that although systemic treatment with dipyridamole may not be efficacious because of inadequate serum levels, its antiproliferative action on smooth muscle cells may reduce restenosis when the drug is delivered locally after coronary angioplasty.

Effect of Ionic Calcium and Magnesium on Human Platelet Aggregation

Summary The ionic calcium requirement for platelet aggregation is much lower than that required for fibrin formation. Maximal aggregation can still take place with the [Ca2+] well below 5 × 10−6 M. Chelation of Ca2+ with EGTA results in a decrease in aggregation at a higher [Ca2+] than when EDTA is employed. This seems to indicate that the [Ca2+]/[Mg2+] ratio may be of importance at low ionic concentrations. However, excess [Ca2+] and/or [Mg2+] above the normal levels inhibit aggregation. In fact, when both of these ions are added in excess of the normal levels their inhibitory effects are additive, indicating that the [Ca2+]/[Mg2+] ratio is of little consequence under these conditions. Platelet aggregation is not inhibited by the calcium complex of either EDTA or EGTA.

Effect of a New Anti-Inflammatory Drug, Fenoprofen, on Platelet Aggregation and Thrombus Formation

Summary Fenoprofen sodium (a new antiinflammatory drug), aspirin, and phenylbutazone were compared with respect to their inhibitory activity on platelet function. These compounds inhibit collagen-induced platelet aggregation both in vitro (human, rabbit, and guinea pig) and in vivo (rabbit and guinea pig). In an extracorporeal shunt experiment in the rabbit, both fenoprofen sodium and aspirin inhibited thrombus formation. Of the three compounds tested, fenoprofen sodium appears to be the most active inhibitor of platelet function.

Enhanced binding of radioligands to receptors of γ-aminobutyric acid and benzodiazepine by a new anticonvulsive agent, LY81067

A diaryltriazine, LY81067, effectively protects against pentylenetetrazole- and picrotoxin-induced convulsions in mice, with ED50 values of 5.7 and 5.8 mg/kg i.p., respectively. LY81067 enhances the binding of both 3H-GABA and 3H-flunitrazepam to specific sites in rat brain membranes. The degree of enhancement by LY81067 varies from one brain region to another and is different for the binding of 3H-GABA and 3H-flunitrazepam. In cortical membranes, LY81067 increases the affinity of 3H-GABA for both high and low affinity sites and increases the number of sites. LY81067 increases the affinity of 3H-flunitrazepam for its binding sites without greatly increasing the number of sites. Like the pyrazolopyridines, the enhancement of 3H-flunitrazepam binding by LY81067 is dependent on chloride or related anions and is reversed by picrotoxin, suggesting that LY81067 exerts its anticonvulsant effects by binding to or near picrotoxin binding sites. The differential effects of LY81067 on the enhancements of 3H-GABA and 3H-flunitrazepam binding in several brain regions suggest extensive multiplicity of GABA/benzodiazepine/picrotoxin/anioin receptor complexes.

Chapter 10. Class I and III Antiarrhythmic Drugs

Publisher Summary An abundance of reviews on the electrophysiological basis of cardiac arrhythmias and therapeutic use of anti-arrhythmic drugs have appeared recently. The local anesthetic anti-arrhythmic drugs are class I; and the drugs that prolong action potential duration (APD) selectively are class III drugs. This chapter discusses class I and III agents, with emphasis on new compounds. Recent reports relevant to the mechanism of action of older agents are also mentioned. The Vaughan Williams classification recognizes four distinct anti-arrhythmic groups. Class I agents may be further divided into three subgroups on the basis of effects on APD. The potent conduction depressants flecainide, encainide and lorcainide are Ic agents that have little effect on APD, while lidocaine, tocainide and mexiletine are examples of Ib compounds that shorten APD. Quinidine, disopyramide and procainamide represent Ia agents that prolong repolarization. In addition, the observation that local anesthetics possess unique affinities for the sodium channel depending on whether the channel is in the resting, open or inactivated state (modulated-receptor hypothesis), has provided added biophysical support for the subclassification of class I drugs. Thus, Ib agents tend to rapidly associate with and dissociate from open and/or inactivated sodium channels with time constants in the 100–300 msec range, while Ic agents require tens of seconds for block onset and recovery; Ia agents are intermediate. On C lass I and Class III, the chapter concentrates on update of established agents and recently reported new chemical entities. The chapter also considers properties of some agents with mixed activity; and some miscellaneous agents. Arrhythmogenic situations are studied, with future directions in the goal for drug development efforts mentioned.

Chapter 9. Antithrombotic Agents

Publisher Summary This chapter summarizes research reports of 1972 on all types of agents for the management of thromboembolic disease. In a study, thrombin, in concentrations that induce flatelet aggregation, was reported to increase cyclic AMP (cAMP) levels. A cAMP-binding protein with protein kinase activity was isolated from the soluble fraction of homogenized platelets. The observation that cAMP phosphodiesterase from human platelets is strongly inhibited by dipyridamole, an inhibitor of platelet aggregation, and only slightly inhibited by psychotropic drugs, whereas the reverse is observed with the brain enzyme, led to the proposal of different isoenzymes. The antithrombotic effect of aspirin continued to be the subject of many investigations. It was reported effective in (1) reducing thrombus formation on catheters placed in the inferior vena cava of cats, (2) in reducing the incidence and extent of occlusive platelet aggregation in dog arteries following endothelial injury, and (3) in inhibiting the circulatory and ventilatory effects of protamine induced platelet aggregation in dogs. Sulfinpyrazone was reported to prolong survival of renal allografts in dogs and to reduce the incidence of recurrent venous thrombosis associated with carotid artery stenosis in man. The anticoagulant activity of the coumarins was attributed to their ability to block the synthesis of vitamin K.