Alpha1A-adrenoceptor antagonist improves underactive bladder associated with diabetic cystopathy via bladder blood flow in rats.

BACKGROUND: Patients with diabetes experience lower urinary tract symptoms. Cystopathy may evolve into underactive bladder (UAB), depending on the degree and duration of the symptoms. In the present study, we aimed to investigate the effects of silodosin, an alpha1A-adrenoceptor (AR) antagonist, on UAB in a rat model of diabetes mellitus (DM). METHODS: Female Sprague-Dawley rats (6 weeks old) were administered streptozotocin (STZ) (50 mg/kg, i.v.) to establish a DM model. One week after STZ administration, vehicle or silodosin (0.3 or 1 mg/kg/day) was delivered subcutaneously through an osmotic pump. Nine weeks after STZ administration (8 weeks after drug treatment), a catheter was implanted into the bladder under urethane anesthesia. After the measurement of emptied bladder blood flow (BBF), saline was continuously infused into the bladder and intravesical pressure and micturition volume were measured. In another experiment, the bladder was isolated and nerve markers were quantified. RESULTS: A cystometrogram showed that bladder capacity (BC), residual volume (RV), and bladder extension (BC/bladder weight) increased by 7.43, 10.47, and 3.59 times, respectively, in vehicle rats in comparison with normal rats. These findings suggested the occurrence of UAB-like symptoms in this model. Silodosin (1 mg/kg/day) inhibited the increase in BC and RV by 49.0% and 46.8%, respectively, and caused a decrease in BBF of approximately 25.5% (when the difference between normal and vehicle was set as 100%) in STZ rats. The nerve marker expression levels tended to be decreased in the bladders of STZ rats and these effects were ameliorated by silodosin. CONCLUSIONS: The STZ rats showed increased bladder extension and RV, symptoms that were suggestive of UAB, and these symptoms were ameliorated by silodosin. These results suggested that the alpha1A-AR antagonist would be useful for the prevention or treatment of UAB.

Silodosin, an α(1A)-Adrenoceptor Antagonist, May Ameliorate Ischemia-Induced Bladder Denervation and Detrusor Dysfunction by Improving Bladder Blood Flow.

BACKGROUND/AIMS: This study was performed to investigate the detailed mechanism underlying the effects of the selective α(1A)-adrenoceptor antagonist, silodosin, on bladder function in a rat model of atherosclerosis-induced chronic bladder ischemia (CBI). METHODS: The CBI model was prepared by balloon endothelial injury of the bilateral iliac arteries in male rats. Using an osmotic pump, the CBI rats received either silodosin or vehicle alone subcutaneously for 8 weeks. Rats received a 2% cholesterol diet throughout the experiment. Bladder blood flow (BBF) was measured. Immunohistochemical staining was performed to determine the nerve distribution and nerve growth factor expression in the bladder. Bladders were used for muscle strip contraction analysis. The expression levels of muscarinic M2 and M3 receptors were measured. RESULTS: Silodosin abrogated the decrease in BBF in CBI rats. Silodosin prevented the decrease in nerve distribution and increase in nerve growth factor expression in the CBI model. Bladder contractile response was reduced in the CBI group. Silodosin ameliorated the effect on the bladder contractile response. The level of muscarinic M3 receptor mRNA present in the bladder of CBI rats was increased by silodosin. CONCLUSION: The results of this study suggest that silodosin ameliorates the denervation of the bladder and effects on detrusor contractile function under ischemic conditions by restoring BBF.

Effect of rovatirelin, a novel thyrotropin-releasing hormone analog, on the central noradrenergic system.

Rovatirelin ([1-[-[(4S,5S)-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)-l-alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702nM) than taltirelin (Ki=3877nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD.

Effect of silodosin, a selective α(1A)-adrenoceptor antagonist, on voiding behavior and bladder blood flow in a rat model of bladder outlet obstruction.

