Biomedical subjects

Hidetoshi Yonemochi

Publications and source records attributed to Hidetoshi Yonemochi.

At least 19 recordsLinked to original sources

PubMed2007

Smoking is associated with urinary albumin excretion: an evaluation of premenopausal patients with type 2 diabetes mellitus.

Cigarette smoking and an increase in urinary albumin excretion are associated with high mortality in patients with type 2 diabetes mellitus. We tested the hypothesis that the presence of a smoking habit correlates with increased urinary albumin excretion in premenopausal Japanese women with type 2 diabetes mellitus. The study consisted of 20 premenopausal Japanese patients with type 2 diabetes mellitus in the current-smokers group (age, 45 +/- 4 years, mean +/- SD). The control group consisted of 35 age-matched never-smoker patients (age, 45 +/- 5 years). Serum triglyceride levels were higher and high-density lipoprotein cholesterol levels were lower in the current-smokers group than in the never-smokers group (P < .05 and P < .01, respectively). Furthermore, fasting plasma insulin concentrations and the homeostasis model assessment index were higher in the current-smokers group than in the never-smokers group (P < .005 and P < .001, respectively). Urinary albumin excretion also was higher in the current-smokers group than in the never-smokers group (P < .0001). Multivariate logistic analysis revealed that urinary albumin excretion is independently associated with current smoking in Japanese premenopausal with type 2 diabetes mellitus (odds ratio, 1.79; 95% confidence interval, 1.08-3.87; P < .01). The results of this study show that current smoking is associated with an increased level of urinary albumin excretion, suggesting that smoking was a risk factor in the development of increased urinary albumin excretion in these patients.

Adult↗

PubMed2006

Homocysteine levels are associated with the results of 123I-metaiodobenzylguanidine myocardial scintigraphy in type 2 diabetic patients.

PURPOSE: Elevated total plasma homocysteine (tHcy) levels and cardiovascular autonomic dysfunction are associated with a high mortality in type 2 diabetic patients. We tested the hypothesis that hyperhomocysteinemia is associated with insulin resistance and cardiovascular autonomic dysfunction in type 2 diabetic patients not receiving insulin treatment. METHODS: The study group consisted of 17 type 2 diabetic patients with high tHcy levels (>15 mmol/l, age 58+/-5 years, high tHcy group). The control group consisted of 23 age-matched type 2 diabetic patients with normal tHcy levels (<or=15 mmol/l, age 58+/-9 years, normal tHcy group). Cardiovascular autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations, and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: Early and delayed (123)I-MIBG myocardial uptake values were lower (p<0.005 and p<0.01, respectively) and the percent washout rate of (123)I-MIBG was higher (p<0.001) in the high tHcy group than in the normal tHcy group. The fasting plasma insulin concentrations (p<0.0001) and the homeostasis model assessment (HOMA) index values (p<0.0001) were higher in the high tHcy group than in the normal tHcy group. Multiple regression analysis revealed that the level of tHcy was independently predicted by the HOMA index values and the myocardial uptake of (123)I-MIBG at the delayed phase. CONCLUSION: Our results demonstrate that high levels of tHcy are associated with depressed cardiovascular autonomic function and insulin resistance in patients with type 2 diabetes mellitus.

3-Iodobenzylguanidine↗

PubMed2006

Diazoxide-induced cardioprotection via DeltaPsim loss depending on timing of application.

