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Volume 88 (2002)
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Volume 88, Issue 3
Displaying 1-18 of 18 articles from this issue
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Review
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Richard Sercombe, Yves R. Tran Dinh, Philippe GomisSubject area: Infomation Science
2002 Volume 88 Issue 3 Pages 227-249
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSAneurysmal subarachnoid hemorrhage frequently results in complications including intracranial hypertension, rebleeding and vasospasm. The extravasated blood is responsible for a cascade of reactions involving release of various vasoactive and pro-inflammatory factors (several of which are purported to induce vasospasm) from blood and vascular components in the subarachnoid space. The authors review the available evidence linking these factors to the development of inflammatory lesions of the cerebral vasculature, emphasizing: 1) neurogenic inflammation due to massive release of sensory nerve neuropeptides; 2) hemoglobin from lysed erythrocytes, which creates functional lesions of endothelial and smooth muscle cells; 3) activity, expression and metabolites of lipoxygenases cyclooxygenases and nitric oxide synthases; 4) the possible role of endothelin-1 as a pro-inflammatory agent; 5) serotonin, histamine and bradykinin which are especially involved in blood-brain barrier disruption; 6) the prothrombotic and pro-inflammatory action of complement and thrombin towards endothelium; 7) the multiple actions of activated platelets, including platelet-derived growth factor production; 8) the presence of perivascular and intramural macrophages and granulocytes and their interaction with adhesion molecules; 9) the evolution, origins, and effects of pro-inflammatory cytokines, especially IL-1, TNF-α and IL-6. Human and animal studies on the use of anti-inflammatory agents in subarachnoid hemorrhage include superoxide and other radical scavengers, lipid peroxidation inhibitors, iron chelators, NSAIDs, glucocorticoids, and serine protease inhibitors. Many animal studies claim reduced vasospasm, but these effects are not always confirmed in human trials, where symptomatic vasospasm and outcome are the major endpoints. Despite recent work on penetrating vessel constriction, there is a paucity of studies on inflammatory markers in the microcirculation.View full abstractDownload PDF (232K)
Full Papers
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Lih-Chi Chen, Mei-Huei Chou, Ming-Fang Lin, Ling-Ling YangSubject area: Infomation Science
2002 Volume 88 Issue 3 Pages 250-255
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSPaeoniflorin, a monoterpene glycoside, is the principal bioactive component of Paeoniae Radix. The traditional prescription Shao-yao Gan-chao Tang (SGT; Kampo: Shakuyaku-Kanzo-To), which is composed of Paeoniae Radix and Glycyrrhizae Radix, has been widely used in China and Japan. Quantification of paeoniflorin in mouse plasma after oral administration of SGT (at a dose containing 10 mg/kg paeoniflorin) was achieved using a simple and rapid high-performance liquid chromatography method. The plasma concentration-time curves were fitted with mean terminal half-lives (t1/2) of 116.17 min. The maximum plasma concentration (Cmax) of paeoniflorin was 111.56 ng/ml, time to reach maximum concentration (tmax) was 17.00 min, the area under the plasma concentration-time curve (AUC)0-t was 12293.42 ng · min/ml, clearance / bioavailability (CL/F) value was 644.74 ml/min · kg, apparent volume of distribution / bioavailability (Vd/F) value was 103.05 l/kg, and the mean residence time (MRT) was 169.64 min. These results, together with the previously reported kinetic data of paeoniflorin after oral administration of Paeoniae Radix extract alone, indicated that absorption of paeoniflorin after oral administration of SGT was significantly greater than that after oral administration of Paeoniae Radix alone.View full abstractDownload PDF (138K) -
Terumasa Hashimoto, Yuuki Nakano, Miyuki Yamashita, Yang-Il Fang, Hisa ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 256-261