This study was performed to investigate the effects of silodosin (selective α1A-adrenoceptor antagonist) on bladder blood flow (BBF) and bladder function in a rat model of bladder outlet obstruction (BOO) and to determine the expression of α1-adrenoceptor subtype mRNA in human and rat bladder microvessels. BOO was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. The BOO rats received either silodosin at a rate of 0.3mg/kg/day or vehicle subcutaneously via an osmotic pump for 2 weeks after BOO surgery. A metabolic cage study was performed in conscious animals. BBF was measured using a Laser Speckle Blood Flow Imager. Urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nerve growth factor (NGF) were measured. Immunohistological examinations of nerve distribution and NGF expression in the rat bladder were conducted. The expression of each α1-adrenoceptor subtype mRNA in human and rat bladder microvessels was determined by in situ hybridization. Silodosin ameliorated the increase in voiding frequency and decrease in mean voided volume in BOO rats in the metabolic cage study. Silodosin also abrogated the decrease in BBF in BOO rats. The levels of 8-OHdG and NGF in BOO rats were significantly decreased by administration of silodosin. Silodosin prevented the decrease in nerve distribution and increase in NGF expression. Human and rat bladder microvessels showed expression of all α1-adrenoceptor subtype mRNAs. The results presented here suggest that silodosin improves voiding behavior in rat models with BOO by inducing recovery of BBF.

Effects of Silodosin, an α1A-Adrenoceptor Antagonist, and Distigmine, an Acetylcholinesterase Inhibitor, and Their Combined Effects on Impaired Voiding Function in Zucker Diabetic Fatty Rats.

BACKGROUND/AIMS: To evaluate the effects of silodosin (α1A-adrenoceptor antagonist) and distigmine (acetylcholinesterase inhibitor), alone or in combination, on voiding dysfunction in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model, by pressure flow study. METHODS: Male ZDF rats were anesthetized with urethane and a catheter was implanted into the bladder through the dome. Saline was continuously infused into the bladder at 6 ml/h to induce the micturition reflex. Intravesical pressure and micturition volume were recorded continuously and various urodynamic parameters were calculated using a waveform analysis system. RESULTS: Increased bladder capacity, residual volume, and urethral resistance and decreased maximum detrusor contraction velocity and urine flow rate, considered to be detrusor underactivity-like symptoms, were observed in ZDF rats. Although both silodosin and distigmine improved impaired voiding function, administration of both drugs in combination was more effective than either drug alone. CONCLUSIONS: ZDF rats showed symptoms suggestive of detrusor underactivity, and silodosin tended to ameliorate these symptoms in ZDF rats. These results suggested that an α1A-adrenoceptor antagonists may be effective against the voiding disorder accompanying not only bladder outlet obstruction but also deficiency of bladder function. Moreover, combined administration of an α1A-adrenoceptor antagonist with an acetylcholinesterase inhibitor may have additive efficacy in clinical use.

Comparison of the effects of four α1-adrenoceptor antagonists on ejaculatory function in rats.

OBJECTIVE: To compare the effects of four α(1)-adrenoceptor (AR) subtype-selective antagonists on ejaculatory function in rats to investigate whether the differences in their modes of action-based on their selectivities for the α(1A)-AR subtype-would be related to the prevalence of ejaculation disorder (EjD). METHODS: The effects of α(1)-AR antagonists on noradrenaline-induced contractions were studied in rat isolated seminal vesicles, vas deferens, bladder trigone, and prostate. Male rats were given α(1)-AR antagonists orally and, 1 hour after the drug administration they were cohoused in pairs for 1 hour with untreated female rats certified to be in estrus. The number of copulatory plugs (NP) present after mating was measured as a marker of EjD. Drug effects on ejaculatory function (ie, on NP) were compared with those on the prostatic urethra (ie, phenylephrine-induced increase in intraurethral pressure [IUP]). RESULTS: All α(1)-AR antagonists concentration-dependently inhibited noradrenaline-induced contraction in all 4 tissues, and there were no differences in the rank order of potencies (tamsulosin > silodosin > alfuzosin > naftopidil) among the tissues. All α(1)-AR antagonists dose-dependently decreased NP and inhibited the phenylephrine-induced increase in IUP. There was little difference in the dose ratio ID(50) value (dose required to produce 50% inhibition) for NP/ID(50) value for IUP response among the four drugs. Drug potencies associated NP and IUP correlated closely with affinities for the human α(1A)-AR. CONCLUSION: α(1)-AR antagonists cause EjD as a class effect that depends on affinity for α(1A)-AR. Differences in α(1A)-AR selectivity would be unlikely to be related to the incidence of EjD.