Although the role of mitochondrial ATP-sensitive potassium (mitoKATP) channels in cardioprotection is widely accepted, it remains unclear when their opening is critical for protection. We tested the hypothesis that the mitoKATP channel acts as a trigger or mediator of protection against apoptosis through loss of mitochondrial inner membrane potential (DeltaPsim). Exposure of neonatal rat cardiomyocytes to H2O2 (0.5 mmol/L) resulted in apoptosis associated with severe DeltaPsim loss. Pretreatment with diazoxide (20 to 100 micromol/L) prevented H2O2-induced apoptosis and DeltaPsim loss at 2 but not 18 h after exposure, while the latter was prevented by cotreatment with diazoxide. Lack of protection by pretreatment with diazoxide was observed in cardiomyocytes cultured in a medium containing H2O2 for 2 h and then not containing for 16 h. The slopes of the regression lines of the relationship between the proportion of apoptotic cells and DeltaPsim loss (y = -0.89 vs. -0.42) and the proportion of cells with high side scatter signal differed between cardiomyocytes exposed H2O2 for 2 and 18 h. Diazoxide per se caused a transient DeltaPsim loss (within 30 min) with a recovery followed by persistent DeltaPsim loss (after 6 h). Inhibition of the former by 5-hydroxydecanoate (5-HD, 0.5 mmol/L) abolished protection of pretreatment with diazoxide (trigger phase), while that of the latter prevented the protection of cotreatment with diazoxide (mediator phase). Our results suggest that mitoKATP channels act as a trigger and mediator of cardioprotection through a transient or persistent DeltaPsim loss depending on phenotypic consequence in response to oxidants.

Animals↗

PubMed2006

Hyperhomocysteinemia is a significant risk factor for silent cerebral infarction in patients with chronic renal failure undergoing hemodialysis.

In patients with chronic renal failure undergoing hemodialysis (HD), the presence of silent cerebral infarction (SCI) is associated with high mortality. Plasma total homocysteine (tHcy), which increases with renal dysfunction, has been flagged as a novel predictor for cerebrovascular events. We tested the hypothesis that the presence of SCI correlates with tHcy in HD patients. Based on brain magnetic resonance imaging findings, 44 patients undergoing HD were divided into a with-SCI group (61+/-9 years [mean+/-SD]; n=24) and a without-SCI group (60+/-8 years, n=20), in whom 24-hour ambulatory blood pressure monitoring was performed. The number of patients with diabetes or hypertension was not different between the 2 groups. We made the following observations: (1) the percentage of smokers was higher in the with-SCI group than in the without-SCI group (P<.05); (2) plasma levels of high-density lipoprotein cholesterol were lower and tHcy was higher in the with-SCI group than in the without-SCI group (P<.05 and P<.0001, respectively); (3) and systolic ambulatory blood pressure and mean heart rate during nighttime were higher in the with-SCI group than in the without-SCI group (P<.05). Multivariate logistic analysis identified hyperhomocysteinemia as an independent and significant risk factor for SCI (odds ratio, 1.22; 95% CI, 1.10-1.36; P<.01). Our findings indicate that plasma tHcy may be a novel useful predictor for SCI in patients with chronic renal failure undergoing HD.

Blood Pressure Monitoring, Ambulatory↗

PubMed2006

Influence of menstrual cycle on QT interval dynamics.

OBJECTIVES: The aim of this study was to investigate the effects of the menstrual cycle on QT interval dynamics and the autonomic tone in healthy women. METHODS: Holter ECGs were recorded in 11 healthy women aged 18-32 years during the follicular and luteal phases of their regular menstrual cycle. The interval from QRS onset to the apex (QaT) and to the end of the T-wave (QeT), the interval between the apex and the end of the T-wave (Ta-e), and RR intervals were measured automatically in the course of 24 hours by Holter ECGs. The QeT/RR, QaT/RR, and Ta-e/RR relationships were evaluated in each subject. The autonomic tone was assessed by the serum catecholamine level at rest and heart rate variability was measured by Holter ECGs. RESULTS: (1) The follicular and luteal phases did not differ significantly with respect to the slopes of the QeT/RR, QaT/RR, and Ta-e/RR relationships. However, QeT and QaT intervals were significantly shorter for all RR intervals in the luteal than in the follicular phase (P < 0.0001). (2) The serum progesterone concentration was significantly higher in the luteal than in the follicular phase (P < 0.001). (3) Noradrenaline was significantly higher in the luteal than in the follicular phase (P < 0.05). There was no significant difference in the follicular and luteal phases with respect to heart rate variability measurements. CONCLUSIONS: Our results suggest that the menstrual cycle affects the QT intervals. The observed shorter QT interval during the luteal than the follicular phase may be attributable to the increase in serum progesterone and sympathetic tone.

Adolescent↗

PubMed2006

Phosphatidylinositol 3-kinase-dependent activation of akt, an essential signal for hyperthermia-induced heat-shock protein 72, is attenuated in streptozotocin-induced diabetic heart.

