Cardiovascular Profile of Xanthone-Based 1,4 Dihydropyridines Bearing a Lidoflazine Pharmacophore Fragment.

As a follow-up to our previous studies on differently substituted 1,4-dihydropyridines endowed with a peculiar cardiac selectivity, in this paper, a small series of hybrid compounds bearing the pharmacophore fragment of lidoflazine in position 2 or 3 on a 4-(xanthen-9-one)-dihydropyridine core was reported. Lidoflazine was selected due to our promising previously reported data, and the xanthen-9-one substituent was introduced in position 4 of the dihydropyridine scaffold based on the cardiac selectivity observed in several of our studies. The new hybrid compounds were tested to assess cardiac and vascular activities, and the data were evaluated in comparison with those previously obtained for 4-(xanthen-9-one)-dihydropyridines and lidoflazine⁻nifedipine hybrid compounds. The functional studies indicated an interesting peculiar selectivity for the cardiac parameter inotropy, in particular when the lidoflazine fragment was introduced in position 2 of the dihydropyridine scaffold (4a⁻e), and thus a possible preferential binding with the Cav 1.2 isoform of l-type calcium channels, which are mainly involved in cardiac contractility.

NRBF2-mediated autophagy contributes to metabolite replenishment and radioresistance in glioblastoma.

Overcoming therapeutic resistance in glioblastoma (GBM) is an essential strategy for improving cancer therapy. However, cancer cells possess various evasion mechanisms, such as metabolic reprogramming, which promote cell survival and limit therapy. The diverse metabolic fuel sources that are produced by autophagy provide tumors with metabolic plasticity and are known to induce drug or radioresistance in GBM. This study determined that autophagy, a common representative cell homeostasis mechanism, was upregulated upon treatment of GBM cells with ionizing radiation (IR). Nuclear receptor binding factor 2 (NRBF2)-a positive regulator of the autophagy initiation step-was found to be upregulated in a GBM orthotopic xenograft mouse model. Furthermore, ATP production and the oxygen consumption rate (OCR) increased upon activation of NRBF2-mediated autophagy. It was also discovered that changes in metabolic state were induced by alterations in metabolite levels caused by autophagy, thereby causing radioresistance. In addition, we found that lidoflazine-a vasodilator agent discovered through drug repositioning-significantly suppressed IR-induced migration, invasion, and proliferation by inhibiting NRBF2, resulting in a reduction in autophagic flux in both in vitro models and in vivo orthotopic xenograft mouse models. In summary, we propose that the upregulation of NRBF2 levels reprograms the metabolic state of GBM cells by activating autophagy, thus establishing NRBF2 as a potential therapeutic target for regulating radioresistance of GBM during radiotherapy.

Species differences in sensitivity of nucleoside transport in erythrocytes and cultured cells to inhibition by nitrobenzylthioinosine, dipyridamole, dilazep and lidoflazine.

Differences in sensitivity of uridine transport in erythrocytes and cultured cells to inhibition by dipyridamole, dilazep and lidoflazine were largely species-specific; uridine transport in human cells, and probably in pig and rabbit cells, was 2-3- and 10-times more sensitive to inhibition by dipyridamole (IC50 approx. 50 nM) and about 10- and 20-times more sensitive to dilazep inhibition (IC50 approx. 5 nM) than transport in mouse and rat cells, respectively. Uridine transport in human erythrocytes and HeLa cells was strongly inhibited by lidoflazine (IC50 10-140 nM), whereas that in both mouse and rat cells was highly resistant (IC50 greater than 10 microM). Superimposed on species-specific differences were some cell type specific differences in sensitivity of nucleoside transport to these inhibitors. Uridine transport in Walker 256 rat carcinoma cells was more resistant to dipyridamole and dilazep than that of other rat cells. Transport in human Hep-2 cells was more resistant to lidoflazine (IC50 2000 nM) than that of human erythrocytes and HeLa cells, whereas it showed similar sensitivity to dilazep and dipyridamole. Uridine transport in Chinese hamster cells was also more resistant to dilazep than that of baby hamster kidney cells. In addition HeLa cells and clones thereof expressed uridine transporters (about 50% each) with difference of about 1000-fold in sensitivity to inhibition by dilazep (IC50 approx. 5 nM and 5 microM, respectively).

Effects of Ca2+-channel antagonists on nucleoside and nucleobase transport in human erythrocytes and cultured mammalian cells.

