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Biomedical subjects

Masafumi Kitakaze

Publications and source records attributed to Masafumi Kitakaze.

At least 37 records · Page 2Linked to original sources
PubMed2006

Catabolism of adenine nucleotides favors adenosine production following exercise in patients with chronic heart failure.

BACKGROUND: Adenosine 5'-triphosphate is catabolized to adenosine 5'-monophosphate (AMP), which is further degraded by 2 pathways: deamination to inosine 5'-monophosphate and ammonia by AMP deaminase, or dephosphorylation to adenosine and inorganic phosphate by 5'-nucleotidase. Because adenosine is believed to be cardioprotective and we have reported that ammonia production decreased after exercise in patients with chronic heart failure (CHF), we determined if plasma adenosine levels after exercise increases in patients with CHF. METHODS AND RESULTS: Maximal ergometer exercise tests with expired gas analysis were performed in 51 patients with CHF (age = 61 +/- 2 years, New York Heart Association [NYHA] class I/II/III = 19/18/14) and 20 age-matched normal controls. Serial changes in both plasma ammonia and adenosine levels were determined. The ratio for delta ammonia to peak work rate became smaller (control, NYHA I/II/III: 0.59 +/- 0.13/0.41 +/- 0.06/0.37 +/- 0.10/0.22 +/- 0.11 microg/dL x watts, respectively) and the ratio for delta adenosine to peak work rate was significantly higher in class III CHF (control, NYHA I/II/III: 0.93 +/- 0.21/0.86 +/- 0.14/1.11 +/- 0.27/2.92 +/- 0.67 nmol/L x watts, respectively). CONCLUSION: In patients with CHF after exercise, the plasma levels of adenosine increased along with the decrease in the plasma levels of ammonia. Considering the physiologic cardioprotective actions of adenosine, the enhanced adenosine production after exercise may be an important adaptive response in patients with CHF.

Adenine Nucleotides↗
PubMed2006

Acute improvement in myocardial function assessed by myocardial strain and strain rate after aortic valve replacement for aortic stenosis.

OBJECTIVES: We investigated whether Doppler tissue imaging (tissue velocity, strain, and strain rate) could be useful to detect subtle left ventricular (LV) dysfunction in patients with aortic stenosis and changes in regional myocardial function after aortic valve replacement (AVR). METHODS: We studied 34 patients (age 69.2 +/- 10.4 years) with severe aortic stenosis, 21 of whom underwent AVR. Tissue velocity, systolic strain, strain rate, time to peak strain, and time to peak systolic and diastolic strain rates of basal and midsegments were measured in the apical 4-, 3-, and 2-chamber views before and 2 weeks after AVR. RESULTS: Strain and systolic strain rate showed the best correlation with LV ejection fraction (r = 0.80 and r = 0.70, respectively, both P < .0001). Early and late diastolic strain rates showed significant correlations with LV mass index (r = 0.45, P < .01; and r = 0.64, P < .0001, respectively) and time to peak strain, to peak systolic strain rate, and to peak early diastolic strain rate with aortic pressure gradient (r = 0.45, P < .01; r = 0.44, P < .01; and r = 0.56, P < .001, respectively) before AVR. Although LV mass index and LV systolic function did not change significantly after 2 weeks (LV mass index, 137 +/- 54 vs 125 +/- 36 g/m2; LV ejection fraction, 60 vs 58%, both P = not significant), peak strain and strain rates increased (P < .001) and time to peak strain and strain rate shortened after AVR (P < .001). Tissue velocities did not change significantly after AVR. CONCLUSIONS: Strain and strain rate parameters seemed to relate to LV function and aortic stenosis severity. Further, they seemed to be superior to tissue velocity and conventional echocardiography in detecting subtle changes in myocardial function after AVR before LV mass and LV function showed improvement.

Aged↗
PubMed2006

Tiotropium, a novel muscarinic M3 receptor antagonist, improved symptoms of chronic obstructive pulmonary disease complicated by chronic heart failure.