Bladder selectivity of the novel ß3-agonist ritobegron (KUC-7483) explored by in vitro and in vivo studies in the rat.

We performed in vitro and in vivo experiments to evaluate the pharmacological profile of ritobegron and its effects on the bladder in rats. ß(3)-AR selectivity was assessed using CHO cells expressing various subtypes of the human ß-adrenoceptor (AR). Effects on isolated organs were evaluated using the organ-bath method. Effects on intravesical pressure, heart rate, and mean blood pressure were evaluated in urethane-anesthetized rats. Ritobegron increased cAMP accumulation in a concentration-dependent manner in CHO cells expressing any one of three human ß-AR, its selectivity for ß(3)-AR being 301-fold and 32-fold higher versus ß(1)-AR and ß(2)-AR, respectively. Ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50), 7.7 × 10(-8) mol/L; maximal relaxation, 97.0 %), and the ß(3)-AR antagonist SR58894A produced a parallel rightward-shift of this concentration-response curve without altering the maximal response [pK(B) value, 6.43]. Ritobegron concentration-dependently increased atrial rate and decreased myometrial contractions in vitro, and its selectivity for the bladder was 2,078-fold higher versus the atria and 14-fold higher versus the uterus. In vivo, ritobegron induced a dose-dependent decrease in intravesical pressure (ED(50) 0.4 mg/kg), without affecting heart rate and only slightly lowering mean blood pressure. Thus, ritobegron displayed potent and selective ß(3)-AR agonistic activity toward transfected human ß-AR and exhibited a high selectivity for the bladder versus other organs in rats. Moreover, it decreased intravesical pressure with minimal effects on the cardiovascular system in anesthetized rats. These results suggest that ritobegron shows promise as a potential agent for the treatment of overactive bladder.

Effects of ritobegron (KUC-7483), a novel selective ß3-adrenoceptor agonist, on bladder function in cynomolgus monkey.

We evaluated the pharmacological profile of ritobegron [KUC-7483; (-)-ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)-2,5-dimethylphenyloxy]acetate monohydrochloride] and its effects on the bladder in cynomolgus monkeys by in vitro and in vivo experiments. In vitro, ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50) 8.2 ± 2.3 × 10(-7) M; maximal relaxation 88.7 ± 3.7%). The ß(3)-adrenoceptor (AR) antagonist 3-(2-allylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR58894A) produced a rightward shift of this concentration-response curve without altering the maximal response (pK(B) value 6.56 ± 0.35). In isolated atria, ritobegron increased the atrial rate only at high concentrations (EC(50) 6.5 ± 1.2 × 10(-5) M). Ritobegron had no effect on tracheal contraction at concentrations from 10(-9) to 10(-4) M, and even at the highest concentration tested, 10(-3) M, the maximal relaxation it induced was only 26.7 ± 8.1%. Tests of the selectivity of ritobegron for the bladder gave values of 79.3- and 1200-fold higher versus atria and trachea, respectively. In the in vivo study ritobegron significantly decreased intravesical pressure (ED(50) 1.44 mg/kg) without affecting either mean blood pressure or heart rate. In conclusion, ritobegron displayed potent and selective ß(3)-AR agonistic activity and relaxed the monkey isolated bladder, and in vivo it decreased intravesical pressure without affecting cardiovascular parameters. These results suggest that ritobegron may be a promising potential agent for the treatment of overactive bladder.