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSInhalation of oleoyl lysophosphatidic acid (LPA) induced airway hyperresponsiveness to acetylcholine (ACh). In contrast, palmitoyl and stearoyl LPA exerted minimal effects. Airway hyperresponsiveness was inhibited by inhalation of Y-27632, an inhibitor of Rho-associated protein kinase (ROCK). Mepyramine, an H1 histamine receptor antagonist and ketotifen, an inhibitor of histamine release and H1 histamine receptor antagonist, also inhibited airway hyperresponsiveness induced by LPA; however, aspirin failed to attenuate this response. The incubation of lung fragments with LPA gave rise to releases in histamine. On the other hand, LPA produced no significant changes on the smooth muscle contraction evoked by ACh. These findings suggest that LPA-induced airway hyperresponsiveness is attributable to activation of the Rho/ROCK-mediated pathway via endothelial cell differentiation gene (EDG) receptors, probably EDG 7. Moreover, histamine release may be involved.View full abstractDownload PDF (168K) -
Yuki Sugawara, Kuniaki Suzuki, Mino Koshikawa, Masaki Ando, Junichiro ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 262-269
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSAlkaline phosphatase (ALP) is supposed to be important for bone formation; however, its role is not clear. In this study, we examined the importance of enzymatic activity of ALP and anchoring of ALP protein to the cells for mineralization of an osteoblastic cell line, MC3T3-E1. While we cultured the cells in the presence of tetramisole, an inhibitor of ALP activity, ALP protein was expressed at a similar level to that in the control. Although tetramisole showed no effect on cell growth and increased hydroxyproline accumulation, it decreased the osteocalcin production and the accumulation of calcium and phosphate in the matrices. Tetramisole also inhibited mineralized nodule formation, which was observed by optical microscopy and detected by Von Kossa staining. On the other hand, when ALP protein was released from the cell membranes with the use of phosphatidylinositol-specific phospholipase C, no marked changes were detected in hydroxyproline, calcium and phosphate accumulations in the matrices at late calcification stage, which was consistent with the morphological findings. These results clearly show that enzymatic activity of ALP is necessary for mineralization of MC3T3-E1 cells, but not the presence of ALP protein or anchoring of ALP to the cells.View full abstractDownload PDF (382K) -
Štefan Mátyás, Vladimír Pucovský, V ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 270-278
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSReactive oxygen species (ROS) are key factors playing important roles in tissue damage of airways under different pathological conditions. Effects of ROS (superoxide anion, H2O2 and hydroxyl radical) were recorded on isometric tension of intact and epithelium denuded, not precontracted guinea pig trachea. Superoxide anion was produced by xanthine/xanthine oxidase and hydroxyl radical either by FeSO4/H2O2 or FeSO4/ascorbic acid. In intact preparations, the muscle tension was unaffected by superoxide anion, while H2O2 and hydroxyl radical produced a biphasic response, contraction followed by relaxation. Both the amplitude and duration of contractions evoked by H2O2 were larger than those caused by hydroxyl radical producing systems. On denuded tracheal strips, superoxide anion elicited also a biphasic response, and the H2O2 and hydroxyl radical produced contractions were of higher amplitude and of longer duration than in intact tissues. Indomethacin pretreatment enhanced or slightly reduced the amplitude of contractions evoked by both H2O2 and hydroxyl radical on the intact and denuded preparations, respectively. Moreover, the duration of contractions of the trachea induced by oxidative systems was prolonged. Indomethacin did not affect the action of superoxide anion on the intact tissues and reduced the amplitude of the biphasic response on denuded ones. Nordihydroguaiaretic acid pretreatment did not alter the responses elicited by ROS in intact preparations and reduced their action on the denuded ones. Our results suggest that a) various ROS contract tracheal smooth muscle with simultaneous release of epithelium derived relaxing factors, b) epithelium possesses superoxide anion scavenging capacity which is high enough to protect smooth muscle from its actions, and c) cyclooxygenase products participate in relaxation and lipoxygenase products in contraction caused by ROS in the guinea pig trachea.View full abstractDownload PDF (239K) -
