European Journal of Pharmacology (v.431, #1)

In isolated rat peritoneal mast cells, an outwardly rectifying Cl channel has been described. Influx of Cl through this Cl channel (ICl(OR)) causes hyperpolarization, which facilitates Ca2+ currents through store-operated Ca2+ channels. The exocytotic effect of nerve growth factor (NGF) in the presence of lyso-phosphatidylserine strictly depends on the presence of extracellular [Ca2+]o. The aim of the present study was to assess the importance of ICl(OR) for exocytosis induced by NGF/lyso-phosphatidylserine. Therefore, we investigated the effects on NGF/lyso-phosphatidylserine-induced exocytosis of [3H]5-hydroxytryptamine ([3H]5-HT) in rat peritoneal mast cells: (a) of two inhibitors of ICl(OR) (4,4′-diisothiocyanatostilbene2,2′-disulfonic acid [DIDS] and diethylstilbestrol), and (b) of replacement of extracellular Cl by methylsulfate. Additionally, whole-cell patch-clamp experiments (nystatin-perforated patch) were performed. Diethylstibestrol and DIDS, in concentrations sufficient to abolish the ICl(OR) (10 μM) and the replacement of (Cl)o by methylsulfate, were ineffective in impairing the NGF/lyso-phosphatidylserine-induced [3H]5-HT-release. These findings argue against a role of outwardly rectifying Cl channels in exocytosis induced by NGF/lyso-phosphatidylserine in rat peritoneal mast cells.
Keywords: Exocytosis; Secretion; Cl channel; NGF; Mastoparan; Mast cell; Patch-clamp; Membrane potential;

Effect of FR194738, a potent inhibitor of squalene epoxidase, on cholesterol metabolism in HepG2 cells by Masae Sawada; Masahiko Matsuo; Hiroyuki Hagihara; Noriko Tenda; Akira Nagayoshi; Hiroyuki Okumura; Ken-ichi Washizuka; Jiro Seki; Toshio Goto (11-16).
(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[2-methyl-2-(3-thienylmethoxy)propyloxy]benzylamine hydrochloride (FR194738) inhibited squalene epoxidase activity in HepG2 cell homogenates with an IC50 value of 9.8 nM. In the study using intact HepG2 cells, FR194738 inhibited cholesterol synthesis from [14C]acetate with an IC50 value of 4.9 nM, and induced intracellular [14C]squalene accumulation. On the other hand, the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor simvastatin reduced both cholesterol and squalene synthesis from [14C]acetate. Incubation with simvastatin for 18 h produced increases in HMG-CoA reductase activity in HepG2 cells, which was related to the degree of reduction in cholesterol synthesis. The HMG-CoA reductase activity increased by 13- and 19-fold at the concentrations of simvastatin that inhibited cholesterol synthesis by 65% and 82%, respectively. In contrast, FR194738 did not increase HMG-CoA reductase activity at the concentrations that inhibited cholesterol synthesis by 24% and 69%, and moderate increase (4.6-fold) was observed at the concentration that inhibited cholesterol synthesis by 90%. These results suggest that non-sterol metabolite(s) derived from mevalonate prior to the squalene epoxidation step in the cholesterol synthetic cascade have a regulatory role in the suppression of HMG-CoA reductase activity. We speculate that FR194738 inhibits cholesterol synthesis with a minimal change of the regulator(s) and would be highly effective in the treatment of hypercholesterolemia.
Keywords: FR194738; Squalene epoxidase; Simvastatin; HMG-CoA reductase; HepG2 cell;