Effects of ritobegron (KUC-7483), a novel ß3-adrenoceptor agonist, on both rat bladder function following partial bladder outlet obstruction and on rat salivary secretion: a comparison with the effects of tolterodine.

The objective of this study was to investigate the effects of the ß3-adrenoceptor (AR) agonist ritobegron on rat bladder function following partial bladder outlet obstruction and on rat salivary secretion. In addition, the effects of ritobegron were compared with those of the anti-muscarinic agent tolterodine. After a 6-week partial bladder outlet obstruction (BOO), drug effects on bladder functions were evaluated using cystometrography. Effects on carbachol (CCh)-induced salivary secretion were evaluated in urethane-anesthetized rats. Ritobegron significantly decreased the frequency of non-voiding contractions (NVC), while both ritobegron and tolterodine each significantly decreased the amplitude of NVC. Ritobegron had no effect on either the micturition pressure (MP) or the residual volume (RV). In contrast, tolterodine dose-dependently decreased MP and increased RV. Ritobegron had no effect on CCh-induced salivary secretion, whereas tolterodine dose-dependently decreased it. Ritobegron decreased both the frequency and amplitude of NVC, which is similar to its effect on the contractions associated with detrusor overactivity (DO) in patients with an overactive bladder (OAB), without affecting MP, RV, or CCh-induced salivary secretion. Although tolterodine reduced the amplitude of NVC, it also markedly increased RV and significantly inhibited CCh-induced salivary secretion. These results suggest that use of ritobegron, a ß3-AR agonist, is unlikely to lead to the residual urine and dry mouth symptoms that are associated with anti-muscarinic drugs, and that ritobegron may hold promise as a safe and effective agent for OAB treatment.

Effects of four different alpha(1)-adrenoceptor antagonists on alpha-adrenoceptor agonist-induced contractions in isolated mouse and hamster ureters.

PURPOSE: To compare the efficacy of the selective alpha(1A)-adrenoceptor antagonist silodosin with those of doxazosin, terazosin, and alfuzosin against alpha-adrenoceptor agonist-induced contractions in mouse and hamster ureters. METHODS: The four alpha(1)-adrenoceptor antagonists were evaluated against norepinephrine-induced phasic contractions in mouse isolated ureteral preparations and against phenylephrine-induced sustained contractions in hamster isolated ureteral preparations using a functional experimental technique. RESULTS: In mouse ureters, silodosin (a selective alpha(1A)-adrenoceptor antagonist), doxazosin (a nonselective alpha(1)-adrenoceptor antagonist), terazosin (a nonselective alpha(1)-adrenoceptor antagonist), and alfuzosin (a nonselective alpha(1)-adrenoceptor antagonist) all shifted the norepinephrine concentration-response curve to the right. The rank order of potencies (pK(B) value) was silodosin (9.47 +/- 0.16) > doxazosin (8.62 +/- 0.15) > terazosin (8.39 +/- 0.16) > alfuzosin (8.03 +/- 0.12). In hamster ureters, all four antagonists shifted the phenylephrine concentration-response curve to the right, the rank order of potencies being silodosin (10.09 +/- 0.13) > doxazosin (8.22 +/- 0.16) > terazosin (7.75 +/- 0.15) > alfuzosin (7.70 +/- 0.10). In each case, silodosin was much more potent than the other three drugs. CONCLUSION: In this study, silodosin suppressed both mouse and hamster ureteral contractions more potently than doxazosin, terazosin, or alfuzosin. Hence, this alpha(1A)-adrenoceptor antagonist warrants further study as a potentially very useful medication for stone passage in urolithiasis patients.

Salivation triggered by pilocarpine involves aquaporin-5 in normal rats but not in irradiated rats.