Lidoflazine strongly inhibited the equilibrium exchange of uridine in human erythrocytes (Ki approximately 16 nM). Uridine zero-trans influx was similarly inhibited by lidoflazine in cultured HeLa cells (IC50 approximately to 80 nM), whereas P388 mouse leukemia and Novikoff rat hepatoma cells were three orders of magnitude more resistant (IC50 greater than 50 microM). Uridine transport was also inhibited by nifedipine, verapamil, diltiazem, prenylamine and trifluoperazine, but only at similarly high concentrations in both human erythrocytes and the cell lines. IC50 values ranged from about 10 microM for nifedipine and about 20 microM for verapamil to more than 100 microM for diltiazem, prenylamine and trifluoperazine. The concentrations required for inhibition of nucleoside transport are several orders higher than those blocking Ca2+ channels. Lidoflazine competitively inhibited the binding of nitrobenzylthioinosine to high-affinity sites in human erythrocytes, but did not inhibit the dissociation of nitrobenzylthioinosine from these sites on the transporter as is observed with dipyridamole and dilazep.

Studies on the possible mechanisms of lidoflazine arrhythmogenicity.

Lidoflazine is a calcium channel blocking agent that is effective and safe in the treatment of angina pectoris, but has been reported to be associated with sudden death when administered for the treatment of supraventricular arrhythmias. Studies were performed in dogs to determine if lidoflazine caused a rise in serum digoxin concentration that could cause arrhythmias or if it was directly arrhythmogenic. Dogs received chronic injections of digoxin and then digoxin in combination with lidoflazine. No increase in digoxin concentration was found. Dogs also underwent programmed electrical stimulation while not receiving medications and then after incremental doses of lidoflazine administered intravenously. Lidoflazine did not cause spontaneous ventricular tachycardia and did not lower the threshold of ventricular tachycardia induction. Combined administration of lidoflazine and digoxin did not facilitate arrhythmia induction. These studies do not support a digoxin-lidoflazine interaction or a direct arrhythmogenic action of lidoflazine.

Lidoflazine combined with nucleotide precursors increases ATP content and adenosine production in cardiomyocytes.

We have previously identified that the nucleoside transport blocker dipyridamole increases adenosine production but may cause depletion of the nucleotide pool in cardiomyocytes during extended exposure and that this effect was abolished by co-administration of adenine and ribose. The present study aimed to establish whether lidoflazine, a newer generation of nucleoside transport inhibitor with calcium antagonist properties, would cause a similar effect. We conclude that lidoflazine did not affect the nucleotide pool while the combined application of lidoflazine with precursors of nucleotide resynthesis increased ATP concentration and further enhanced adenosine production.

Myocardial reoxygenation damage: can it be circumvented?

We investigated whether reoxygenation damage could be prevented by interventions directed towards reducing calcium influx only during the reoxygenation period. We measured reoxygenation contracture and recovery of contractile performance, using isolated papillary muscle preparations from cat and rabbit, pretreated with ouabain so as to exaggerate the phenomenon of reoxygenation contracture. Reoxygenation contracture was abolished and contractile recovery achieved by lowering extracellular calcium during early reoxygenation and then gradually replacing it. Gradual reoxygenation only postponed contracture and contractile failure. The slow channel blocker, diltiazem, but not verapamil or lidoflazine--in similarly negative inotropic concentrations of 10(-4) mol X litre-1, 10(-4) mol X litre-1 and 2 X 10(-5) mol X litre-1 respectively--reduced early reoxygenation contracture, as did Mg2+ (30 mmol X litre-1), Mn2+ (8 mmol X litre-1), or metabolic acidosis (pH 6.5), without in any case allowing contractile recovery. These observations indicate that reoxygenation damage is not an irrevocable consequence of the preceding hypoxic insult. They imply that calcium entry during early reoxygenation contributes both to contracture and contractile failure, that this occurs through paths other than the slow calcium channel, and that diltiazem may have properties additional to those of blocking the slow calcium channel.

Lidoflazine does not improve neurologic outcome when administered after complete cerebral ischemia in primates.