Yuki Yoshida, Mineko Ichikawa, Minoru Ohta, Setsuko Kanai, Mikako Koba ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 279-284
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSOtsuka Long Evans Tokushima Fatty (OLETF) rats were developed as a model of non-insulin-dependent diabetes mellitus (NIDDM) with mild obesity. We reported that the daily profiles of energy expenditure associated with two peaks (one between 05:00 and 08:00 and the other between 20:00 and 22:00) were observed at 8 weeks of age (without NIDDM), while these two peaks disappeared at 24 weeks of age with NIDDM. As a new anti-diabetic drug, a peroxisome proliferator-activated receptor γ agonist pioglitazone hydrochloride has been developed, we examined whether pioglitazone normalized daily profiles of energy expenditure at 24 weeks of age. A control diet and pioglitazone (0.1%)-containing diet were fed from 6 weeks of age. The two peaks of daily profiles of energy expenditure, which disappeared in OLETF rats with the control diet at 24 weeks of age, were reproduced by administration of pioglitazone. The respiratory quotient was lower and fat derived energy used for combustion was increased by pioglitazone at both ages. The body weight, daily food intake, plasma levels of fat, insulin, leptin and the wet weight of visceral fat were not influenced, but the levels of blood hemoglobin A1c and plasma tumor necrosis factor α were decreased by pioglitazone. Administration of pioglitazone improved daily profiles of energy expenditure via affecting glucose and fat metabolisms.View full abstractDownload PDF (184K) -
Takayuki Miyamoto, Hiroshi Nojima, Tomoko Shinkado, Takashi Nakahashi, ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 285-292
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSThe present study was conducted to establish a new mouse model of dry skin pruritus. The rostral back was treated daily with cutaneous application of acetone/ether (1:1) mixture (AE), water following AE (AEW), 1% sodium lauryl sulfate (SLS) or tape stripping (TS). On the day after 5-day treatment, although all four treatments significantly decreased stratum corneum (SC) hydration and increased transepidermal water loss (TEWL), only AEW treatment significantly increased spontaneous scratching. An increase in the frequency of TS produced the marked increase of TEWL, without significant effects on SC hydration and spontaneous scratching. In AEW-treated mice, changes in SC hydration and TEWL were marked in the initial 2-day period, while spontaneous scratching increased gradually from 3 days after starting the treatment. The degranulation of cutaneous mast cells was increased by SLS treatment but not by other treatments. There was no apparent difference in AEW-induced spontaneous scratching between mast cell-deficient mice (WBB6F1-W/WV) and normal littermates (WBB6F1-+/+). Opioid antagonists, naloxone and naltrexone, (1 mg/kg, subcutaneously) significantly suppressed spontaneous scratching in AEW-treated mice. It is suggested that spontaneous scratching of AEW-treated mice is an itch-related response and a useful model for studying the mechanisms of dry skin pruritus.View full abstractDownload PDF (1109K) -
Hiroaki Araki, Takahiko Yamamoto, Yuri Kobayashi, Koujiro Futagami, Hi ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 293-299
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSIschemia-induced hyperactivity is recognized several hours after both common carotid arteries’ occlusion for 5 min in Mongolian gerbils, and it continues for at least 7 days. The aim of this study is to investigate the possible mechanisms of this abnormal behavior. Methamphetamine (MAP) (1 and 3 mg/kg) was administered for 7 days and imipramine (IMP) (5 and 10 mg/kg) was administered for 7 or 14 days. Bilateral carotid artery was occluded for 5 min 24 h after the last administrations of these drugs. MAP, which had been administered every day for 1 week, showed marked inhibition in the ischemia-induced hyperactivity. However, IMP did not have any effect even though it had been injected every day for 2 weeks. Hippocampal CA1 neuronal changes also appeared in the MAP- and IMP-administered groups. As the dopaminergic neurotransmission is facilitated by the repeated administration of MAP, the ischemia-induced hyperactivity may be related to abnormalities in dopaminergic function. The participation of the other neurotransmitters is also discussed.View full abstractDownload PDF (412K) -