1. Using rats, we examined the muscarinic receptor subtype mediating pilocarpine-induced parotid salivary secretion and the contributions of ion transporter systems (effluxes of K+ and Cl(-)) and aquaporin-5 (AQP5) translocation to this response in parotid glands in irradiated-induced xerostomia. 2. Salivary secretion was significantly lower in irradiated compared with sham-irradiated (normal) rats. In xerostomia rats, 0.4 and 0.8 mg/kg pilocarpine significantly increased parotid salivary secretion, although the salivary volume was still significantly less than in normal rats after the same dose of pilocarpine. 3. Pirenzepine (1 x 10(-6) to 1 x 10(-1) mol/L), AF-DX 116 (3 x 10(-6) to 3 x 10(-2) mol/L) and N-2-chloroethyl-4-piperidinyl diphenylacetate (4-DAMP; 1 x 10(-8) to 1 x 10(-2) mol/L) dose-dependently displaced radioligand binding to M(1), M(2) and M(3) receptors, respectively, in parotid membranes from both normal and irradiated rats. In each group of rats, 4-DAMP had the highest binding affinity. Pretreatment with 4-DAMP or pirenzepine dose-dependently inhibited pilocarpine-induced parotid secretion in both normal and irradiated rats, with 4-DAMP being markedly more potent than pirenzepine. 4. Normal and irradiated-rat parotid cells did not differ significantly in terms of pilocarpine-induced changes in [Ca2+](i), [K+](i) and [Cl(-)](i). Pilocarpine markedly increased the amount of AQP5 in the apical plasma membrane of parotid cells isolated from normal but not irradiated rats. 5. Thus, pilocarpine induces parotid salivary secretion mainly via the M(3) receptor subtype in both irradiated and normal rats. The reduction in this pilocarpine-induced secretion seen in irradiated rats is due not to disturbances of intracellular Ca2+ mobilization or ion transporter systems, but rather to a disturbance of AQP5 translocation, which may be involved in the pathogenesis of X-ray irradiation-induced xerostomia.

Bezafibrate prevents hepatic stellate cell activation and fibrogenesis in a murine steatohepatitis model, and suppresses fibrogenic response induced by transforming growth factor-beta1 in a cultured stellate cell line.

AIM: The aim of this study was to investigate the preventive actions of bezafibrate against non-alcoholic steatohepatitis (NASH), the activation of hepatic stellate cells (HSC), and fibrogenesis by using a model of NASH and an in vitro model. METHODS: Male KK-A(y)/TaJcl (KK-A(y)) mice were fed a methionine and choline-deficient (MCD) diet or a MCD diet containing bezafibrate or pioglitazone for 7 weeks, after which biochemical parameters, pathological changes, and hepatic mRNA levels were assessed. An in vitro HSC model was designed by using a previously described RI-T cell line stimulated by transforming growth factor-beta1 (TGF-beta1). RESULTS: MCD diet-fed KK-A(y) mice developed hepatic steatosis, oxidative stress, inflammation, and hepatic fibrosis. Bezafibrate markedly decreased the hepatic content of triglyceride accumulation of fatty droplets within hepatocytes, and increased the expression of hepatic fatty acid beta-oxidative genes in MCD diet-fed KK-A(y) mice. Bezafibrate markedly inhibited the increases in the plasma alanine aminotransferase level and hepatic content of thiobarbituric acid-reactive substances in this model. Moreover, it dramatically reduced hepatic inflammatory changes and fibrosis concomitantly with marked reductions in the mRNA levels for inflammatory cytokine, chemokine, and profibrogenic genes. Importantly, both bezafibrate and pioglitazone markedly reduced the mRNA levels of profibrogenic and fibrogenic genes in TGF-beta1-stimulated cells. CONCLUSION: Bezafibrate improved hepatic steatosis and potently prevented inflammation, oxidative stress, HSC activation, and fibrogenesis in the liver. Moreover, this study was the first to demonstrate that bezafibrate directly inhibits hepatic fibrogenic response induced by TGF-beta1 in vitro. Hence bezafibrate may be a new therapeutic strategy against NASH and hepatic fibrosis.

Bezafibrate regulates the expression and enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes.