We tested the hypothesis that phosphatidylinositol 3-kinase (PI 3-kinase)-dependent activation of Akt is essential for the expression of cardiac heat-shock protein 72 (HSP72) and that this pathway is impaired in the streptozotocin (STZ)-induced diabetic heart. STZ-induced male diabetic rats were treated with insulin (STZ-insulin group, n = 26) or vehicle (STZ-vehicle group, n = 61) for 3 weeks. Whole-body hyperthermia (43 degrees C for 20 min) was applied, and the heart was isolated 24 h later. Compared with control heart, hyperthermia-induced HSP72 expression and phosphorylation of Akt were attenuated in the STZ-vehicle heart. Pretreatment with wortmannin attenuated hyperthermia-induced HSP72 expression and phosphorylation of Akt. In isolated perfused heart experiments, the hyperthermia-treated STZ-vehicle heart showed poor left ventricular functional recovery during reperfusion after no-flow global ischemia compared with hyperthermia-treated control heart. Insulin treatment restored HSP72 expression and reperfusion-induced functional recovery. In cultured neonatal rat cardiomyocytes, hyperthermia-induced HSP72 expression was enhanced by insulin, together with tolerance against hypoxia-reoxygenation injury. Wortmannin and LY294002 inhibited hyperthermia-induced HSP72 expression and phosphorylation of Akt. Our results indicate that activation of Akt, in a PI 3-kinase-dependent manner, is essential for hyperthermia-induced HSP72 expression in association with cardioprotection, suggesting impairment of this signaling pathway in the STZ-induced diabetic heart, probably due to insulin deficiency.

Androstadienes↗

PubMed2006

Pioglitazone but not glibenclamide improves cardiac expression of heat shock protein 72 and tolerance against ischemia/reperfusion injury in the heredity insulin-resistant rat.

We tested the hypothesis that pioglitazone could restore expression of heat shock protein (HSP)72 in insulin-resistant rat heart. At 12 weeks of age, male Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control (LETO) rats were treated with pioglitazone (10 mg x kg(-1) x day(-1)) or glibenclamide (5 mg x kg(-1) x day(-1)) for 4 weeks. Thereafter, hyperthermia (43 degrees C for 20 min) was applied. In response to hyperthermia, the activation of serine/threonine kinase Akt depending on phosphatidylinositol 3 (PI3) kinase was necessary for cardiac expression of HSP72. Hyperthermia-induced activation of Akt and HSP72 expression were depressed in OLETF rat hearts. Pioglitazone but not glibenclamide improved insulin sensitivity in OLETF rats, which was associated with the restoration of Akt activation and HSP72 expression. In experiments with isolated perfused heart, reperfusion-induced cardiac functional recovery was suppressed in OLETF rat hearts, which was improved by pioglitazone but not glibenclamide. Our results suggest that PI3 kinase-dependent Akt activation, an essential signal for HSP72 expression, is depressed in the heart in insulin-resistant OLETF rats, and the results suggest also that the restoration of HSP72 expression and tolerance against ischemia/reperfusion injury by treatment with pioglitazone might be due to an improvement of insulin resistance, leading to restoration of impaired PI3 kinase-dependent Akt activation in response to hyperthermia.

Animals↗

PubMed2006

[Evaluation of autonomic function using posture change].

There are several examinations to evaluate cardiac autonomic function. Autonomic neuropathy is a common complication of diabetes mellitus and is associated with increased mortality. Baroreflex sensitivity (BRS) is a marker for the ability to augment vagal activity. Several studies have shown that BRS is impaired in diabetes with autonomic neuropathy. The head-up tilt test is the most useful tool to diagnose the neurally mediated syncope. We have developed a new non-invasive method to evaluate the baroreflex using downward tilting (DT-BRS). In our previous study conducted in healthy volunteers and diabetic patients, we demonstrated a strong correlation between systolic blood pressure increase and corresponding RR interval lengthening during downward tilting, which yielded DT-BRS values that correlated well with the BRS value obtained by the phenylephrine method (Phe-BRS). Heart rate responses observed after both squatting and standing (squatting test) are assumed to be a simple and useful tool to assess autonomic activity. We reported that indices of the squatting test showed a significant correlation with BRS assessed by Phe-BRS in diabetes. DT-BRS and the squatting test may provide promising information for the assessment of reflex vagal activity in diabetes.

