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Biomedical subjects

Y Kihara

Publications and source records attributed to Y Kihara.

At least 55 records · Page 3Linked to original sources
PubMed1998

Cardiac endothelin-1 plays a critical role in the functional deterioration of left ventricles during the transition from compensatory hypertrophy to congestive heart failure in salt-sensitive hypertensive rats.

BACKGROUND: To investigate whether endogenous ET-1 participates in an adaptive process of left ventricular hypertrophy (LVH) or a maladaptive process from LVH to congestive heart failure (CHF), we used a Dahl salt-sensitive (DS) rat model, in which systemic hypertension caused compensated concentric LVH at the age of 11 weeks followed by marked LV dilatation and global hypokinesis at the age of 17 weeks. METHODS AND RESULTS: By specific sandwich enzyme immunoassay, serum and myocardial ET-1 levels at the LVH stage were not elevated compared with age-matched Dahl salt-resistant (DR) rats, despite the marked increase of LV/body weight ratio (LV/BW). However, at the CHF stage, serum and LV ET-1 levels increased by 3. 8-fold and 5.4-fold, respectively. LV ET-1 contents had close relationships with the fractional shortening (r=0.763) and the systolic wall stress (r=0.858) measured by in vivo transthoracic echocardiography. Immunohistochemistry demonstrated that the remarkably increased ET-1 in LV is located mainly in cardiomyocytes. By competitive reverse transcriptase-polymerase chain reaction, LV prepro-ET-1 mRNA levels increased by 4.1-fold in CHF rats. We randomized 11-week-old LVH rats to chronic treatment with the endothelin receptor antagonist bosentan (Bos, 100 mg. kg-1. d-1, n=14), the alpha1-receptor antagonist doxazosin (Dox, 1 mg. kg-1. d-1, n=12), or vehicle (Cont, n=14). Bos treatment did not alter the LV geometry and function at 15 weeks; however, it attenuated the decrease of LV fractional shortening by 51% (P<0.01) without reducing the LV/BW at 17 weeks. Conversely, Dox, which decreased the blood pressure to the same extent as Bos, did not affect the progression of LV dysfunction. Bos (93%; P<0.0001 versus Cont) but not Dox (42%; P=0.8465 versus Cont) ameliorated the survival rate at 17 weeks (Cont; 36%). CONCLUSIONS: The accelerated myocardial synthesis of ET-1 contributes directly to LV contractile dysfunction during the transition from LVH to CHF. Unelevated levels of LV ET-1 at the established LVH stage and lack of effects on LV mass by chronic bosentan treatment suggest that myocardial growth is mediated through alternative pathways. These studies indicate that chronic ET antagonism may provide an additional strategy for heart failure therapy in humans.

Adaptation, Physiological↗
PubMed1998

2(1H)-quinolinone derivatives as novel anti-arteriostenotic agents showing anti-thrombotic and anti-hyperplastic activities.

In order to search for anti-arteriostenotic agents, a series of 2(1H)-quinolinone derivatives was synthesized and evaluated for anti-thrombotic activity and for anti-hyperplastic activity. From this series, (-)-6-[3-[3-cyclopropyl-3-[(1R,2R)-2-hydroxycyclohexyl]ureido]propoxy]-2 (1H)-quinolinone (1p, OPC-33509) was selected as the best candidate by balancing the efficacy on anti-thrombosis and anti-hyperplasia.

Animals↗
PubMed1998

Importance of alpha 1-sympathetic activity for diurnal change in ischemic threshold in patients with stable angina.