A 77-year-old man was referred to hospital because of dyspnea on exertion. Although the patient had been fully medicated for chronic heart failure (CHF) caused by hypertensive heart disease, the echo-estimated left ventricular end-diastolic pressure (LVEDP) and brain natriuretic peptide (BNP) level had continued to be high for at least 2 years. Pulmonary functional examination revealed concomitant chronic obstructive pulmonary disease (COPD). Because beta-agonists were expected to exacerbate the CHF, inhalation of tiotropium, a non-beta-adrenergic bronchodilator and novel M3 muscarinic receptor antagonist, was used to treat the COPD. Not only did the pulmonary function improved but the treatment also safely ameliorated CHF signs including LVEDP and plasma BNP.

Aged↗
PubMed2006

Heart failure elevates serum levels of cibenzoline in arrhythmic patients.

BACKGROUND: Cibenzoline dosing is generally based on renal function, but serum concentrations might be greater than the expected therapeutic levels when standard oral dosing is used. Because heart failure might modify cibenzoline pharmacokinetics, the difference in cibenzoline pharmacokinetics between patients with and without heart failure was evaluated. METHODS AND RESULTS: The study enrolled 368 patients (233 men, 135 women) that had been hospitalized and received cibenzoline therapy at the National Cardiovascular Center from January 2001 to May 2005. There were 89 patients with heart failure (51 men, 38 women) and 279 patients without heart failure (182 men, 97 women). They had therapeutic drug monitoring > or = 3 days after the beginning of treatment with cibenzoline. Brain natriuretic peptide (BNP) was measured in 81 patients (50 men, 31 women) concurrently with therapeutic drug monitoring of cibenzoline. The difference in serum cibenzoline concentration/(dose/weight) (C/D) values between patients with and without heart failure was analyzed using analysis of covariance (ANCOVA) with creatinine clearance (Ccr) serving as the covariate. The effects of dose/weight and the log-transformed BNP (log-BNP) values on serum cibenzoline concentrations were also assessed using ANCOVA. There were 135 and 361 measurements of serum cibenzoline concentration in patients with and without heart failure, respectively. Pearson's correlation coefficient analyses in the patients with and without heart failure revealed that the C/D values were significantly correlated with Ccr (with heart failure, y = -0.837x + 169, r = -0.211, p = 0.014; without heart failure, y = -0.789x + 132, r = -0.393, p < 0.001), and the ANCOVA model indicated that C/D values were significantly higher in patients with heart failure than without heart failure. The ANCOVA model also showed that dose/weight, Ccr and the log-BNP value were significant factors. CONCLUSIONS: The selection of a cibenzoline dose based only on renal function may increase the risk of toxicity in patients with heart failure. Cardiac function should be taken into account in cibenzoline dosing. The log-BNP may be a useful index for predicting serum cibenzoline concentrations.

Adult↗
PubMed2006

Angiotensin II type 1 receptor blocker prevents atrial structural remodeling in rats with hypertension induced by chronic nitric oxide inhibition.

The prevalence of atrial fibrillation (AF) increases in patients with hypertension. Angiotensin II is involved in structural atrial remodeling, which contributes to the onset and maintenance of AF in paced animal models. We investigated the role of angiotensin II in atrial structural remodeling in rats with hypertension. Ten-week-old male Wistar-Kyoto rats were randomly divided into 4 groups: a control group (no treatment), an Nomega-nitro-L-arginine methyl ester (L-NAME) group (administered L-NAME, an inhibitor of nitric oxide synthase, 1 g/l in drinking water), an L-NAME+candesartan group (L-NAME plus candesartan-an angiotensin II receptor blocker (ARB)-at 0.1 mg/kg/day), and an L-NAME + hydralazine group (L-NAME plus hydralazine at 120 mg/l in drinking water). Eight weeks after treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (197 +/- 12 vs.138 +/- 5 mmHg, p < 0.05). Candesartan or hydralazine with L-NAME reduced systolic blood pressure to baseline. Chronic inhibition of NO synthesis increased the extent of fibrosis and transforming growth factor-beta expression in atrial tissue, and both of these effects were prevented by candesartan, but not by hydralazine. Cardiac hypertrophy and dysfunction were induced in the L-NAME group, and these effects were also prevented by candesartan, but not by hydralazine. In contrast, the decrease in thrombomodulin expression in the atrial endocardium in hypertensive rats was restored by candesartan and hydralazine. The ARB prevented atrial structural remodeling, a possible contributing factor for the development of AF, in the hearts of rats with hypertension induced by long-term inhibition of NO synthesis.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Sequence-based analysis of the CYP2D6*36-CYP2D6*10 tandem-type arrangement, a major CYP2D6*10 haplotype in the Japanese population.