In order to investigate the effects of the calcium entry blocker lidoflazine on neurologic outcome in primates following an episode of global brain ischemia, 12 pigtail monkeys (Macaca nemestrina) were subjected to 17 min of complete cerebral ischemia, followed by 48 h of intensive care treatment and daily neurologic evaluations for 96 h. The monkeys were randomly assigned to receive, in a blind fashion, either lidoflazine 1.0 mg/kg (n = 6) or inactive lidoflazine solvent (n = 6) at 5 min, 8 h, and 16 h postischemia. One monkey in the lidoflazine group did not meet preestablished protocol criteria and was excluded from data analysis. The remaining monkeys were well matched for age, sex, and other physiologic variables. Neurologic outcome was not significantly different between the lidoflazine- and placebo-treated groups (p greater than 0.5). No monkey in either group achieved a normal neurologic exam by 96 h postischemia. Three lidoflazine-treated monkeys and two placebo-treated monkeys died prior to the 96-h neurologic evaluation. These deaths were judged to be neurologic in origin. The authors concluded that lidoflazine does not improve neurologic outcome in primates when administered after 17 min of complete cerebral ischemia.

Cerebral ischemia and reperfusion: prevention of brain mitochondrial injury by lidoflazine.

Mitochondrial degradation is implicated in the irreversible cell damage that can occur during cerebral ischemia and reperfusion. In this study, the effects of 10 min of ventricular fibrillation and 100 min of spontaneous circulation on brain mitochondrial function was studied in dogs in the absence and presence of pretreatment with the Ca2+ antagonist lidoflazine. Twenty-three beagles were separated into four experimental groups: (i) nonischemic controls (ii) those undergoing 10-min ventricular fibrillation, (iii) those undergoing 10-min ventricular fibrillation pretreated with 1 mg/kg lidoflazine i.v., and (iv) those undergoing 10-min ventricular fibrillation followed by spontaneous circulation for 100 min. Brain mitochondria were isolated and tested for their ability to respire and accumulate calcium in a physiological test medium. There was a 35% decrease in the rate of phosphorylating respiration (ATP production) following 10 min of complete cerebral ischemia. Those animals pretreated with lidoflazine showed significantly less decline in phosphorylating respiration (16%) when compared with nontreated dogs. Resting and uncoupled respiration also declined following 10 min of fibrillatory arrest. One hundred minutes of spontaneous circulation following 10 min of ventricular fibrillation and 3 min of open-chest cardiac massage provided complete recovery of normal mitochondrial respiration. Energy-dependent Ca2+ accumulation by isolated brain mitochondria was unimpaired by 10 min of complete cerebral ischemia. However, by 100 min after resuscitation, there was a small, but significant rise in the capacity for mitochondrial Ca2+ sequestration when compared to either control or fibrillated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina pectoris: effects of lidoflazine on exercise tolerance and chest pain.

In a double-blind study involving 24 patients, treatment with lidoflazine in comparison with placebo was associated with a significant improvement in exercise tolerance; the median increase in work performed was 62 percent. This increase was significant at the 6th week of assessment. Ten patients were followed up for a further 2 years. Lidoflazine therapy was associated with a significant improvement in work done over that period. Lidoflazine was well tolerated and apparent adverse effects were minor.

Beneficial and detrimental effects of lidoflazine in microvascular angina.

Lidoflazine, a piperazine derivative calcium antagonist, was investigated as therapy in 22 patients with microvascular angina (chest pain, angiographically normal coronary arteries and left ventricle, microvascular constrictor response to pacing after ergonovine administration and limited coronary flow response to dipyridamole). Eighteen of 22 patients reported symptom benefit while taking lidoflazine 360 mg daily. Compared to baseline exercise treadmill testing, lidoflazine resulted in significant improvement in exercise duration (812 +/- 337 vs 628 +/- 357 seconds, p less than 0.01) and time to onset of chest pain (530 +/- 343 vs 348 +/- 246 seconds, p less than 0.01). The 5 patients with ischemic ST-segment changes during baseline testing demonstrated an almost 4-minute delay in ST-segment depression (3 patients) or no ST-segment depression (2 patients) while taking lidoflazine. Repeat invasive study of coronary flow in 11 patients taking lidoflazine demonstrated significantly greater coronary vasodilation at rest, during pacing, during pacing after ergonovine and after dipyridamole administration (all p less than 0.03), compared to the initial drug-free study. During the randomized, placebo-controlled phase of the study with 7-week treatment periods, 9 of 11 patients who completed this phase of the study preferred lidoflazine and all demonstrated improved exercise capacity with lidoflazine compared to placebo. However, 3 patients developed malignant ventricular arrhythmias, and 1 died while taking lidoflazine, resulting in termination of the study. Limited coronary vasodilator response in microvascular angina has a reversible vasoconstrictor component and may be due to elevated systolic calcium levels. Despite the hemodynamic, symptom and exercise benefit, lidoflazine may be unsafe for clinical use because of its propensity to cause potentially fatal ventricular arrhythmias.