BACKGROUND: Although ischemic threshold reportedly is lower in the early morning than in the afternoon, the mechanisms that account for the diurnal change in minimal coronary vascular resistance in the potentially ischemic area are unknown. HYPOTHESIS: We hypothesized that calcium-channel blockers and alpha 1 blockers may affect the ischemic threshold in the early morning and afternoon in patients with stable angina. METHODS: Before and after the administration of the calcium antagonist amlodipine (5 mg) alone and combined with the alpha 1 blocker prazosin (1 mg), a treadmill exercise test using the Balke-Ware protocol was undertaken in the morning (8:00 A.M.) and repeated in the afternoon (1:00 P.M.) with 15 stable angina patients. The ischemic threshold was defined as a reciprocal of minimal coronary vascular resistance in the presence of comparable levels of myocardial ischemia indicated by 0.1 mV ST depression. Minimal coronary vascular resistance was calculated as mean blood pressure divided by coronary blood flow. Since the coronary blood flow is closely related to myocardial oxygen consumption, which can be replaced by the double product of heart rate and systolic blood pressure, minimal coronary vascular resistance was approximated to 1/heart rate. RESULTS: At baseline, minimal coronary vascular resistance was significantly higher in the early morning than in the afternoon (8.5 +/- 0.3 x 10(-3) min/beats vs. 7.8 +/- 0.4 x 10(-3) min/beats, p < 0.01). Although treatment with amlodipine alone did not abolish the circadian pattern of minimal coronary vascular resistance (8.0 +/- 0.6 x 10(-3) min/beats vs. 7.7 +/- 0.6 x 10(-3) min/ beats, p < 0.05), the addition of prazosin virtually eliminated the diurnal difference in minimal coronary vascular resistance (7.4 +/- 0.5 x 10(-3) min/beats vs. 7.5 +/- 0.5 x 10(-3) min/beats, p = NS). CONCLUSIONS: These findings indicate that alpha 1-sympathetic activity may play a role in the pathogenesis of the diurnal change of ischemic threshold in patients with stable angina.

Adrenergic alpha-Antagonists↗
PubMed1998

Defects of cholecystokinin (CCK)-A receptor gene expression and CCK-A receptor-mediated biological functions in Otsuka Long-Evans Tokushima Fatty (OLETF) rats.

Recent studies in genetically obese and diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats suggest defects of cholecystokinin (CCK)-A receptor gene expression and CCK-A receptor-mediated biological functions such as pancreatic juice, protein, and gastric acid secretion. The present studies were undertaken to further examine CCK-A receptor gene expression and CCK-A receptor-mediated biological functions in the pancreas, stomach, and brain of OLETF rats. Expression of the CCK-A receptor gene could not be detected in the stomach, pancreas and brain by the reverse-transcription polymerase chain reaction (RT-PCR) method and Southern blotting of the PCR products. Southern blot analysis of genomic DNA from OLETF and control Long-Evans Tokushima Otsuka (LETO) rats with CCK-A receptor fragment as a probe revealed different restriction bands. Expression of the CCK-B receptor gene was observed in the stomach, pancreas, and brain in both OLETF and LETO rats by the RT-PCR method, with expression of the CCK-B receptor gene markedly enhanced in OLETF rats compared with that in LETO rats. Consistent with the defect of CCK-A receptor gene expression, CCK-A receptor-mediated biological functions were not observed in these organs. Perfused exocrine and endocrine pancreas of OLETF rats were insensitive to CCK stimulation but not to carbamylcholine stimulation. Basal gastric acid and pepsinogen secretions in OLETF rats were higher than in LETO rats. OLETF rats showed a significantly higher average daily food intake, gained body weight faster, and were heavier than LETO rats. The present study confirmed that OLETF rats have CCK-A receptor gene anomalies and demonstrated deficient CCK-A receptor-mediated biological function in the pancreas, stomach, and brain.

Animals↗
PubMed1998

Marked elevation of brain natriuretic peptide levels in pericardial fluid is closely associated with left ventricular dysfunction.