Autonomic Nervous System↗

PubMed2005

Effects of valsartan and perindopril combination therapy on left ventricular hypertrophy and aortic arterial stiffness in patients with essential hypertension.

OBJECTIVE: To compare the effects of combined therapy of an angiotensin II receptor blocker (ARB; valsartan) and an angiotensin converting enzyme inhibitor (ACEI; perindopril) on blood pressure (BP), metabolic profiles, plasma brain natriuretic peptide (BNP) levels, echocardiographic findings, and aortic pulse wave velocity (PWV) with those of respective monotherapy in never-treated patients with essential hypertension. METHODS: This was a prospective randomized trial, in which there were 31 patients with essential hypertension and left ventricular hypertrophy (LVH) who visited the outpatient clinic of Oita Red Cross Hospital (14 women and 17 men; mean+/-SD age, 59+/-5 years). Each patient was randomly assigned to receive valsartan (160 mg/day, V group, n=10), perindopril (8 mg/day, P group, n=11), or a combination of valsartan (80 mg/day) and perindopril (4 mg/day, V+P group, n=10) for 40 weeks. Ambulatory BP monitoring (ABPM), echocardiographic findings, metabolic findings, plasma BNP levels, and brachial-ankle PWV (baPWV) were evaluated before and after the 40-week therapy. RESULTS: The baseline and post-therapeutic BP levels were similar among the three groups. At baseline ABPM, non-dipping was observed in 80, 82, and 80% in the V, P, and V+P groups, respectively. Each 40-week therapy regimen comparably reduced ABP. The plasma BNP levels (P<0.0001 for each), left ventricular mass index (LVMI) (P<0.01 for each), and PWV values (P<0.0001 for each) were also reduced. However, when compared with either V or P group, the percentage reduction in LVMI (P<0.05 and P<0.005, respectively), BNP (P<0.05 for each), and baPWV values (P<0.005 and P<0.001, respectively) was greater in the V+P group. CONCLUSIONS: Our findings suggest that, when compared with each monotherapy, perindopril and valsartan combination therapy exerts greater beneficial effects regarding the regression of LVH, reduction in BNP, and improvement of PWV in a selected group of essential hypertensive patients with LVH and high prevalence of non-dipping patterns.

Aged↗

PubMed2005

Heterogeneous expression of connexin 43 in the myocardium of rabbit right ventricular outflow tract.

The right ventricular outflow tract (RVOT) has been demonstrated as an important focus in idiopathic ventricular arrhythmias. However, the role of the gap junction in this region in arrhythmic events has not been fully investigated. The purpose of this study was to evaluate the expression and distribution of the gap junction protein connexin 43 (Cx43) in the myocardium of the RVOT area of normal adult rabbits. Tissue samples were obtained from 6 regions of normal rabbit heart, i.e. the left ventricle (LV) free wall, the LV papillary muscle, the RVOT free wall, and the RVOT septum which was subdivided into the RV side, the central layer, and the LV side. Immunohistochemical analysis was performed to investigate the characteristics of Cx43 distribution in the RVOT area. In the LV free wall and papillary muscle, Cx43 was abundantly, homogeneously, and approximately equally expressed in end-to-end- and side-to-side intercellular connections. In the free wall of the RVOT, Cx43 expression was poor compared to both these LV regions and side-to-side cell connections were predominant. Cx43 was as richly and homogeneously distributed in the central layer and LV side of the RVOT septum as in the two LV regions. However, in the RV side of the RVOT septum, its distribution was scant and an unstained area was noted. The heterogeneous expression of Cx43 in the RVOT area may serve as substrate for idiopathic ventricular arrhythmia.

Animals↗

PubMed2005

Gender differences in autonomic modulation of ventricular repolarization in humans.