KF31327, a new potent and selective inhibitor of cyclic nucleotide phosphodiesterase 5 by Ryo Hirose; Hiroshi Okumura; Akiko Yoshimatsu; Junko Irie; Yasuo Onoda; Yuji Nomoto; Haruki Takai; Tetsuji Ohno; Michio Ichimura (17-24).
The effects of KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione dihydrochloride) on phosphodiesterase 5 (cyclic GMP-specific phosphodiesterase) activity and platelet aggregation were investigated and compared with those of sildenafil, a well-known phosphodiesterase 5 inhibitor. KF31327 inhibited phosphodiesterase 5 from canine trachea (K i=0.16 nM) more potently than sildenafil (K i=7.2 nM). The kinetic analysis revealed that KF31327 was a non-competitive inhibitor. In the presence of nitroglycerin (nitric oxide generator), both compounds inhibited the collagen-induced aggregation of rabbit platelets at less than 0.1 μM, augmenting intracellular cyclic GMP level without affecting cyclic AMP. In contrast, in the absence of nitroglycerin, a higher concentration (10 μM) of KF31327 was required to inhibit platelet aggregation and increased both cyclic nucleotide levels. However, 10 μM sildenafil did not affect aggregation despite elevation of cyclic GMP comparable to that in the presence of nitroglycerin. These results indicate that in the presence of nitroglycerin, the inhibition of platelet aggregation by KF31327 is due to the elevation of cyclic GMP, whereas the mechanism underlying the inhibition without nitroglycerin might be related to a rise in intracellular cyclic AMP.
Keywords: KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione dihydrochloride); Phosphodiesterase 5 (cyclic GMP-specific phosphodiesterase); cAMP; cGMP; Platelet; Sildenafil;

The antiepileptic drug valproic acid (2-propylpentanoic acid) is a potent teratogen in both humans and mice. Valproic acid can induce differentiation of F9 teratocarcinoma cells and stimulate peroxisome proliferator-activated receptor (PPAR) activity. In this study, the structure–activity relationship between valproic acid, its teratogenic and non-teratogenic analogues (branched small- and medium chain fatty acids) and the three PPAR subtypes α, γ or δ was investigated. PPAR-α and PPAR-γ were activated by some valproic acid-derivatives; however, no correlation between teratogenicity and receptor activation could be observed. In contrast, only valproic acid and exclusively its teratogenic analogues were able to activate PPAR-δ in different cellular systems. However, valproic acid appears not to be a direct ligand of PPAR-δ, since in contrast to carbaprostacyclin (cPGI), valproic acid showed not to be able to induce complex formation of PPAR-δ–retinoid X receptor (RXR) heterodimers on DNA. In conclusion, in contrast to PPAR-α and PPAR-γ, PPAR-δ shows to be a specific sensor for teratogenic valproic acid-derivatives.
Keywords: PPAR (peroxisome proliferator-activated receptor); Valproic acid; Nuclear receptor; Fatty acid; Teratogenicity;

A novel 5-HT3 receptor agonist, YM-31636, increases gastrointestinal motility without increasing abdominal pain by Tetsuo Kiso; Hiroyuki Ito; Keiji Miyata; Takeshi Kamato; Yuki Naitoh; Kiyoshi Iwaoka; Tokio Yamaguchi (35-41).
We examined the effects of YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate), a novel 5-HT3 receptor agonist, on gastrointestinal functions including visceral pain reflex in rats. Injection of YM-31636 increased the number of fecal pellets. This effect was completely inhibited by ramosetron, a 5-HT3 receptor antagonist. YM-31636 also increased the intracolonic pressure measured in both conscious and anesthetized rats. In isolated distal colon, YM-31636 increased the short-circuit current response. This effect was abolished by ramosetron. Both the maximal response and the potency of YM-31636 were weaker than those of other 5-HT3 receptor agonists. In two visceral pain reflex models, YM-31636 neither changed the magnitude of pressor response to colonic distension in anesthetized rats nor affected the visceromotor threshold to colorectal distension in conscious rats. In conclusion, YM-31636 facilitated defecation without increasing visceral pain. Consequently, 5-HT3 receptor agonists like YM-31636 would be promising in the treatment of chronic constipation.
Keywords: YM-31636; 5-HT3 receptor agonist; Visceral pain; Constipation; Defecation; Short-circuit current;