OBJECTIVES: The purpose of this study was to investigate whether atrial and brain natriuretic peptides (ANP and BNP, respectively) represent autocrine/paracrine factors and are accumulated in pericardial fluid. BACKGROUND: ANP and BNP, systemic hormones produced by the heart, have elevated circulating levels in patients with heart failure. Recent evidence suggests that the heart itself is one of the target organs for these peptides. METHODS: With an immunoreactive radiometric assay, we measured the concentrations of these peptides in plasma and pericardial fluid simultaneously in 28 patients during coronary artery bypass graft surgery. RESULTS: The pericardial levels of BNP were markedly elevated in patients with impaired left ventricular function. We investigated the correlation of ANP and BNP levels in plasma or pericardial fluid with left ventricular hemodynamic variables. None of the hemodynamic variables correlated with ANP levels in plasma or pericardial fluid. Both plasma and pericardial fluid levels of BNP were significantly related to left ventricular end-diastolic and systolic volume indexes (LVEDVI and LVESVI, respectively). In addition, BNP pericardial fluid levels had closer relations with LVEDVI (r = 0.679, p < 0.0001) and LVESVI (r = 0.686, p < 0.0001) than did BNP plasma levels (LVEDVI: r = 0.567, p = 0.0017; LVESVI: r = 0.607, p = 0.0010). BNP levels in pericardial fluid but not in plasma correlated with left ventricular end-diastolic pressure (r = 0.495, p = 0.0074). CONCLUSIONS: BNP levels in pericardial fluid served as more sensitive and accurate indicators of left ventricular dysfunction than did BNP levels in plasma. Thus, BNP may be secreted from the heart into the pericardial space in response to left ventricular dysfunction, and it may have a pathophysiologic role in heart failure as an autocrine/paracrine factor.

Aged↗
PubMed1998

Improvement of exercise capacity by sarpogrelate as a result of augmented collateral circulation in patients with effort angina.

OBJECTIVES: The purpose of this study was to evaluate whether a serotonin blocker, sarpogrelate, improves exercise capacity as a result of vasodilation of coronary collateral channels in patients with effort angina. BACKGROUND: Serotonin has been reported to decrease coronary collateral blood flow by collateral vasoconstriction in a canine model, suggesting that platelet activation in feeding coronary arteries of the collateral network has the potential to cause collateral vasoconstriction. METHODS: The subjects consisted of 22 patients with effort angina and reproducible ischemic threshold (group A, 11 patients with thrombolysis in myocardial infarction (TIMI) grade 2 or 3 flow of the ischemia-related coronary artery and Rentrop's collateral index 0 or 1; group B, 11 patients with TIMI grade 0 or 1 flow and Rentrop's collateral index 2 or 3). We repeated the symptom-limited treadmill exercise test using the Balke-Ware protocol and exercise tetrofosmin myocardial perfusion scintigraphy with and without pretreatment with 200 mg orally administered sarpogrelate. Each exercise test was performed at 9:00 a.m. on different days. The order of tests with and without sarpogrelate was randomized. RESULTS: In group A, sarpogrelate increased neither exercise time at 0.1 mV ST depression nor double product at 0.1 mV ST depression. In contrast, in group B sarpogrelate increased the exercise duration at 0.1 mV ST depression from 181+/-112 (SD) to 248+/-131 s (p < 0.05) and also increased the double product at 0.1 mV ST depression by 21% (p < 0.01). The severity score using myocardial perfusion scintigraphy at the same workload was significantly (p < 0.01) decreased by 37% in group B, but not in group A (11%), due to the sarpogrelate treatment. CONCLUSIONS: Sarpogrelate augments flow reserve of the collateral circulation and improves exercise capacity in anginal patients with well-developed collaterals. These findings indicate that a serotonin blocker, sarpogrelate, is useful not only as an antiplatelet drugs, but as an antianginal drug.

Aged↗
PubMed1998

Marked elevation of vascular endothelial growth factor and basic fibroblast growth factor in pericardial fluid of patients with angina pectoris.

Although we reported that basic fibroblast growth factor (bFGF) levels in pericardial fluid of patients with unstable angina are apparently increased, it was unclear whether vascular endothelial growth factor (VEGF) is also increased in patients with myocardial ischemia. Using an enzyme-linked immunosorbent assay, we measured the concentrations of VEGF and bFGF in pericardial fluid of 51 patients with open heart surgery. Patients were divided into group A (n=10) with class III unstable angina (Braunwald's classification), group B (n=24) with class I or II unstable angina or stable angina and group C (n=17) with non-ischemic heart disease. The VEGF level in pericardial fluid in group A was 83+/-7 pg/ml, being significantly (p<0.001) higher than the 27+/-3 pg/ml in group B and the 28+/-5 pg/ml in group C. The concentrations of bFGF in pericardial fluid in groups A and B were 1461+/-579 and 1224+/-161 pg/ml, respectively, significantly (p<0.05) higher than the 292+/-97 pg/ml in group C. The level of VEGF in pericardial fluid was increased only in patients with severe rest angina within 2 days before emergency coronary artery bypass graft surgery (CABG), while bFGF was increased in all patients undergoing CABG for coronary artery disease. Thus VEGF and bFGF may play important roles in mediating collateral growth in humans.