The frequency of the CYP2D6*10 allele (100C>T) in the Japanese is relatively high (0.3-0.4), and the two *10-related genes, Ch1 (currently *10B) and Ch2 (*36), and their tandem arrangement Ch(2)-Ch(1) (*36-*10B) have been reported. Although the tandem form of *36-*10 is assumed to be a major form, no detailed information has been reported for its intervening and flanking regions. Thus in this study, the tandem-type *36-*10B and the single-type *10 were analyzed by long-range PCR and sequencing of the subsequent nested PCR products. The sequence of the entire *36-*10 region confirmed the recombination of CYP2D6*10 with CYP2D7P. Also, we found that most of the *10B-harboring haplotypes have the upstream *36 gene and that the majority of the remaining haplotypes are the single-type *10B. Haplotype frequencies of the single-type *10 and *36-*10B were 0.06 and 0.30, respectively, in the subjects analyzed. Additionally, several novel single nucleotide polymorphisms (SNPs) were found in the *36 region and several *36 haplotypes were identified. This sequence information is an important addition to the CYP2D6 sequence data that was obtained by the human genome project.

3' Flanking Region↗
PubMed2006

Diverse structures of chimeric CYP-REP7/6-containing CYP2D6 and a novel defective CYP2D6 haplotype harboring single-type *36 and CYP-REP7/6 in Japanese.

Chimeric REP7/6 has been used as a marker of CYP2D6 deletion, such as for CYP2D6*5. However, the CYP2D6*10D (*10D) haplotype found in a Japanese population consist of CYP2D6*10B, CYP2D7P-derived 3'-flanking region, and a chimeric repetitive sequence, CYP-REP7/6 (REP7/6) (Ishiguro et al. Clin. Chim. Acta. 2004: 347, 217-221). From our analysis, REP7/6 was found in 26 out of 254 Japanese subjects. Thus, the REP7/6-containing CYP2D6 genes (2D6-REP7/6) were analyzed in detail. In order to specifically detect the 2D6-REP7/6 structure, primers were designed in CYP2D6 intron 6 and the REP7/6 3'-flanking region. Among 26 subjects analyzed by PCR, 5 had 2D6-REP7/6. The other 21 subjects were confirmed to have *5 by another *5-specific primer set. Three out of five subjects with 2D6-REP7/6 had the *10D structure. However, further analysis by PCR and sequencing revealed that their haplotypes were further divided into tandem-type *36-*10D (n=2) and single-type *10D (n=1). The remaining two subjects had a novel type of a *36-containing defective structure that consists of CYP2D6*36 and 3'-flanking REP7/6 (single-type *36-REP7/6). Then, REP7/6 sequences in *5, *10D, *36-*10D, and single-type *36 were determined and classified into 5 types: types A to D for *5, type E for *10D and *36-*10D, and type F for *36. These findings could be useful for accurate determination of *5 and REP7/6-harboring aberrant CYP2D6 haplotypes.

Asian People↗
PubMed2006

Effect of amiodarone on the serum concentration/dose ratio of metoprolol in patients with cardiac arrhythmia.