Takanori Matsuo, Eiichiro Ishikawa, Masayuki Ohta, Yumiko Shibouta, Yo ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 300-306
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSSpontaneously hypercholesterolemic (SHC) rats exhibit hypercholesterolemia, proteinuria and focal glomerulosclerosis with age, and they finally die as a result of renal failure. In this study, the renoprotective effects of candesartan cilexetil, an angiotensin II type 1 receptor antagonist, and enalapril, an angiotensin I converting enzyme inhibitor, were examined in SHC rats. Candesartan cilexetil (0.1 and 1 mg/kg) and enalapril (10 mg/kg) were administered orally to 10-week-old SHC rats for a 6-week period. Candesartan cilexetil (1 mg/kg) and enalapril (10 mg/kg) significantly inhibited proteinuria and hypercholesterolemia to a similar extent. In untreated 16-week-old SHC rats, glomerulosclerosis, basophilic change, cast formation and interstitial mononuclear cell infiltration were observed. Candesartan cilexetil (1 mg/kg) inhibited all of these histological changes. Enalapril inhibited glomerulosclerosis and cast formation. These results show that candesartan cilexetil and enalapril have renal protective effects in SHC rats. Thus, angiotensin II might play an important role in renal pathogenesis in a model of focal glomerulosclerosis with hypercholesterolemia.View full abstractDownload PDF (432K) -
Atsushi Sugiyama, Akira Takahara, Yoshioki Satoh, Masahiko Yoneyama, Y ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 307-313
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSCardiac effects of 10 kinds of clinically available Kampo medicines were investigated: Kakkon-to (TJ-1), Dai-saiko-to (TJ-8), Boi-ogi-to (TJ-20), Chorei-to (TJ-40), Rokumi-gan (TJ-87), Tsu-do-san (TJ-105), Gosha-jinki-gan (TJ-107), San’o-shashin-to (TJ-113), Sairei-to (TJ-114) and Inchin-gorei-san (TJ-117). Chronotropic and inotropic effects were studied using canine isolated, blood-perfused heart preparations, while subcellular mechanisms were analyzed by measuring the drug-induced changes of the adenylate cyclase activity in the canine ventricular membrane preparation. Intracoronary injections of TJ-1, TJ-20, TJ-105 and TJ-113 increased the sinoatrial rate and developed tension of papillary muscle in a dose-related manner, which was significantly attenuated by the pretreatment of the preparations with β-blocker propranolol. Meanwhile, the other extracts hardly affected these parameters. TJ-1, TJ-20 and TJ-113 increased the adenylate cyclase activity in a dose-related manner, but their potency was significantly less compared with that by an equivalent concentration of isoproterenol. Moreover, TJ-105 did not increase the adenylate cyclase activity. These results suggest that the positive chronotropic and inotropic effects of TJ-1, TJ-20, TJ-105 and TJ-113 may be exerted through the direct stimulation of the β-adrenoceptor and/or the norepinephrine release from the postganglionic nerve terminals in the heart.View full abstractDownload PDF (279K) -
Masafumi Isogaya, Taku Nagao, Hitoshi KuroseSubject area: Infomation Science
2002 Volume 88 Issue 3 Pages 314-318
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSWe have examined the functional significance of the naturally occurring mutation at position 64 of human β3-adrenergic receptor (β3AR), which changes the amino acid from tryptophan to arginine (W64R-β3AR). The affinities of βAR agonists for W64R-β3AR expressed in COS-7 cells were not significantly different from those for wild type β3AR. When two receptors are expressed at various expression levels, and stimulated with CGP12177A, they showed essentially the same EC50 values and maximal responses. Overexpression of Gi and Go, or the treatment with pertussis toxin did not affect the agonist-induced cAMP response, suggesting that Gi and Go did not contribute to the β3AR-induced cAMP response. However, the enhanced cAMP response was observed when W64R-β3AR was coexpressed with the adenylyl cyclase type III isoform, and stimulated by CGP12177A and isoproterenol. These results indicate that the cAMP response of W64R-β3AR can be enhanced under the particular condition that adenylyl cyclase type III was coexpressed.View full abstractDownload PDF (198K) -
Jodie J. Rady, Philip S. Portoghese, James M. FujimotoSubject area: Infomation Science