Journal Article↗
PubMed1998

CCK administration after CCK receptor blockade accelerates recovery from cerulein-induced acute pancreatitis in rats.

We examined the effects of treatment with cholecystokinin (CCK) octapeptide (CCK-8) and the CCK receptor antagonist loxiglumide on the recovery of exocrine pancreas in post-acute pancreatitic rats. Acute pancreatitis was induced in rats by intravenous infusion of 20 microg/kg/h cerulein for 4 h. At 24 h after the start of cerulein infusion, rats were divided into nine treatment groups: oral administration of saline (control), or oral administration of 10 or 50 mg/kg body weight loxiglumide twice daily for the first 3 days, followed by saline administration (Loxi-1 and Loxi-2), 10 or 50 mg/kg body weight loxiglumide twice daily for 6 days (Loxi-3 and Loxi-4), oral administration of saline or 10 or 50 mg/kg body weight loxiglumide twice daily for the first 3 days, followed by subcutaneous injection of 2.5 microg/kg body weight CCK-8 twice daily for the next 3 days (CCK-1, CCK-2, and CCK-3), and subcutaneous injection of 2.5 microg/kg body weight CCK-8 twice daily for 6 days (CCK-4). Pancreatic wet weight and biochemical changes were evaluated on day 8 at 12 h after the last treatment. Treatment with loxiglumide (Loxi-3 and Loxi-4) or CCK-8 for 6 days (CCK-4) or with a high dose of loxiglumide for the first 3 days (Loxi-2) significantly suppressed the recovery of pancreatic weight and DNA content compared to saline treatment or to the untreated normal control rats. However, when loxiglumide treatment was followed by 3 days of CCK-8 injections (CCK-2 and CCK-3), pancreatic protein and DNA content recovered to levels comparable to or above the control levels. The most remarkable increase in enzyme content was obtained in postpancreatitic rats treated with high-dose loxiglumide for the first 3 days, followed by CCK-8 injection (CCK-3). On the other hand, 6 days of CCK-8 treatment (CCK-4) had no significant influences on pancreatic enzyme contents. These results suggest that the most favorable strategy for the treatment of acute pancreatitis is to give high-dose loxiglumide during the early stage for only a short period, followed by CCK-8 administration.

Acute Disease↗
PubMed1998

Slow inactivation of cardiac L-type Ca2+ channel induced by cold acclimation of guinea pig.

Whole cell L-type Ca2+ current was recorded in ventricular myocytes dissociated from guinea pigs that were bred at ambient temperatures ranging between daily averages of 4 and 29 degrees C. The dynamic voltage range of inactivation, as measured using 400-ms conditioning pulses and a holding potential of -40 mV, extended from -50 to -20 mV in myocytes prepared in summer. In winter, the inactivation curve was shifted to more negative potentials than in summer. Double-pulse experiments revealed that the negative shift was due to slow-inactivation kinetics. The negative shift of inactivation could be induced in myocytes prepared from animals that had been kept at 5 degrees C for > 3 wk in the summer. The negative shift in Ca2+ current inactivation could be abolished by adding guanosine 5'-O-(2-thiodiphosphate) (5 mM) to the pipette solution, but not by adding staurosporine (2 microM) or 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (100 microM) to the bath. The cold acclimation may introduce the slow inactivation of the cardiac L-type Ca2+ channel through an unknown pertussis toxin-insensitive G protein.

Acclimatization↗
PubMed1998

Myocardial contractile efficiency and oxygen cost of contractility are preserved during transition from compensated hypertrophy to failure in rats with salt-sensitive hypertension.