Amiodarone has pharmacokinetic interactions with a number of therapeutic drugs, including warfarin, phenytoin, flecainide, and cyclosporine. Metoprolol is mainly metabolized by CYP2D6, and desethylamiodarone, a metabolite of amiodarone, has a markedly greater inhibitory effect on CYP2D6 than amiodarone. Therefore, the goal of this study was to evaluate the effect of amiodarone and desethylamiodarone on the serum concentration/dose ratio (C/D) of metoprolol in 120 inpatients with cardiac arrhythmias that received either metoprolol and amiodarone (MET+AMD group, n=30) or metoprolol alone (MET group, n=90). The ratio of administered metoprolol was compared between the MET and the MET+AMD groups. The dose of metoprolol and patient age were significantly higher in the MET group when compared with the MET+AMD group (1.00+/-0.480 versus 0.767+/-0.418 mg/kg/day, p<0.050; 68.6+/-10.6 versus 57.6+/-14.1 years, p<0.001, respectively), but the C/D ratio was significantly lower in the MET group than in the MET+AMD group (90.8+/-64.0 versus 136+/-97.8, p<0.01). Furthermore, a significant correlation was found between the C/D ratio and desethylamiodarone concentration (n=30, r=0.371, p<0.01). The results suggest that there is a significant interaction between amiodarone and metoprolol via desethylamiodarone-induced inhibition of CYP2D6. Therefore, careful monitoring of metoprolol concentrations/bioactivity of CYP2D6 is required in the context of co-administration of amiodarone and metoprolol.

Adult↗
PubMed2005

Depression of proteasome activities during the progression of cardiac dysfunction in pressure-overloaded heart of mice.

The ubiquitin-proteasome system contributes to regulation of apoptosis degrading apoptosis-regulatory proteins. Marked accumulation of ubiquitinated proteins in cardiomyocytes of human failing hearts suggested impaired ubiquitin-proteasome system in heart failure. Since cardiomyocyte apoptosis contributes to the progression of cardiac dysfunction in pressure-overloaded hearts, we investigated the role of ubiquitin-proteasome system in such conditions. We found that proteasome activities already depressed before the onset of cardiac dysfunction in pressure-overloaded hearts of mice. Cardiomyocyte apoptosis was observed along with depression of proteasome activities and elevation of proapoptotic/antiapoptotic protein ratio in failing hearts. In cultured cardiomyocytes, pharmacological inhibition of proteasome accumulated proapoptotic proteins such as p53 and Bax. Gene silencing of these proapoptotic proteins by RNA interference prevented the accumulation of respective proteins and attenuated cardiomyocyte apoptosis induced by proteasome inhibition. We conclude that depression of proteasome activities contributes to cardiac dysfunction resulting from cardiomyocyte apoptosis through accumulation of proapoptotic proteins by impaired degradation.

Adult↗
PubMed2005

Evidence for proteasomal degradation of Kv1.5 channel protein.

BACKGROUND: The voltage-gated potassium channel Kv1.5 plays a critical role in the maintenance of the membrane potential. While protein degradation is one of the major mechanisms for the regulation of channel functions, little is known on the degradation mechanism of Kv1.5. METHODS AND RESULTS: Kv1.5 was expressed in COS cells and its degradation, intracellular localization, and channel activities were assessed by pulse-chase analysis, immunofluorescence, and patch clamp techniques, respectively. Expressed Kv1.5 had a half-life time of approximately 6.7 h, which was prolonged by the proteasome inhibitors of MG132, ALLN, proteasomal inhibitor 1, or lactacystine, but not by a lysosomal inhibitor chloroquine. MG132 increased the protein level of Kv1.5, as well as the level of its ubiquitinated form in a dose-dependent manner. Similar effects of MG132 on endogenous Kv1.5 were seen in cultured rat atrial cells. Within a cell, Kv1.5 was mainly localized in both the endoplasmic reticulum and Golgi apparatus. MG132 increased the immunoreactivity of Kv1.5 in these compartments and also increased Ik(ur) currents through the cell-surface Kv1.5. Pretreatment with either brefeldin A or colchicine abolished MG132-induced increase in Ik(ur) currents. CONCLUSION: Kv1.5 is degraded by the proteasome. The inhibition of the proteasome increased Ik(ur) currents secondary to stabilization of the channel protein in the endoplasmic reticulum/Golgi apparatus.