A clinically employed antihyperlipidemic drug, bezafibrate, has been characterized as a PPAR(alpha, -gamma, and -delta) pan-agonist in vitro. Recent extended trials have highlighted its antidiabetic properties in humans. However, the underlying molecular mechanism is not fully elucidated. The present study was designed to explore potential regulatory mechanisms of intracellular glucocorticoid reactivating enzyme, 11beta-HSD1 and anti-diabetic hormone, adiponectin by bezafibrate in murine adipose tissue, and cultured adipocytes. Treatment of db/db mice with bezafibrate significantly ameliorated hyperglycemia and insulin resistance, accompanied by a marked reduction of triglyceride and nonesterified fatty acids. Despite equipotent in lipid-lowering effects, another fibrate, fenofibrate, did not show such beneficial effects on glycemic control. Treatment of bezafibrate caused a marked decrease in the mRNA level of 11beta-HSD1 preferentially in adipose tissue of db/db mice (-47%, P<0.05), concomitant with a significant increase in plasma adiponectin level (+37%, P<0.01). Notably, treatment of bezafibrate caused a marked decrease in the mRNA level (-34%, P<0.01) and enzyme activity (-32%, P<0.01) of 11beta-HSD1, whereas the treatment substantially augmented the expression (+71%, P<0.01) and secretion (+27%, P<0.01) of adiponectin in 3T3-L1 adipocytes. Knockdown of 11beta-HSD1 by siRNA confirmed that 11beta-HSD1 acts as a distinct oxoreductase in adipocytes and validated the enzyme activity assays in the present study. Effects of bezafibrate on regulation of 11beta-HSD1 and adiponectin in murine adipocytes were comparable with those in thiazolidinediones. This is the first demonstration that bezafibrate directly regulates 11beta-HSD1 and adiponectin in murine adipocytes, both of which may contribute to metabolically-beneficial effects by bezafibrate.

Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet.

We evaluated the effects of bezafibrate, a peroxisome proliferator-activated receptor (PPAR) pan-agonist, and GW501516, a PPARdelta agonist, on mice fed a methionine- and choline-deficient (MCD) diet, a model of non-alcholic steatohepatitis (NASH), to investigate (a) the efficacy of bezafibrate against non-alcholic steatohepatitis and (b) the relation between non-alcholic steatohepatitis and the functional role of PPARdelta. Bezafibrate (50 or 100 mg/kg/day) and GW501516 (10 mg/kg/day) were administered by gavage once a day for 5 weeks. Hepatic lipid contents, plasma triglyceride, high density lipoprotein (HDL)-cholesterol and alanine aminotransferase (ALT) concentrations were evaluated, as were histopathological changes in the liver and hepatic mRNA expression levels. Bezafibrate and GW501516 inhibited the MCD-diet-induced elevations of hepatic triglyceride and thiobarbituric acid-reactants contents and the histopathological increases in fatty droplets within hepatocytes, liver inflammation and number of activated hepatic stellate cells. In this model, bezafibrate and GW501516 increased the levels of hepatic mRNAs associated with fatty acid beta-oxidation [acyl-CoA oxidase (ACO), carnitine palmitoyltransferase-1 (CPT-1), liver-fatty acid binding protein (L-FABP) and peroxisomal ketothiolase], and reduced the levels of those associated with inflammatory cytokines or chemokine [transforming growth factor (TGF)-beta1, interleukin (IL)-6, IL-1beta, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF) alpha and nuclear factor (NF)-kappaB1]. In addition, bezafibrate characteristically reduced the elevation in the level of plasma ALT, but enhanced that in plasma adiponectin and increased the mRNA expression levels of its receptors (adiponectin receptors 1 and 2). These results suggest that (a) bezafibrate (especially) and GW501516 might improve hepatic steatosis via an improvement in fatty acid beta-oxidation and a direct prevention of inflammation, (b) treatment with a PPARdelta agonist might improve non-alcholic steatohepatitis, (c) bezafibrate may improve non-alcholic steatohepatitis via activation not only of PPARalpha but also of PPARdelta, because bezafibrate is a PPAR pan-agonist.