In Dahl-Iwai rats, salt-sensitive hypertension causes concentric left ventricular hypertrophy (LVH) at the age of 11 weeks, which is followed by LV dilatation with global hypokinesis and pulmonary congestion, ie, LV failure (LVF), at 16 to 18 weeks of age. To address the question of whether the cardiac remodeling from LVH to LVF is associated with modulations of mechanoenergetic properties, we serially measured the LV pressure-volume area (PVA) and myocardial oxygen consumption (MVO2) in isolated, isovolumically contracting hearts from this animal model. The end-systolic pressure-volume relationships obtained by stepwise changes of the LV volume were fit into a binominal regression model, which provided a value of LV contractility (E(es)) and a volume intercept (V0). A slope (the reciprocal of the LV contractile efficiency) and a PVA-independent MVO2 were determined by a regression analysis of the MVO2-PVA relation. The procedure was repeated at different Ca2+ concentrations in perfusate to estimate the oxygen cost of contractility (dMVO2/dE(es)). The MVO2 was further evaluated during K+-induced cardiac arrest to delineate the basal metabolism, which was independent of the E-C coupling. During the transition from LVH to LVF, the E(es) was decreased by 50% (from 681 to 338 mm Hg x g x mL(-1), P<.001), which was associated with a substantial increase in V0 (from 0.002 to 0.07 mL, P<.01). These alterations in both the inotropic state and the ventricular shape were associated with a 45% decrease in the PVA-independent MVO2 (from 800 to 440 mL O2 x beat(-1) x g(-1), P<.01). Despite these marked changes between the two stages, both the LV contractile efficiency and the oxygen cost of contractility remained unchanged. The MVO2 during cardiac arrest also showed an equal level among the groups; hence, from LVH to LVF, the nonmechanical O2 consumption by the E-C coupling decreased in a manner parallel to the basal contractile state. We conclude that (1) in this animal model, the heart failure transition is associated with a marked decrease in myocardial contractility and with ventricular remodeling; (2) despite these changes, the efficiency of the chemomechanical conversion is highly preserved; and consequently, (3) the total energy consumption per unit of failing myocardium is diminished along with its reduced nonmechanical energy expenditure for E-C coupling. These mechanoenergetic properties might constitute an adaptive mechanism in the energy-starved condition of chronically diseased myocardium.

Analysis of Variance↗
PubMed1997

Early changes in the functions of cardiac sarcoplasmic reticulum in volume-overloaded cardiac hypertrophy in rats.

By sequestering activator calcium, the sarcoplasmic reticulum (SR) plays the central role in the excitation-contraction (E-C) cycle of cardiac muscle. Hence, functional changes in the SR in diseased myocardium might critically determine its mechanical characteristics. Previously, we demonstrated that both Ca2+ release and uptake were increased in SR isolated from hearts showing compensatory left ventricular (LV) hypertrophy taken from pressure-overloaded rats. However, it has not been elucidated whether such alterations also occur in the volume-overloaded myocardium. Rats in which volume-overloaded hypertrophy had been induced by aortocaval shunt 12 weeks prior to the investigation were compared to sham-operated controls in terms of SR Ca2+ uptake and release, and density of Ca2+ releasing channels (ryanodine receptors, RyR). Isometric tension and intracellular Ca2+ transients were also measured using the bioluminescent Ca2+ indicator, aequorin, in isolated LV papillary muscles. The extent of hypertrophy was verified by measuring the ratio of biventricular weight to body weight. In vivo, the aortocaval shunt rats showed normal LV contractility and slightly depressed LV relaxation, indicating a compensatory (adaptive) stage of LV function. In contrast, Ca2+ release, uptake, and maximal number of [3H]-ryanodine binding sites were all significantly lower in aortocaval shunt rats than in controls. Both the Ca2+ transients and isometric relaxation of the isolated myocardium were significantly prolonged in aortocaval shunt rats, though their amplitudes were similar in the two groups. Thus, the volume-overloaded cardiac hypertrophy, even at its hemodynamically compensatory (adaptive) stage, (i) was accompanied by abnormal Ca2+ handling, as indicated by prolonged intracellular Ca2+ transients and isometric tension traces, (ii) seems to involve subcellular mechanisms related to decreases in SR Ca2+ release and uptake functions, as well as to a decrease in the number of RyR. Therefore, changes in the intracellular processes underlying cardiac E-C coupling, including SR function, precede the development of this type of heart disease.