Animals↗
PubMed2005

A role of opening of mitochondrial ATP-sensitive potassium channels in the infarct size-limiting effect of ischemic preconditioning via activation of protein kinase C in the canine heart.

The opening of mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels triggers or mediates the infarct size (IS)-limiting effect of ischemic preconditioning (IP). Because ecto-5'-nucleotidase related to IP is activated by PKC, we tested whether the opening of mitoK(ATP) channels activates PKC and contributes to either activation of ecto-5'-nucleotidase or IS-limiting effect. In dogs, IP procedure decreased IS and activated ecto-5'-nucleotidase, both of which were mimicked by transient exposure to either cromakalim or diazoxide, and these effects were blunted by either GF109203X (a PKC inhibitor) or 5-hydroxydecanoate (a mitoK(ATP) channel blocker), but not by HMR-1098 (a surface sarcolenmal K(ATP) channel blocker). Either cromakalim or diazoxide activated both PKC and ecto-5'-nucleotidase, which was blunted by either GF109203X or 5-hydroxydecanoate, but not by HMR-1098. We concluded that the opening of mitoK(ATP) channels contributes to either activation of ecto-5'-nucleotidase or the infarct size-limiting effect via activation of PKC in canine hearts.

5'-Nucleotidase↗
PubMed2005

Increased gene expression of collagen Types I and III is inhibited by beta-receptor blockade in patients with dilated cardiomyopathy.

AIMS: To elucidate the cellular mechanisms of cardioprotection of beta-blockers in patients with heart failure, we investigated the effects of beta-blockers on collagen synthesis in patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: We examined the gene expression before and 4 months after the administration of a beta-blocker in 17 DCM patients. The messenger ribonucleic acid expression of collagen Types I and III (Col I and III) and transforming growth factor-beta(1) (TGF-beta(1)) of right ventricular tissues obtained by the endomyocardial biopsy were assessed by quantitative reverse transcriptase-polymerase chain reaction. Cardiac sympathetic nerve activity was assessed by the washout rate (WR) of (123)I-metaiodobenzylguanidine from the heart. Left ventricular ejection fraction (21 +/- 7 vs. 35 +/- 9%) and WR (53+/-14 vs. 42 +/- 13%) improved significantly. Before the beta-blocker treatment, the expressions of both Col I (r = 0.560, P = 0.041) and Col III (r = 0.630, P = 0.008) genes were correlated with WR. The expression levels of both Col I (1.08 +/- 0.72 vs. 0.65 +/- 0.26, P = 0.024) and Col III (2.06 +/- 1.81 vs. 1.05 +/- 0.74, P = 0.018) were reduced by a beta-blocker. Changes in TGF-beta(1) correlated with those in WR (r = 0.606, P = 0.002). CONCLUSION: beta-Blockers are considered to inhibit the expression of collagen-related genes in DCM, which seems to be mediated by TGF-beta(1).

Adrenergic beta-Antagonists↗
PubMed2005

Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism.