BACKGROUND: Gender differences in the incidence of ventricular arrhythmias have been reported and torsades de pointes associated with long QT syndrome are more common in women than men. Although increased sympathetic tone has an important role in vulnerability to arrhythmia, little is currently known regarding gender differences in the dynamic electrophysiological response to sympathetic stimulation. Therefore, we investigated whether there is a gender difference in humans with respect to the dynamic response of ventricular repolarization to beta-adrenergic stimulation and to autonomic blockade. METHODS: Twelve-lead ECGs were continuously recorded during isoproterenol infusion (protocol 1) and autonomic blockade with propranolol and atropine infusion (protocol 2) in 24 healthy volunteers (12 men, 23 +/- 2 years; 12 women, 23 +/- 5 years). QT (QTc) intervals were measured at the baseline and at a heart rate of 75, 100, and 120 beats/min. RESULTS: (1) The morphology of the T wave dynamically and transiently changed to bifid or biphasic during the acute phase of isoproterenol infusion. The incidence of these morphologic changes was higher in women than men (P < 0.05). (2) The QTc interval was initially prolonged and then shortened in both men and women during isoproterenol administration. However, QTc prolongation was significantly greater in women (0.44 +/- 0.02 to 0.55 +/- 0.03 sec) than men (0.42 +/- 0.03 to 0.51 +/- 0.04 sec; P < 0.05). (3) The QTc interval was significantly prolonged under autonomic blockade and the intrinsic QTc interval was longer in women than men (P < 0.05). CONCLUSION: While sympathetic stimulation and autonomic blockade modulated the dynamics of ventricular repolarization in both sexes, it was more pronounced in women. This gender difference may partially account for the susceptibility of women to arrhythmogenesis.

Adult↗

PubMed2004

Patients with mild hypertensive heart disease and left ventricular outflow tract obstruction: treatment with angiotensin II antagonists.

Systolic anterior motion of the mitral leaflet (SAM) combined with obstruction at the left ventricular (LV) outflow tract is often observed on echocardiography in elderly hypertensive patients with severe concentric LV hypertrophy. We experienced, however, two patients with mild hypertension who had an ejection systolic murmur, SAM, and LV outflow tract obstruction with a pressure gradient of 46 and 45 mmHg, respectively, despite very mild symmetric hypertrophy of LV wall (12 mm) by echocardiography. Treatment with angiotensin II type 1 receptor blocker improved intraventricular obstruction and LV hypertrophy in both patients. Left ventricular outflow tract obstruction should be suspected in hypertensive patients with mild LV hypertrophy, particularly in those with an ejection systolic murmur. Angiotensin II antagonists could be considered as the treatment of choice for such patients.

Aged↗

PubMed2004

Characteristics of new-onset ventricular arrhythmias in pregnancy.

The characteristics and underlying mechanisms of new-onset ventricular arrhythmia during pregnancy have not been adequately investigated. We studied 11 pregnant women aged 35.4 +/- 3.1 years who experienced new-onset ventricular arrhythmias during pregnancy. The onset of their first episode of ventricular arrhythmia was distributed equally over the 3 trimesters. Ventricular premature contractions (VPCs) and ventricular tachycardia (VT) exhibited a monomorphic configuration in all patients; in 8 (73%) they originated from the right ventricular outflow tract. The frequency of VPCs decreased by more than 95% in 83% of the patients; couplets and VTs disappeared completely in all patients during the postpartum period. All parameters of heart rate variability were significantly lower during pregnancy than postpartum (P < .05). QT and QTc intervals were normal during pregnancy in all patients. The slope and the intersect of the QT/RR relationship obtained from Holter ECGs were not significantly different during pregnancy and in the postpartum period. New-onset ventricular arrhythmias in pregnancy manifest characteristics similar to those of idiopathic VT. Our findings suggest that various hemodynamic and neurohormonal changes associated with pregnancy play an important role in ventricular arrhythmogenesis.

Adult↗

PubMed2004

Estrogen inhibits hyperthermia-induced expression of heat-shock protein 72 and cardioprotection against ischemia/reperfusion injury in female rat heart.