Animals↗
PubMed1997

Safe and effective treatment of diabetes mellitus associated with chronic liver diseases with an alpha-glucosidase inhibitor, acarbose.

Glucose intolerance and diabetes mellitus are both prevalent in patients with chronic liver diseases. We examined the efficacy and systemic safety of therapy with an alpha-glucosidase inhibitor, acarbose, in diabetes mellitus associated with chronic liver diseases. Twenty patients with chronic hepatitis or liver cirrhosis and overt diabetes mellitus received acarbose (taken orally) for 8 weeks. The initial dosage of acarbose was 50 mg three times daily, taken before meals; this was increased to 100 mg three times daily after 2 weeks. The mean fasting plasma glucose level was 173.7 +/- 18.6 mg/dl (mean +/- SE) at entry, and was significantly decreased to 132.9 +/- 7.5 mg/dl (P < 0.05) after 8 weeks of acarbose treatment. The improved glycemic control was reflected by a significant decrease in glycosylated hemoglobin (HbA1c) from 7.2 +/- 0.3% at entry to 6.3 +/- 0.2% (P < 0.05) after 8 weeks. Serum levels of both aspartate and alanine aminotransferases fluctuated during acarbose treatment, probably due to the natural course of chronic liver diseases, but the mean values had decreased after 8 weeks of treatment. Plasma ammonia levels increased, from 61.3 +/- 10.7 micrograms/dl to 71.1 +/- 9.6 micrograms/dl after 8 weeks of acarbose treatment but the increase was not significant. Clinically significant elevation of plasma ammonia concentration was seen in 2 cirrhotic patients (121 and 124 micrograms/dl); this was asymptomatic and gradually returned to the normal range despite continuous acarbose treatment in one patient, and was reversed after the withdrawal of acarbose with the concomitant administration of lactulose in the other patient. No other blood tests results, including albumin, cholinesterase, and prothrombin time, or lipid profile and nutritional status, in terms of rapid turnover proteins, prealbumin, retinol binding protein, and transferin, were altered throughout the study period. These results indicate that diabetes mellitus associated with chronic liver diseases may be safely and effectively treated with acarbose. However, clinicians must be aware of the possibility of hyperammonemia when they prescribe acarbose for patients with diabetes mellitus and advanced liver cirrhosis.

Acarbose↗
PubMed1997

Effects of tilisolol, a nonselective beta-adrenergic blocker, on the membrane currents of isolated guinea pig ventricular myocytes.

The effects of tilisolol, a nonselective beta-adrenoceptor blocker, on transmembrane ionic currents were studied in single guinea pig ventricular myocytes by using the whole-cell voltage clamp technique. In the absence of beta-adrenergic stimulation, 10 microM tilisolol, a concentration higher than that used in the clinical therapeutic regimen, did not affect the L-type Ca2+ current (ICa), the inwardly rectifying K+ current (IK1), or the delayed rectifying K+ current (IK). In addition, it did not induce currents through the adenosine triphosphate (ATP)-sensitive K+ channels. However, under the nonselective beta-adrenergic stimulation with 1 microM isoproterenol, 1 microM tilisolol almost completely reversed the agonist-induced increase of IK. The increase of ICa by isoproterenol was blocked only by approximately 30% with tilisolol. We concluded that, at therapeutic concentrations (0.01-0.15 microM), tilisolol is a pure beta-adrenoceptor antagonist that has no direct effects on the transmembrane ionic currents of mammalian ventricular myocytes, such as ICa, IK1, or IK. Comparison of the dose-dependent effects of tilisolol on ICa and IK suggested that tilisolol may selectively inhibit catecholamine-induced increase of IK at the therapeutic concentrations. The virtually selective inhibition of IK, leaving ICa intact, may be favorable to prevent the catecholamine-induced arrhythmia without inhibiting contraction.