Effect of glucose on antipsychotic drug-induced changes in dopamine neuronal activity by Arthur S Freeman; F.Karl Weddige; Joseph L Lipinski (43-46).
The effect of glucose on antipsychotic drug-induced changes in the spontaneous activity of rat midbrain dopaminergic neurons was tested with the cells-per-track extracellular electrophysiology method. After daily s.c. treatment with vehicle, haloperidol (0.5 mg/kg), or clozapine (20 mg/kg) for 21 days, rats were anesthetized and recordings performed on one side of the brain. Then, glucose (250 mg/kg, i.v.) was administered and recordings were made from the contralateral midbrain. Glucose significantly reduced the number of spontaneously active A9 and A10 dopaminergic cells per track in control rats, but significantly attenuated the chronic haloperidol- and clozapine-induced reductions in dopaminergic cells per track. These results suggest that caloric intake may influence antipsychotic drug-induced changes in the population activity of midbrain dopaminergic neurons.
Keywords: Antipsychotic; Clozapine; Haloperidol; Dopamine electrophysiology; Obesity;

Effects of dextromethorphan on nocturnal behavior and brain c-Fos expression in adolescent rats by Jeong Won Jahng; Tie Yuan Zhang; Seoul Lee; Dong Goo Kim (47-52).
Dextromethorphan, an antitussive widely available over-the-counter, is abused, mostly by teenagers at high doses. In our previous report, a high dose of dextromethorphan activated the midbrain dopamine neurons of adolescent rats. In the present study, we performed c-Fos immunohistochemistry in the dopaminergic terminal regions of adolescent rat brain after the intraperitoneal administration of dextromethorphan at different doses (0, 10, 20, and 40 mg/kg), and also examined the effects on nocturnal behavior. The results showed that dextromethorphan increased c-Fos expression dose dependently in the anterior cingulate cortex, caudate putamen, nucleus accumbens, and central amygdala. Significant ataxia occurred and both locomotor and rearing activity decreased immediately after the dextromethorphan injection. We conclude that the neurons in the reward pathway of the adolescent rat brain appear to be activated by a single injection of dextromethorphan, and that activation of this pathway by dextromethorphan may correlate with the behavioral effects and abuse potential of the drug.
Keywords: Dextromethorphan; c-Fos; Drug abuse; Nocturnal behavior; Reward pathway;

Effects of cocaine and cocaine metabolites on cardiovascular function in squirrel monkeys by Charles W Schindler; Ji-Wang Zheng; Steven R Goldberg (53-59).
The effects of cocaine and the cocaine metabolites norcocaine, ecgonine methyl ester, benzoylecgonine and cocaethylene were evaluated in conscious squirrel monkeys for their effects on blood pressure and heart rate. Norcocaine, ecgonine methyl ester and benzoylecgonine are produced in vivo following cocaine use. Cocaethylene is produced in vivo following concurrent cocaine and alcohol use. Increases in both blood pressure and heart rate were observed following cocaine doses of 0.3–3.0 mg/kg. Ecgonine methyl ester and benzoylecgonine had no effect on either parameter up to doses of 10.0 mg/kg. Norcocaine increased blood pressure, but was less potent than cocaine. Norcocaine did not affect heart rate at doses up to 3.0 mg/kg. In contrast to the other metabolites, cocaethylene increased blood pressure and heart rate similarly to cocaine. These results suggest that ecgonine methyl ester and benzoylecgonine are devoid of cardiovascular effects at doses comparable to cocaine and would not be expected to contribute to cocaine's overall cardiovascular effects. Norcocaine's effect on blood pressure might contribute to the cardiovascular effects of cocaine, but this metabolite is produced only at low levels in vivo. The one metabolite that might be expected to contribute to cocaine's overall cardiovascular effect is cocaethylene, although the degree of this contribution is not clear.
Keywords: Cocaine; Cocaine metabolites; Blood pressure; Heart rate; Squirrel monkeys;

The present study was undertaken to investigate relaxant effect of l-citrulline in phenylephrine precontracted endothelium intact thoracic aortic rings obtained from control or lipopolysaccharide (1 mg/kg)-treated rats. l-Citrulline produced 40±3% (n=36) and 60±5% (n=24) relaxations in control and lipopolysaccharide-treated rings, respectively. Nitric oxide (NO) release and cyclic guanosine-3′,5′-monophosphate levels from the rings were also increased following treatment with l-citrulline. Inhibition of guanylate cyclase, l-citrulline recycling to l-arginine or denudation of the endothelium, significantly reduced l-citrulline-induced relaxations both in control and lipopolysaccharide-treated rings. Treatment of rings with protein synthesis inhibitors prevented relaxations to l-citrulline. Inhibitor of Ca2+-activated K+ channels, tetrabutylammonium or precontraction of the rings with KCl (80 mM), significantly attenuated l-citrulline mediated relaxations in control and lipopolysaccharide-treated rings. Thus, l-citrulline seems to exert significant relaxation by supplementing the release of NO due to its recycling to l-arginine, which gets further augmented after lipopolysaccharide treatment.
Keywords: l-Citrulline; l-Arginine; Nitric Oxide (NO); Vascular relaxation; Lipopolysaccharide; Aortic ring;