Randomized, placebo-controlled evaluation of lidoflazine in patients receiving beta-blocker therapy with propranolol: improvement in anginal symptoms and exercise tolerance with combined drug therapy.

Twenty-nine patients symptomatic despite beta-blocker therapy were entered into a randomized, double-blind, placebo-controlled, crossover trial of lidoflazine added to propranolol. After clinically documented beta blockade was achieved, patients were randomized to either propranolol plus placebo (P) or propranolol plus lidoflazine (L). Patients initially receiving lidoflazine (group with treatment sequence LP) showed improvement in exercise tolerance from propranolol alone (7.2 to 9.3 minutes, p less than 0.05). Those randomized initially to propranolol plus placebo (group with treatment sequence PL) had unchanged exercise tolerance (7.3 minutes). After 4 months, patients were crossed over to the alternative form of therapy. Patients (group PL) now receiving lidoflazine in addition to propranolol increased their exercise duration (7.8 minutes), but not, significantly. However, patients switched to propranolol plus placebo (group LP) continued to sustain their improved exercise capacity, showing a "carryover" effect. Symptomatic improvement was manifested by a statistically significant reduction in both anginal attack rate and nitroglycerin consumption. The therapeutic efficacy of combined therapy was associated with further blunting of the heart rate response to exercise achieved by beta blockade alone. The combination of agents was well tolerated.

Second-generation calcium antagonists: search for greater selectivity and versatility.

Calcium antagonists have a variable specificity for cardiac and peripheral activity. Based on such activity, these compounds, new and old, can be classified into 4 categories. Type 1 agents, typified by verapamil, its congeners (tiapamil and gallopamil) and diltiazem, prolong atrioventricular nodal conduction and refractoriness with little effect on ventricular or atrial refractoriness. These actions, to a large extent, account for the antiarrhythmic properties of this type of calcium antagonists. Type 2 agents include nifedipine and other dihydropyridines. In vivo, these agents are devoid of electrophysiologic effects in usual doses and concentrations. They are potent peripheral vasodilators with some selectivity of action for different vascular beds; their overall hemodynamic effects are dominated by this peripheral vasodilatation and reflex augmentation of sympathetic reflexes. Type 3 agents are flunarizine and cinnarizine (piperazine derivatives); in vitro and vivo, they are potent dilators of peripheral vessels, with no corresponding calcium-blocking actions in the heart. Type 4 agents (perhexiline, lidoflazine and bepridil) have a broader pharmacologic profile; they block calcium fluxes in the heart, in the peripheral vessels or in both. They may inhibit the fast channel in the heart and have other electrophysiologic actions. A clear understanding of the varied pharmacologic properties of the different classes of calcium antagonists is likely to provide a rational basis for the use of the newer agents in clinical therapeutics.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative protective effects of nicardipine, flunarizine, lidoflazine and nimodipine against ischaemic injury in the hippocampus of the Mongolian gerbil.

1. Morphological changes characterizing delayed neuronal death (DND) of selectively vulnerable CA1 pyramidal cells in the hippocampus of the Mongolian gerbil brain occurred 72 h after transient (5 min) bilateral occlusion of the common carotid arteries. 2. Different groups of animals were treated 15 min before carotid artery occlusion and twice daily during the 72 h post-ischaemia period with either saline alone, nicardipine, flunarizine, lidoflazine or nimodipine at doses of 500 micrograms kg-1 intraperitoneally. 3. At 72 h the animals were killed and their brains examined histologically. Absolute cell counts were made from 5 sites distributed linearly throughout the hippocampal CA1 subfield in each hemisphere to determine the percentage DND in each group. Normal brains and those of sham-operated animals were included in the study for comparison. 4. Features of DND were distributed evenly throughout the CA1 subfield in both hemispheres in all groups of gerbils. Nicardipine, lidoflazine and flunarizine, but not nimodipine, were protective. This protection extended linearly throughout the hippocampus without altering the pattern of neuronal damage. 5. Compared to saline-treated (78.3 +/- 2.9% DND) and nimodipine-treated (76.5 +/- 3.4% DND) gerbils, the overall protection afforded by nicardipine (41.8 +/- 3.8% DND) was statistically significant. The effects of lidoflazine (53.6 +/- 7.1%) and flunarizine (55.8 +/- 3.9% DND) were of borderline significance. 6. Abnormal neurones appeared in normal and sham-operated brains to the extent of 4.5 +/- 1.0% and 4.6 +/- 0.4%, respectively. Such changes can be attributed to fixation artefacts. 7. The results demonstrate that overall protection is conferred on ischaemic hippocampal CA1 neurones by nicardipine and to a lesser extent by flunarizine and lidoflazine, but not by nimodipine.