2002 Volume 88 Issue 3 Pages 319-331
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSAntinociceptive tail flick responses to heroin and 6-monoacetylmorphine mediated in the brain by μ-opioid receptor are switched by morphine pellet implantation to δ1-and δ2-opioid-receptors mediation, respectively. Present results showed that the μ-receptor response (inhibited by β-funaltrexamine) to methadone was changed by morphine pellet implantation to δ1 (inhibited by 7-benzylidenenaltrexone)- and δ2 (inhibited by naltriben)-opioid-receptor responses. Methadone pellet implantation likewise changed mediation from μ- to δ-opioid receptors for heroin and methadone but not for morphine (β-funaltrexamine continued to inhibit). Methadone μ action in the brain was linked through a descending system to activate spinal serotonin receptors (inhibited by methysergide), but this link was gone in the methadone-pellet-implanted group. In the latter group, the new δ1- and δ2-receptor responses were mediated by spinal GABAA (inhibited by bicuculline) and GABAB (inhibited by 2-hydroxysaclofen) receptors. These shifts in neuronal systems meant that μ receptors on a given neuron were not changed into δ receptors. Preliminary results showed that δ-agonist action for methadone was prevented from appearing by MK801, a NMDA-receptor antagonist, and did not occur in 129S6/SvEv mice which lack NMDA responsiveness. Could methadone maintenance treatment in humans uncover δ-agonist actions?View full abstractDownload PDF (528K) -
Jun Ishikawa, Yohei Okada, Ian N. Bird, Bharat Jasani, Julia H. Spragg ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 332-340
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSPlatelet-endothelial cell adhesion molecule-1 (PECAM-1) is expressed on the membrane of leukocytes and vascular endothelial cells. PECAM-1 has been shown to play an important role in the process of leukocyte transmigration in various animal models of acute inflammation. We investigated the role of PECAM-1 in the progression of arthritis by systemically administering anti-murine PECAM-1 monoclonal antibody, 2H8, to DBA/1J mice with collagen-induced arthritis (CIA). Subcutaneous administration of dexamethasone (0.5 mg/kg per 2 days) significantly reduced hindpaw swelling and the clinical score of established CIA. Intraperitoneal administration of 2H8 (0.25 mg/mouse per 2 days) significantly inhibited hindpaw swelling in a time-dependent manner. 2H8 also significantly prevented further deterioration in the clinical score, but failed to reverse joint destruction discernible at the histological level. Both dexamethasone and 2H8 inhibited body weight decrease by preventing the further development of arthritis. Histopathological assessment revealed that 2H8, as well as dexamethasone, inhibited inflammatory cell transmigration into the synovium of the hind paw joint and ameliorated synovitis and cartilage erosion. These results suggest that PECAM-1 plays an important role in the progression of CIA and that an inhibitor of PECAM-1 might have therapeutic value for clinical treatment of rheumatoid arthritis.View full abstractDownload PDF (423K) -
Atsushi Sugiyama, Yuko Ishida, Yoshioki Satoh, Shigeki Aoki, Masaaki H ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 341-350
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSThe present study was designed to investigate what kinds of adaptation occurred in the canine chronic AV block model, which has been used to study torsade de pointes (TdP). Dogs at 7 – 10 days (acute phase) and 28 – 56 days (chronic phase) after AV block were assessed. Ventricular effective refractory period and monophasic action potential duration were prolonged in chronic animals compared with acute animals; moreover the electrically vulnerable period was prolonged in chronic animals. Non-specific IKr channel blocker cisapride (1 and 10 mg/kg, p.o.) was administered without anesthesia to estimate the feasibility of QT prolongation. In chronic animals, QT prolongation followed by TdP was induced in one dog by the low dose and in all by the high dose, which was not observed in acute animals. MR images indicated increases of diameter and wall thickness of both ventricles in chronic animals. The degree of hypertrophy was prominent in the right ventricular wall and septal wall. Heart weight of the chronic animals was 1.7 times greater than that of normal control subjects. Photo- and electron-micrograph analyses showed myocardial cell hypertrophy with parallel increases of collagen fiber and extracellular space in chronic animals. These electrophysiological, anatomical and histological adaptations may predispose the chronic AV block heart to drug-induced QT prolongation with enhanced risk of re-entry and early afterdepolarization, leading to the onset of TdP.View full abstractDownload PDF (611K)