Adrenergic beta-Antagonists↗
PubMed1997

Assessment of UDP-galactosyl-transferase activity in gastric mucosa of patients with chronic liver disease using an enzyme-linked peanut agglutinin binding assay.

Gastric mucin plays an important role in protecting mucosa from irritants such as acids and pepsin, and UDP-galactosyltransferase is a key enzyme in mucin synthesis. In order to study the synthesis of gastric mucin in patients with chronic liver disease, we developed a new assay using a peanut agglutinin lectin to measure this enzyme in human gastric mucosa obtained by endoscopic biopsy. Enzyme activity correlated well with that determined with a previous method using radiolabeled galactose. The enzyme activity in gastric mucosa of cirrhotic patients was significantly lower than in patients with chronic hepatitis or in normal controls and correlated with the amount of mucin in surface epithelial cells. Our findings suggest that the synthesis of gastric mucin is impaired in patients with liver cirrhosis.

Adult↗
PubMed1997

Increased expression of interleukin-1 beta and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in the hypertrophied and failing heart with pressure overload.

Studies on the effects of proinflammatory cytokines on the heart suggest that they play some roles in the pathogenesis of congestive heart failure (CHF). To determine the involvement of proinflammatory cytokine in cardiac hypertrophy and CHF induced by mechanical overload, we investigated the expression of interleukin (IL)-1 beta and monocyte chemotactic and activating factor (MCAF)/monocyte chemoattractant protein-1 (MCP-1) in the left ventricle (LV) of Dahl salt-sensitive (DS) rats that showed hypertrophy of the LV induced by hypertension and subsequently developed CHF. The IL-1 beta mRNA content in the LV of DS rats increased 3.9-fold when LV hypertrophy developed, and the increase reached 6.2-fold at the CHF stage compared with that of age-matched Dahl salt-resistant (DR) rats. The amount of IL-1 beta in the LV was positively correlated with the LV weight/body weight ratio. Most of the IL-1 beta immunoreactivity was localized in the endothelial cells and interstitial macrophages. The mRNA levels of MCAF in the LV increased 3.6-fold at 11 weeks and reached 4.8-fold at the CHF stage relative to the age-matched DR rats. MCAF protein was localized to the endothelial cells and interstitial macrophages. In DS rats, the number of interstitial macrophages increased diffusely throughout the LV. We suggest that increased chemokine expression, macrophage infiltration, and proinflammatory cytokine expression play some role in the pathogenesis of cardiac hypertrophy and failure induced by chronic mechanical overload.

Animals↗
PubMed1997

Geranylgeranylacetone and cetraxate hydrochloride increase UDP-galactosyltransferase activity in rat gastric mucosa.

UDP-galactosyltransferase (UDP-Gal-T) is a key enzyme in the synthesis of mucus glycoprotein which plays an important role in gastric mucosal defensive mechanisms. Analysis of gastric UDP-Gal-T activity should clarify the mechanisms of the action of antiulcer drugs regarding gastric defensive factors. Here, we examined UDP-Gal-T activity in rat gastric mucosa treated with the antiulcer drugs geranylgeranylacetone (GGA) and cetraxate hydrochloride (CET). The effects of coadministration of indomethacin and exogenous administration of prostaglandins (PGs) were also studied. GGA and CET significantly increased UDP-Gal-T activity, and coadministration of indomethacin inhibited the increase of enzyme activity. UDP-Gal-T activity level with GGA was significantly higher than the control level, even in the presence of indomethacin. With CET, however, this was not the case. Among PGs, PGE1 significantly increased enzyme activity. Concomitant administration of PGE1 and GGA or CET increased UDP-Gal-T activity even with indomethacin to the levels achieved when these antiulcer drugs were administered without indomethacin. Our findings suggest that GGA and CET exert antiulcer effects by increasing mucus glycoprotein synthesis and that endogenous PG synthesis may be involved in this process. However, mechanisms not mediated by endogenous PGs may also exist in the stimulatory action of GGA on UDP-Gal-T activity.

Animals↗