Comparison of negative inotropic potency, reversibility, and effects on calcium influx of six calcium channel antagonists in cultured myocardial cells.

The negative inotropic effects of calcium channel antagonists on the myocardium were used as a standard for the definition and determination of potency of this group of drugs. The effects of six calcium channel antagonists (verapamil, methoxyverapamil (D600), nifedipine, lidoflazine, perhexiline and diltiazem) were compared on cultured chick embryo ventricular cells. Drug concentrations producing 50% inhibition of contractile amplitude, derived from linearized concentration-response curves, varied from 2.8 X 10(-8)M for nifedipine to 8.3 X 10(-7)M for perhexiline. Equipotent negative inotropic concentrations of verapamil, D600, perhexiline, diltiazem and lidoflazine produced a similar inhibitory effect on 45Ca uptake into cultured cells. Nifedipine produced no significant inhibition of 45Ca uptake. The time required for recovery of contractility after cessation of drug superfusion varied in the order lidoflazine greater than perhexiline greater than D600 greater than verapamil greater than nifedipine greater than diltiazem. This relative order accords closely with the reported in vivo half-lives of these drugs. It is concluded that while some inhibition of 45Ca2+ uptake into cardiac cells can be demonstrated with five of the six calcium channel blockers studied, the relationship between the degree of inhibition of calcium influx and negative inotropic effects may not be uniform for all calcium channel antagonists.

The accumulation of adenosine in rabbit intestinal muscle.

1 Strips of longitudinal muscle from rabbit intestine accumulated radioactivity when exposed to [(3)H]-adenosine.2 Accumulation of radioactivity was not sodium-dependent or ouabain-sensitive, but was reduced by cooling, zero glucose plus bubbling with N(2), 2,4,dinitrophenol, dipyridamole, hexobendine and lidoflazine.3 After 7 min exposure to [(3)H]-adenosine, the tissue was found to contain radioactive adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and adenosine itself in the approximate ratio 13: 6: 4: 1.4 In the presence of dipyridamole, hexobendine or lidoflazine (each 1 muM), the amounts of radioactive ATP, ADP, AMP and adenosine were reduced with the concentration of adenosine not significantly different from controls.5 It is concluded that energy-dependent uptake of adenosine does not occur in the longitudinal muscle of rabbit intestine. Adenosine enters the tissue by a passive process and rapidly becomes phosphorylated giving rise to apparently high tissue: medium ratios.6 The drugs dipyridamole, hexobendine and lidoflazine appear to reduce the accumulation of radioactivity by preventing the formation of adenosine phosphate derivatives.

Lidoflazine in the early stages of acute myocardial ischaemia.

1 Pretreatment of anaesthetized rats with intravenously administered lidoflazine (an antianginal agent) reduced the incidence and severity of ventricular arrhythmias which resulted from acute coronary artery ligation. Ventricular fibrillation was completely prevented by doses of 50 micrograms/kg and 2 mg/kg and no animal so treated died ( contrast 50% incidence of fibrillation in the controls and 30% mortality). 2 In anaesthetized greyhound dogs, lidoflazine (2 mg/kg) administration resulted in transient reductions in systemic arterial pressure, LV dP/dt max and cardiac output. Coronary sinus Po2 was markedly increased, indicating pronounced coronary vasodilatation. 3 Lidoflazine pretreatment inhibited the increase in epicardial ST-segment elevation which resulted, in dogs, from short (3 min) occlusions of the left anterior descending coronary artery. This effect was especially marked at sites where, in control occlusions, ST-segment elevation was most pronounced. 4 Lidoflazine greatly reduced the number of ventricular ectopic beats which usually resulted from more prolonged (30 min) periods of acute coronary artery occlusion. There was no ventricular fibrillation in these dogs (contrast 25% incidence in the controls). 5 Lidoflazine did not modify the ventricular fibrillation which results from reperfusion of a previously ischaemic area of the left ventricular wall.