Effects of mitiglinide and sulfonylureas in isolated canine coronary arteries and perfused rat hearts.

Our aim was to compare the cardiovascular effects of mitiglinide ((+)-monocalcium bis[(2S,3a,7a-cis)-alpha-benzylhexahydro-gamma-oxo-2-isoindolinebutyrate] dehydrate), a novel hypoglycemic drug, with those of glibenclamide and glimepiride, two sulfonylurea drugs. In isolated canine coronary arteries (organ-bath method), mitiglinide, glibenclamide, and glimepiride competitively antagonized the cromakalim-induced relaxation (pA2 values, 5.29, 7.36, and 7.49, respectively). In isolated perfused rat hearts (Langendorff method) subjected to a 12-min global ischemia followed by a 30-min reperfusion, mitiglinide (3 x 10(-6) mol/l) altered neither the change in coronary perfusion flow nor the alterations in cardiac functions associated with reperfusion. In contrast, both glibenclamide (3 x 10(-8) mol/l) and glimepiride (1 x 10(-7) mol/l) significantly reduced coronary perfusion flow after reperfusion. Moreover, at 30 min of reperfusion: (1) glibenclamide induced a significant increase in left ventricular end-diastolic pressure and significant decreases in left ventricular systolic pressure, left ventricular developed pressure, and the maximum first derivative of left ventricular pressure, while (2) glimepiride induced significant decreases in left ventricular developed pressure and the maximum first derivative of left ventricular pressure. Thus, the cardiovascular effects of mitiglinide (at least, in these rat and dog preparations) may be weaker than those of glibenclamide and glimepiride.

Effects of pilocarpine hydrochloride and cevimeline on submandibular/sublingual salivation in rat xerostomia model produced by X-ray irradiation.

The present study was performed to assess the effects of pilocarpine hydrochloride ((3S,4R)-3-ethyl-dihydro-4-[(1-methyl-1H-imidazole-5-yl)methyl]-2(3H)-furanone monohydrochloride, CAS 54-71-7) and cevimeline ((+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate, CAS 153504-70-2), muscarinic receptor agonists, on salivary secretion from the submandibular/sublingual (SM/SL) glands in normal rats and in rats with xerostomia induced by X-ray (15 Gy) irradiation. To clarify their pharmacological safety profiles, the two drugs were further compared with regard to subtype selectivity for muscarinic receptors (M1, M2, and M3) and central nervous, respiratory, and cardiovascular effects. Pilocarpine hydrochloride (0.1-0.8 mg/kg i.d.) and cevimeline (3-30 mg/kg i.d.) dose-dependently increased salivary flow rate and total salivary volume in a 120-min period from SM/SL glands in both normal and irradiated rats, the minimum effective doses for their sialagogic effects being 0.2 and 10 mg/kg, respectively. Both drugs also increased protein output from SM/SL glands to a degree that depended on the increase in salivary volume in normal and irradiated rats. In a binding study using radiolabeled antagonists, neither pilocarpine hydrochloride nor cevimeline displayed subtype selectivity for muscarinic receptors, indicating non-selective muscarinic agonism. Effects on the central nervous system (CNS) were assessed by monitoring changes in body temperature in conscious normal rats. Pilocarpine hydrochloride (0.4-4 mg/kg p.o.) had no effect on body temperature, but cevimeline (30 and 100 mg/kg p.o.) caused a significant hypothermia. In terms of respiratory and cardiovascular effects in anesthetized normal rats, there was no clear difference in safety margin between pilocarpine hydrochloride and cevimeline, both drugs inducing significant changes in respiratory rate, heart rate, and blood pressure at doses close to those inducing sialagogic effects. These results suggest that pilocarpine hydrochloride could be used as a sialagogic drug for postirradiation-induced xerostomia with fewer adverse effects on the CNS.