There is still controversy as to whether estrogen inhibits or enhances heat-shock protein (HSP72) expression in the heart. To evaluate the gender difference, whole-body hyperthermia (HT, 43 degrees C for 20 min) or normothermia (NT, 37 degrees C for 20 min) was applied to both male and female rats. Twenty-four hours after each thermo-treatment, the heart was isolated for either Western blot analysis or isolated-perfused heart experiments. Induction of HSP72 expression and post-ischemic recovery of left ventricular (LV) function was pronounced in male than in female heart. To evaluate the effect of estrogen, female rats received ovariectomy. One week after the operation, ovariectomized rats were treated with 17beta-estradiol in a single administration of 4, 40, or 400 mug/kg or vehicle (placebo) intraperitoneally (IP), followed by HT or NT at 6 h after the administration. In the placebo-treated ovariectomized female, HT-induced cardiac HSP72 expression was more remarkable with better LV functional recovery than sham-operated gonadally intact female. Treatment with 17beta-estradiol reduced HT-induced cardiac HSP72 overexpression and abolished better LV functional recovery observed in placebo-treated ovariectomized female. Inhibition of HT-induced HSP72 expression was in association with the inhibition of activation of heat-shock factor 1 (HSF1). In cultured rat neonatal cardiomyocytes, prior exposure to H(2)O(2)-induced HSP72 expression and rendered protection against hypoxia/reoxygenation, which was attenuated by the treatment with 17beta-estradiol. The washout of 17beta-estradiol for 48 h recovered the H(2)O(2)-induced HSP72 expression and tolerance against hypoxia/reoxygenation. Our results suggest that the male heart is more sensitive than gonadally intact female heart in terms of response to HT to express HSP72 in association with protection against ischemic insult. This observation may be due to the inhibitory effects of estrogen on HSP72 expression at a transcriptional level.

Animals↗

PubMed2004

Dynamics of T-U wave in patients with idiopathic ventricular tachycardia originating from the right ventricular outflow tract.

Postextrasystolic U wave augmentation is observed in patients with long QT syndrome and those with organic heart disease. This phenomenon is considered a marker of increased risk of arrhythmia. However, the characteristics of the U wave have not been evaluated in patients with idiopathic VT originating from the right ventricular outflow tract (RVOT-VT). The present study evaluated the dynamic change in the T-U wave in patients with RVOT-VT. Holter ECGs obtained from 14 patients with RVOT-VT and 11 healthy control subjects were analyzed. The amplitude of T and U waves (Tamp and Uamp) and preceding RR intervals were measured during stable sinus rhythm (rate dependent change) and in the postextrasystolic sinus complex (pause dependent change). Uamp correlated negatively and significantly with the preceding RR interval in 13 (93%) RVOT-VT patients but in only 2 (18%) control subjects. The average value of the slope of the Uamp/RR relationship was negative (-0.22 +/- 0.10 mV/s) in the RVOT-VT group, but was positive (0.04 +/- 0.07 mV/s, P < 0.001) in the control group. Pause dependent U wave augmentation was observed in 12 (86%) of 14 patients. Increased frequency of consecutive preceding premature ventricular contractions (PVCs) was associated with a larger postextrasystolic Uamp. PVC or the first ventricular beat of VT arose from near the peak of augmented U waves. The dynamic changes in the T-U wave were observed in patients with RVOT-VT. Further investigations are required to elucidate the precise role of the U wave in arrhythmogenesis in those patients.

Adult↗

PubMed2004

Gender differences in the dynamics of terminal T wave intervals.

This study was designed to investigate gender differences in the dynamic changes of the terminal T wave (Ta-e interval) of healthy subjects. Holter ECGs were recorded in 24 healthy volunteers (12 men aged 23 +/- 2 years). The intervals from QRS onset to the apex (QaT) and to the end of the T wave (QeT), and the interval between the apex and the end of the T wave (Ta-e) were measured. Then, the QeT/RR, QaT/RR, and Ta-e/RR relationship was evaluated by linear regression analysis in each subject. The QeT and QaT intervals were significantly longer in women than men and the slope of the QeT/RR and QaT/RR relationship was steeper in women than men. The Ta-e intervals showed a significant but weaker positive correlation with the preceding RR intervals in 7 (58.3%) men and 9 (75.0%) women. The average values of the slope and the correlation coefficient of the Ta-e/RR relationship were significantly smaller compared to those of QeT and QaT in both men and women (P < 0.0001). The slope of the Ta-e/RR relationship was significantly greater in women than men (0.025 +/- 0.009 vs 0.011 +/- 0.012, P < 0.005). However, the Ta-e intervals were significantly longer over the entire range of RR intervals in men than women (P < 0.0001). The rate-correcting formulas of Bazett and Framingham overcorrected the Ta-e intervals. The observed gender difference in the measurement and dynamics of the Ta-e interval may help to understand the mechanisms underlying the gender difference in the incidence of ventricular arrhythmias.