Some effects of dipyridamole, hexobendine and lidoflazine on inhibitory processes in rabbit duodenum.

Some of the effects of dipyridamole, hexobendine and lidoflazine on mechanical responses in rabbit duodenum have been investigated. In concentrations known to inhibit tissue accumulation of adenosine and its metabolites, none of these agents potentiated inhibitory responses to intramural nerve stimulation or to application of adenosine, adenosine triphosphate or phenylephrine. These results neither support nor dispute the suggestion that adenosine or a related nucleotide is the intramural inhibitory transmitter but do show that tissue accumulation in rabbit duodenum is not an important feature in the termination of the action of adenosine.

Nucleoside influx and efflux in guinea-pig ventricular myocytes. Inhibition by analogues of lidoflazine.

Adenosine influx and formycin B influx and efflux were characterized in guinea-pig ventricular myocytes at 22 degrees. Transport by both modes was saturable and inhibited by nitrobenzylthioinosine (NBMPR), indicating the presence of an equilibrative NBMPR-sensitive nucleoside transporter in the cardiomyocytes. The kinetic constants for influx and efflux of formycin B, a non-metabolized nucleoside, were similar, suggesting that the nucleoside transporter exhibits symmetrical kinetics (apparent Km 490 +/- 160 and 700 +/- 140 microM; Vmax 6.5 +/- 1.7 and 3.5 +/- 0.3 nmol/10(6) cells per min for influx and efflux, respectively). No evidence was found of either NBMPR-insensitive equilibrative nucleoside transport or sodium-dependent concentrative nucleoside transport. Inhibition of adenosine influx (apparent Km100 +/- 33 microM), by lidoflazine and the analogues mioflazine, soluflazine and R73-335, gave average Ki values of 730, 100, 64 and 2.9 nM, respectively. These compounds also inhibited formycin B efflux with a similar potency to that of adenosine influx. NBMPR-sensitive nucleoside transport was associated with high affinity binding of NBMPR (apparent Kd approximately 1 nM; 9.6 x 10(5) sites/cell). Specific binding of NBMPR was also inhibited by lidoflazine and its analogues. Mioflazine and soluflazine were 20-30-fold more potent at inhibiting NBMPR-sensitive nucleoside influx in guinea-pig erythrocytes than ventricular myocytes, indicating that the potency of some of the compounds studied is tissue dependent.

Differential inhibition of nucleoside transport systems in mammalian cells by a new series of compounds related to lidoflazine and mioflazine.

The sensitivity of facilitated-diffusion and Na(+)-dependent nucleoside transporters to inhibition by a series of novel compounds related to lidoflazine and mioflazine was investigated. Uridine transport by rabbit erythrocytes, which proceeds solely by the nitrobenzylthioinosine (NBMPR)-sensitive facilitated-diffusion system, was inhibited with apparent Ki values of less than 10 nM by lidoflazine, mioflazine, soluflazine and R73-335. These compounds also blocked site-specific [3H]NBMPR binding to rabbit erthrocyte membranes in a competitive fashion. The NBMPR-sensitive system in rat erythrocytes was also inhibited by lidoflazine, mioflazine, soluflazine and R73-335 but was two to three orders of magnitude less sensitive to inhibition than the system in rabbit erythrocytes (apparent Ki 7.3, 2.4, 5.7 and 0.1 microM, respectively). Lidoflazine, mioflazine and R73-335 exhibited a similar potency for the NBMPR-sensitive and -insensitive nucleoside transporters in rat erythrocytes. In contrast, soluflazine was 20- to 100-fold more potent as an inhibitor of the NBMPR-insensitive nucleoside transport component in rat erythrocytes (IC50 of 0.08-0.2 microM) compared to the NBMPR-sensitive nucleoside carrier in these cells (IC50 approximately 10 microM). None of the test compounds were potent inhibits of Na(+)-dependent uridine transport in bovine renal brush-border membrane vesicles. These results indicate that lidoflazine, mioflazine, soluflazine and R73-335 are selective inhibitors of nucleoside transport in animal cells and that the potency of these compounds as nucleoside transport inhibitors is species dependent.