Gender differences and antioxidant treatment affect aortic reactivity in short-term diabetic rats by Christian Pinna; Andrea Cignarella; Rossella Zanardo; Chiara Bolego; Lina Puglisi (71-79).
Diabetes is associated with gender-specific macrovascular complications arising from increased oxidant stress in the vascular wall. In this study, male and female rats were treated with two structurally unrelated drugs sharing antioxidant properties, lercanidipine and Leucoselect™ (both 3 mg/kg/day), for 1 week starting 1 day after streptozotocin-diabetes induction. Concentration–response curves to l-nitroarginine methylester (l-NAME), superoxide dismutase and acetylcholine in aortic rings showed significantly greater nitric oxide-mediated relaxation in female compared with male non-diabetic rats. Diabetes increased contractility to noradrenaline and l-NAME in both genders, whereas relaxation to acetylcholine and iloprost were significantly attenuated in females only. Treatment with lercanidipine and Leucoselect restored, at least in part, responses to noradrenaline, acetylcholine and iloprost without affecting those to l-NAME and sodium nitroprusside. Unexpectedly, both drugs impaired superoxide dismutase response in female tissues. In conclusion, female rat aorta is markedly exposed to short-term diabetic vascular injury, which may be prevented by antioxidant treatment.
Keywords: Diabetes; Aorta; Nitric oxide (NO); Lercanidipine; Leucoselect; Antioxidant;

Isolated preparations of rat prostate responded to electrical field stimulation (2 strains every 60 s, 0.5 ms, 10 Hz, 80 V) with contractions. The adrenoceptor agonists adrenaline, isoprenaline and noradrenaline (0.1 nM–10 μM) elicited concentration-dependent inhibition of electrical field stimulation-induced contractions of the rat prostate. Phenylephrine had no effect on the amplitude of electrical field stimulation-induced contractions. The rank order of potency was isoprenaline≥adrenaline=noradrenaline>phenylephrine. Inhibition of electrical field stimulation-induced contractions by isoprenaline was attenuated by propranolol (1 μM). The selective β1-adrenoceptor agonist (−)-1-(3,4-dimethoxy-phenethylamino)-3-(3,4-dihydroxyphenoxy)-2-propanol)oxalate (RO363) and the selective β2-adrenoceptor agonist salbutamol (1 nM–100 μM) were approximately equipotent in inhibiting electrical field stimulation-induced contractions but the selective β3-adrenoceptor agonist sodium 4-(2-[2-hydroxy-{3-chlorophenyl}ethylamino]propyl)phenoxyacetate (BRL 37344, 1 nM–100 μM) did not inhibit electrical field stimulation-induced contractions. The selective β2-adrenoceptor antagonist, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118 551, 0.1 μM) attenuated inhibitory responses to isoprenaline and salbutamol, while the selective β1-adrenoceptor antagonist atenolol (3 μM) did not. Contractions induced by electrical field stimulation were also inhibited by forskolin (10 nM–3 mM) but unaffected by sodium nitroprusside (10 nM–1 mM) indicating the presence of an inhibitory cAMP mechanism. These data suggest that stimulation of β2-adrenoceptors can inhibit contractions of the rat prostate induced by electrical field stimulation.
Keywords: (Rat); Neuromuscular transmission; Inhibitory receptor; Isoprenaline; Propranolol; Salbutamol;