OBJECTIVE: Insulin resistance (IR) was reported to be associated with chronic heart failure (CHF). Adiponectin, an insulin-sensitizing hormone with anti-inflammatory activity, improves energy metabolism via AMP-activated protein kinase (AMPK). AMPK deficiency is associated with depressed cardiac function under stress conditions. However, it is not clear whether adiponectin plays an important role in CHF. We hypothesize that deficiency of adiponectin might result in deterioration of heart failure. METHODS: Using adiponectin null mice and their littermates, we examined the effects of adiponectin on LV pressure overload-induced cardiac hypertrophy and failure, and investigated the mechanisms involved. RESULTS: Three weeks after transverse aortic constriction (TAC), cardiac hypertrophy (evaluated from the heart-to-body weight ratio: 7.62+/-0.27 in wild-type (WT) mice, 9.97+/-1.13 in knockout (KO) mice, P<0.05) and pulmonary congestion (lung-to-body weight ratio: 9.05+/-1.49 in WT mice, 14.95+/-2.36 in KO mice, P<0.05) were significantly greater in adiponectin KO mice than WT mice. LV dimensions were also increased in KO mice. Compared with WT TAC mice, expression of AMPKalpha protein was lower, while IR was higher in KO TAC mice. CONCLUSION: These findings indicate that adiponectin deficiency leads to progressive cardiac remodeling in pressure overloaded condition mediated via lowing AMPK signaling and impaired glucose metabolism.

Adenylate Kinase↗
PubMed2005

Functional analysis of four naturally occurring variants of human constitutive androstane receptor.

The human constitutive androstane receptor (CAR, NR1I3) is a member of the orphan nuclear receptor superfamily that plays an important role in the control of drug metabolism and disposition. In this study, we sequenced all the coding exons of the NR1I3 gene for 334 Japanese subjects. We identified three novel single nucleotide polymorphisms (SNPs) that induce non-synonymous alterations of amino acids (His246Arg, Leu308Pro, and Asn323Ser) residing in the ligand-binding domain of CAR, in addition to the Val133Gly variant, which was another CAR variant identified in our previous study. We performed functional analysis of these four naturally occurring CAR variants in COS-7 cells using a CYP3A4 promoter/enhancer reporter gene that includes the CAR responsive elements. The His246Arg variant caused marked reductions in both transactivation of the reporter gene and in the response to 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), which is a human CAR-specific agonist. The transactivation ability of the Leu308Pro variant was also significantly decreased, but its responsiveness to CITCO was not abrogated. The transactivation ability and CITCO response of the Val133Gly and Asn323Ser variants did not change as compared to the wild-type CAR. These data suggest that the His246Arg and Leu308Pro variants, especially His246Arg, may influence the expression of drug-metabolizing enzymes and transporters that are transactivated by CAR.

Animals↗
PubMed2005

Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na+ channel blocker aprindine.

ATP-sensitive K+ channels (K(ATP):SUR2A+Kir6.2) play a pivotal role in cardiac protection against ischemia and reperfusion injury. When expressed in COS cells, Kir6.2 was short-lived with a half-life time of 1.9 h. The half-life time of Kir6.2 was prolonged by proteasome inhibitors MG132, ALLN, proteasome inhibitor 1, and lactacystine, but not at all by a lysosomal inhibitor chloroquine. MG132 also increased the level of ubiquitinated Kir6.2 without affecting its localization in the endoplasmic reticulum and Golgi apparatus. In electrophysiological recordings, MG132 augmented nicorandil-activated K(ATP) currents in COS cells expressing SUR2A and Kir6.2 as well as the same currents in neonatal rat cardiomyocytes. Like MG132, a Na+ channel blocker aprindine prolonged the half-life time of Kir6.2 and augmented K(ATP). Finally, both aprindine and MG132 inhibited the 20S proteasome activity in vitro. These results suggest a novel activity of aprindine to enhance K(ATP) currents by inhibiting proteasomal degradation of Kir 6.2 channels, which may be beneficial in the setting of cardiac ischemia.

Animals↗
PubMed2005

Aldosterone nongenomically worsens ischemia via protein kinase C-dependent pathways in hypoperfused canine hearts.

Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors (MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C (PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery (LAD) reduced coronary blood flow (CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone (0.1 nmol/L) rapidly decreased CBF (37.4+/-3.8 to 19.3+/-5.2 mL/100 g/min; P<0.05), along with decreases in fractional shortening (FS) (8.4+/-0.7 to 5.4+/-0.4%; P<0.05) and lactate extraction rate (LER) (-31.7+/-2.9 to -41.4+/-3.7%; P<0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKC-dependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects.

Aldosterone↗