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.

Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.

Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.

Indecainide: effects on arrhythmias, electrophysiology, and cardiovascular dynamics.

The cardiovascular pharmacology of indecainide, a new class I antiarrhythmic agent, was studied in intact animals. Arrhythmias produced by ouabain were converted to sinus rhythm by indecainide (100 micrograms/kg/min, i.v.) at 0.7 +/- 0.1 mg/kg and a corresponding plasma concentration of 1.7 +/- 0.2 micrograms/ml at the time of conversion. Infusion at a slower rate (20 micrograms/kg/min) converted to sinus rhythm at 0.4 +/- 0.1 mg/kg and 0.4 +/- 0.2 micrograms/ml plasma. Arrhythmias produced by prior (24 h) coronary artery occlusion were converted to 50% sinus rhythm by indecainide (100 micrograms/kg/min, i.v.) at 1.3 mg/kg. In conscious dogs, 6 mg/kg indecainide p.o. prolonged the PR and QRS intervals by 31 +/- 5 and 13 +/- 3%, respectively, at a corresponding plasma concentration of 2.8 +/- 0.5 micrograms/ml. His bundle studies revealed that the PR interval prolongation was due to an increase in both A-H and H-V intervals. In anesthetized dogs, indecainide (1-5 mg/kg, i.v.) decreased cardiac contractility, however, this effect was comparable to or less than that produced by other class I agents and was likely due to the Na+-channel-blocking activity of the drug. The autonomic effects of indecainide were slight and no effects were produced on peripheral hemodynamics, the QTc interval, or the central nervous system. It was concluded that indecainide is a potent class I antiarrhythmic agent that would appear to have only minimal propensity for producing adverse side effects in humans.

Metabolism of the antiarrhythmic agent, indecainide, in rats, dogs, and monkeys.

The biotransformation of indecainide, a potent new antiarrhythmic agent, has been studied in rats and dogs. Indecainide was excreted in the urine primarily as the unchanged compound. The major urinary metabolite was desisopropyl indecainide which accounted for approximately 5% of the urinary radioactivity in both species. This metabolite was also detected in the plasma of rats, dogs, and monkeys. Peak plasma levels of the amine metabolite were 15 and 19% of the peak plasma levels of indecainide in rats and dogs, respectively. Loss of isopropylamine resulted in the formation of an aldehyde intermediate which was stabilized as the cyclic acylaminocarbinol. An acidic metabolite presumably derived from oxidation of the aldehyde was detected as well as a cyclic imide metabolite. An additional minor metabolite corresponding to N-formyl indecainide was observed in the urine but the mechanism of its formation is unknown.

Enhanced binding of radioligands to receptors of gamma-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.