Celecoxib, a selective cyclo-oxygenase-2 inhibitor reduces the severity of experimental colitis induced by dinitrobenzene sulfonic acid in rats by Salvatore Cuzzocrea; Emanuela Mazzon; Ivana Serraino; Laura Dugo; Tommaso Centorrino; Antonio Ciccolo; Lidia Sautebin; Achille P Caputi (91-102).
Inflammatory bowel disease is characterised by oxidative and nitrosative stress, leukocyte infiltration, upregulation of the expression of intercellular adhesion molecule 1 (ICAM-1) and upregulation of P-selectin in the colon. Here, we investigate the effects of the selective cyclo-oxygenase-2 inhibitor, celecoxib, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Rats experienced hemorrhagic diarrhoea and weight loss. At 4 days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology, as well as an increase in myeloperoxidase activity in the mucosa) was associated with upregulation of ICAM-1 and P-selectin, as well as high tissue levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) polymerase showed intense staining in the inflamed colon. Celecoxib (5 mg/kg twice a day orally) significantly reduced the degree of hemorrhagic diarrhoea and the weight loss caused by administration of DNBS. Celecoxib also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde, (iv) the increase in staining (immunohistochemistry) for nitrotyrosine, as well as (v) the upregulation of ICAM-1 and P-selectin caused by DNBS in the colon. Thus, we provide the first evidence that a selective cyclo-oxygenase-2 inhibitor celecoxib reduces the degree of colitis caused by DNBS.
Keywords: DNBS (Dinitrobenzene sulfonic acid); Inflammation; Nitric oxide (NO); Peroxynitrite; Poly(ADP-ribose) polymerase; Colon damage; Free radicals; Cyclo-oxygenase-2;

Effects of tumour necrosis factor-α synthesis inhibitors on rat trinitrobenzene sulphonic acid-induced chronic colitis by Christine Bobin-Dubigeon; Xavier Collin; Nicole Grimaud; Jean-Michel Robert; Guillaume Le Baut; Jean-Yves Petit (103-110).
The fact that tumour necrosis factor-α (TNF-α) is clearly involved in the pathogenesis of intestinal bowel disease, especially Crohn's disease, suggests that TNF-α synthesis inhibitors could be beneficial for treatment. The present study assessed the effect of chronic oral gavage of two in vitro TNF-α synthesis inhibitors, JM 34 maleate or [N-(4,6-dimethylpyridin-2-yl)-furane-2-carboxamide)] maleate and XC 21 or (N-βpicolyl-tetrafluorophtalimide), on colonic inflammation in trinitrobenzene sulphonic acid-induced colitis in rats. Rats received JM 34 maleate (100 mg/kg) and XC 21 (50 mg/kg) 1 h before colitis induction and then daily for 8 days by oral gavage. The colon was removed on day 8 and processed for clinical score, myeloperoxidase activity, and soluble TNF-α release. Treatment with XC 21, as well as dexamethasone and sulphasalazine, reduced colonic damage and decreased (except with dexamethasone) the incidence of diarrhoea. JM 34 maleate failed to improve the clinical signs of chronic colitis. After trinitrobenzene sulphonic acid-induced colitis, myeloperoxidase activity and TNF-α colonic mucosal production were substantially increased compared to the control (saline instillation). Both of these inflammatory indicators were then significantly decreased (P≤0.05) after the four chronic treatments (JM 34 maleate, XC 21, sulphasalazine, and dexamethasone). XC 21 appeared to be as efficient as sulphasalazine in improving colonic inflammation.
Keywords: TNF-α (Tumour necrosis factor-α); Colitis; Inflammatory bowel disease; Thalidomide derivative; Phthalimide derivative; Heterocarboxamide; JM 34 maleate;

Effects of taurine on pulmonary responses to antigen in sensitized Brown–Norway rats by Julio Cortijo; Sebastian Blesa; Magdalena Martinez-Losa; Manolo Mata; Enrique Seda; Francesco Santangelo; Esteban J Morcillo (111-117).
Oxidative stress appears relevant to asthma. Therefore, the effects of the antioxidant taurine (oral, 1 and 3 mmol kg−1 day−1 for 7 days before challenge) were examined on antigen-induced responses in sensitized Brown–Norway rats. Taurine did not reduce the bronchospasm produced by aerosol antigen but prevented airway hyperreactivity to 5-hydroxytryptamine (5-HT) at 24 h after antigen exposure, and reduced the eosinophils (from 0.178±0.038×106 to 0.044±0.014×106* and 0.048±0.013×106* cells ml−1 in antigen and antigen+taurine 1 or 3 mmol kg−1, respectively; *P<0.05 vs. antigen), lipid hydroperoxides, and Evans blue dye extravasation in bronchoalveolar lavage fluid. Taurine levels in bronchoalveolar lavage fluid from antigen-challenged rats were higher than control values but treatment with taurine failed to further increase these levels. In conclusion, oral taurine showed beneficial effects in an in vivo model of experimental asthma, which confirm and extend the previous positive findings obtained in other models of lung injury.
Keywords: Experimental asthma; Brown–Norway rat; Taurine;