Short Communications
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Takayuki Miyamoto, Hiroshi Nojima, Yasushi KuraishiSubject area: Infomation Science
2002 Volume 88 Issue 3 Pages 351-354
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSIn the present study, we examined whether cholinergic agonists would elicit an itch-associated response in mice. When mice were given an intradermal injection of carbachol (1 – 10 nmol) or bethanechol (0.3 – 100 nmol) into the rostral back, they showed the dose-dependent increase of scratching. Nicotine (1 – 10 nmol) showed no effect. Pretreatment with naloxone, but not with terfenadine, significantly suppressed the carbachol-induced scratching. When intradermally co-injected with carbachol, atropine and 4-DAMP but neither methoctramine nor pancuronium significantly inhibited the carbachol-induced scratching. Muscarinic agonists are suggested to produce itch through activation of M3 muscarinic receptors in the skin.View full abstractDownload PDF (118K) -
Mi-Hyeon Jang, Min-Chul Shin, Joo-Ho Chung, Hyun-Dae Shin, Yeunhee Kim ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 355-358
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSTraditionally, Puerariae radix had been used for the treatment of alcohol-related problems. In this study, effects of Puerariae radix on cell proliferation and nitric oxide synthase expression in the dentate gyrus of alcohol-intoxicated Sprague-Dawley rats were investigated via 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Alcohol administration was shown to inhibit the numbers of both BrdU-positive and NADPH-d-positive cells, while Puerariae radix treatment was shown to increase those numbers. It is possible that nitric oxide, which might play an important role in the regulation of cell proliferation, is a major target of the toxic effects of alcohol.View full abstractDownload PDF (434K) -
Atsushi Sugiyama, Yutaka Yatomi, Akira Takahara, Yoshioki Satoh, Keita ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 359-361
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSChronotropic, inotropic and coronary effects of Y-27632 ((+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride, monohydrate), a specific inhibitor of Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK), were assessed using canine isolated, blood-perfused heart preparations. Y-27632 slightly enhanced sinoatrial automaticity and significantly increased coronary blood flow, while it decreased ventricular contraction. The concentrations of Y-27632 needed to cause the currently observed changes were similar to those inhibiting ROCK in a previous in vitro study. These results suggest that the constitutional ROCK in the heart mainly regulates the ventricular contractility and coronary vascular tone rather than the sinoatrial automaticity.View full abstractDownload PDF (115K) -
Atsushi Sugiyama, Nobuyasu Takeuchi, Yoshiki Saegusa, Masao Sugita, Ke ...Subject area: Infomation Science
2002 Volume 88 Issue 3 Pages 362-364
Published: 2002
Released on J-STAGE: April 09, 2002
JOURNAL FREE ACCESSTo better understand the molecular mechanisms of the previously described cardiostimulatory action of the phosphodiesterase type-5 (PDE5) inhibitor sildenafil, we first evaluated its effects on cyclic AMP level in the canine ventricular membrane preparation. Sildenafil (10 μmol/L) significantly increased the net cyclic AMP production rate, the potency of which was similar to that of 3-isobutyl-1-methylxanthine (IBMX). Next, we assessed the inhibitory effect of sildenafil on PDE of bovine heart. Sildenafil (≥1 μmol/L) as well as IBMX significantly decreased the cyclic AMP hydrolyzing speed of PDE. These results suggest that a supra-therapeutic concentration of sildenafil may directly inhibit cyclic AMP hydrolyzing PDEs in the heart, although indirect inhibition of PDE3 via the “cross-talk” pathway cannot be totally excluded.View full abstractDownload PDF (114K)
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