Adult↗

PubMed2003

Diazoxide triggers cardioprotection against apoptosis induced by oxidative stress.

Although mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels have been reported to reduce the extent of apoptosis, the critical timing of mitoK(ATP) channel opening required to protect myocytes against apoptosis remains unclear. In the present study, we examined whether the mitoK(ATP) channel serves as a trigger of cardioprotection against apoptosis induced by oxidative stress. Apoptosis of cultured neonatal rat cardiomyocytes was determined by flow cytometry (light scatter and propidium iodide/annexin V-FITC fluorescence) and by nuclear staining with Hoechst 33342. Mitochondrial membrane potential (DeltaPsi) was measured by flow cytometry of cells stained with rhodamine-123 (Rh-123). Exposure to H(2)O(2) (500 microM) induced apoptosis, and the percentage of apoptotic cells increased progressively and peaked at 2 h. This H(2)O(2)-induced apoptosis was associated with the loss of DeltaPsi, and the time course of decrease in Rh-123 fluorescence paralleled that of apoptosis. Pretreatment of cardiomyocytes with diazoxide (100 microM), a putative mitoK(ATP) channel opener, for 30 min before exposure to H(2)O(2) elicited transient and mild depolarization of DeltaPsi and consequently suppressed both apoptosis and DeltaPsi loss after 2-h exposure to H(2)O(2). These protective effects of diazoxide were abrogated by the mitoK(ATP) channel blocker 5-hydroxydecanoate (500 microM) but not by the sarcolemmal K(ATP) channel blocker HMR-1098 (30 microM). Our results suggest for the first time that diazoxide-induced opening of mitoK(ATP) channels triggers cardioprotection against apoptosis induced by oxidative stress in rat cardiomyocytes.

Animals↗

PubMed2003

Norepinephrine evoked by potassium depolarization increases interstitial adenosine concentration via activation of ecto-5'-nucleotidase in rat hearts.

We examined whether the increase of the extracellular potassium ion concentration, [K(+)](o), can increase the production of interstitial adenosine in the ventricular myocardium, with the use of microdialysis techniques in in situ rat hearts. A microdialysis probe was implanted in the left ventricular myocardium of anesthetized rat hearts, and the tissue in the vicinity of the dialysis was perfused with Tyrode's solution containing AMP through the dialysis probe at a rate of 1.0 microl/min to assess the activity of ecto-5'-nucleotidase. When the K(+) concentration of the perfusate ([K(+)](o)) was increased stepwise from 5.4 mM (control) to up to 140.4 mM, the level of dialysate adenosine significantly increased, in a [K(+)](o)-dependent manner. The presence of CsCl or BaCl(2) (20 mM), which markedly depolarized the resting potential, significantly increased the level of adenosine in the dialysate. Equivalent increases in the osmotic concentration of the perfusate, made by adding sucrose (270 mM), did not change the dialysate adenosine concentration. Introduction of high [K(+)](o) (140.4 mM) significantly increased the level of norepinephrine (NE) in the dialysate, and this increase was abolished in the reserpinized rats hearts. In the presence of an antagonist of alpha(1)-adrenoceptor (prazosin, 50 microM) or protein kinase C (PKC) (chelerythrine, 10 microM) and in reserpinized rats, an introduction of high [K(+)](o) failed to increase the AMP-primed dialysate adenosine concentration. We conclude that high [K(+)](o)-induced NE release from sympathetic nerve terminals increases adenosine by stimulating the PKC-ecto-5'-nucleotidase cascade through alpha(1)-adrenoceptors.

5'-Nucleotidase↗