The effects of mitiglinide (KAD-1229), a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion: comparison with the sulfonylureas and nateglinide by Yasuhiro Sunaga; Tohru Gonoi; Tadao Shibasaki; Kiyoshi Ichikawa; Hiroshi Kusama; Hideki Yano; Susumu Seino (119-125).
Mitiglinide (KAD-1229), a new anti-diabetic drug, is thought to stimulate insulin secretion by closing the ATP-sensitive K+ (KATP) channels in pancreatic β-cells. However, its selectivity for the various KATP channels is not known. In this study, we examined the effects of mitiglinide on various cloned KATP channels (Kir6.2/SUR1, Kir6.2/SUR2A, and Kir6.2/SUR2B) reconstituted in COS-1 cells, and compared them to another meglitinide-related compound, nateglinide. Patch-clamp analysis using inside-out recording configuration showed that mitiglinide inhibits the Kir6.2/SUR1 channel currents in a dose-dependent manner (IC50 value, 100 nM) but does not significantly inhibit either Kir6.2/SUR2A or Kir6.2/SUR2B channel currents even at high doses (more than 10 μM). Nateglinide inhibits Kir6.2/SUR1 and Kir6.2/SUR2B channels at 100 nM, and inhibits Kir6.2/SUR2A channels at high concentrations (1 μM). Binding experiments on mitiglinide, nateglinide, and repaglinide to SUR1 expressed in COS-1 cells revealed that they inhibit the binding of [3H]glibenclamide to SUR1 (IC50 values: mitiglinide, 280 nM; nateglinide, 8 μM; repaglinide, 1.6 μM), suggesting that they all share a glibenclamide binding site. The insulin responses to glucose, mitiglinide, tolbutamide, and glibenclamide in MIN6 cells after chronic mitiglinide, nateglinide, or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment. These results indicate that, similar to the sulfonylureas, mitiglinide is highly specific to the Kir6.2/SUR1 complex, i.e., the pancreatic β-cell KATP channel, and suggest that mitiglinide may be a clinically useful anti-diabetic drug.
Keywords: KATP channel; Sulfonylurea receptor (SUR); Mitiglinide; Nateglinide; Insulin secretion;

To examine whether a microsomal triglyceride transfer protein (MTP)-inhibitor is effective in patients with homozygous familial hypercholesterolemia, we administered (2S)-2-cyclopentyl-2-{4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl}-N-[(1S)-2-hydroxy-1-phenylethyl]ethanamide (Implitapide), a new MTP inhibitor, to low-density lipoprotein (LDL)-receptor-deficient Watanabe heritable hyperlipidemic (WHHL) rabbits at doses of 3, 6, and 12 mg/kg for 4 weeks. In the 12 mg/kg group, the plasma cholesterol and triglyceride levels were decreased by 70% and 45%, respectively, and the very low-density lipoprotein (VLDL) secretion rate was decreased by 80%. The composition of newly secreted VLDL was similar in each group. This suggests that Implitapide diminished the number of VLDL particles secreted from the liver. Although the ratio of vitamin E/LDL was not altered by Implitapide, triglyceride accumulation and a decrease in vitamin E were observed in the liver. In conclusion, an inhibition of VLDL secretion led to a decrease of plasma LDL in WHHL rabbits, and MTP inhibitors should have hypolipidemic effects against homozygous familial hypercholesterolemia.
Keywords: MTP inhibitor; Implitapide; VLDL (very low-density lipoprotein) secretion; Hypolipidemic effect; WHHL;