Tatsuru Matsuoka

ATP-regulated K^+ channels are modulated by intracellular H^+ in guinea-pig ventricular cells.

1. The ATP‐regulated potassium channel (K+ATP) was investigated with respect to modulation by intracellular pH (pHi) by using the inside‐out membrane patch clamp technique in ventricular cells isolated from the heart of the guinea‐pig. Channels which had been closed by internal ATP (0.3‐3 mM) were dose‐dependently activated by decreasing the pHi over the range of pH 7.6‐6.0. However, the channel was conversely inhibited when the pHi was further decreased below 6.0. Inwardly rectifying K+ channels were also decreased in activity when pHi fell from 7.2 to 6.0. 2. The channel activation was also observed with constant concentration of free Ca2+ (1 nM) and Mg2+ (1 mM) in the bathing solution, suggesting that a change in divalent cation concentration is not involved in channel modulation by pHi. 3. When the dose‐response relations of the channel activity for ATP concentrations at different pHi were examined, the channel activity obtained at 1 microM ATP was increased by decreasing pH from 7.2 to 6.4. The half‐maximal inhibition for ATP concentration at pH 7.2 and 6.4 was 20 and 40 microM, respectively, and the Hill coefficient was 2.5 in both curves. 4. In the absence of ATP, internal H+ was able to reactivate run‐down channels but it had less effect on the channel as long as the activity was maintained at a higher level. The increase in the channel activity by H+ was facilitated with a proceeding of the run‐down. However, after the channel was completely inactivated by a long exposure of the membrane patch to ATP‐free solution, a reduction of pH could not activate the channel. 5. The decrease of pH from 7.2 to 6.4 reduced single channel conductance from 89.0 to 77.7 pS in the absence of Mg2+, whereas it reduced the conductance only at the negative membrane potentials in the presence of 2 mM Mg2+. 6. Mean open and closed times within the burst‐like openings of the channel remained unaffected during the change in pHi. 7. We conclude that the cardiac K+ATP channel is modulated by a change in the intracellular pH. The channel modulation consisted of the increase in the channel activity and a decrease in the permeability. The former effect was due to the decrease in the sensitivity of the channel to ATP and the reactivation of the channel which is during the process of run‐down in activity.

Homocysteine and hemostatic disorder as a risk factor for myocardial infarction at a young age

INTRODUCTION Hyperhomocysteinemia is a coronary risk factor, but its pathophysiologic mechanism remains unclear. MATERIALS AND METHODS The importance of hyperhomocysteinemia in the pathogenesis of early myocardial infarction, was determined in case-control study of 127 men with a first early myocardial infarction <or=45 years and 150 age-matched male controls. We measured plasma concentrations of homocysteine, fibrinogen, antithrombin, tissue factor, tissue factor pathway inhibitor, tissue plasminogen activator, plasminogen activator inhibitor-I, plasminogen, alpha(2)-antiplasmin, lipoprotein(a), protein C, protein S, factor VII, and activated factor VII. RESULTS Homocysteine concentrations were higher in patients with early myocardial infarction than in controls (11.2+/-5.3 and 8.3+/-5.0 micromol/l, respectively, P<0.001). Hyperhomocysteinemia was associated with early myocardial infarction (odds ratio=2.22, P<0.001) by multivariate logistic regression analysis. Tissue factor, antithrombin, plasminogen, tissue plasminogen activator, plasminogen activator inhibitor-I, lipoprotein(a), diabetes, and smoking also had associations. In a stepwise logistic regression analysis, hyperhomocysteinemia was the strongest predictor of early myocardial infarction (R(2)=0.19, P<0.001). Hyperhomocysteinemia also had positive correlations with tissue factor (rho=0.26, P=0.009), tissue factor pathway inhibitor (rho=0.23, P=0.020), and tissue plasminogen activator (rho=0.25, P=0.011) in patients with early myocardial infarction, but not in controls. CONCLUSIONS Hyperhomocysteinemia is an independent risk factor for early myocardial infarction, and is associated with a hypercoagulable state mediated by the extrinsic coagulation cascade.

Cardiac tamponade due to rupture of coronary artery fistula to the coronary sinus with giant aneurysm of coronary artery: usefulness of transthoracic echocardiography

A 68-year-old woman was admitted to our hospital because of back pain and syncope. Transthoracic echocardiography revealed pericardial effusion, a collapsed right ventricle, a giant aneurysm connected to the coronary sinus, a dilated left main trunk coronary artery, and a dilated left circumflex artery (LCx). Furthermore, there was a coronary artery fistula arising from the LCx that drained into the coronary sinus. We diagnosed cardiac tamponade due to rupture of the coronary artery fistula or giant aneurysm, and successful emergency surgery was performed. Rupture of coronary artery aneurysm or coronary artery fistula is very rare. Transthoracic two-dimensional echocardiography was very useful in our case for the diagnosis of cardiac tamponade, giant coronary aneurysm, and coronary artery fistula.

Chlorpromazine-induced cardiomyopathy in rats

SummaryWe studied the chronic effects of chlorpromazine (CPZ) on the myocardium of rats using light and electron microscopy. Wistar strain rats were divided into two groups and given either normal saline or CPZ intraperitoneally at a dose of 5 mg/kg body weight/day for 30 consecutive days. Myocardial degeneration, atrophic muscle fiber, and myocardial fibrosis were observed by light microscopy in all CPZ-treated rats. Ultrastructural alterations of the myocardium were also found in all CPZ-treated rats. They consisted of contracted myofibers, mitochondriosis, degenerated mitochondria, dilated sarcoplasmic reticulum, and increased collagen fibers. However, no abnormal histologic or ultrastructural changes were observed in the normal saline-treated rats. We therefore conclude that a chronic administration of a sedative dose of CPZ causes myocardial damage in rats.

Cultured heart cells from the spontaneously diabetic KK mouse

SummaryIn order to clarify the mechanism of myocardial changes in KK mice, cultured heart cells from both normal and spontaneously diabetic KK mice were studied by electron microscopy, photoelectric recording, and45Ca activity. Compared with cultured heart cells from normal mice, those from KK mice showed a decrease in beating frequency and ceased beating more rapidly. The rhythm of the beating cells from KK mice became irregular, while that of the heart cells from normal mice was not changed significantly over a period of 10 days. Electron micrographs of cultured heart cells from KK mice showed an increased number of mitochondria, an intricate arrangement of myofibrils, poorly formed Z bands, and a lipidlike substance. The45Ca activity of heart cells from KK mice, after incubation for 24 h in a medium containing45Ca, was increased compared with heart cells from normal mice.Based on these findings, we conclude that ultrastructural alterations exist in cultured heart cells from KK mice and we suggest that an increase of intracellular Ca might play an important role in the pathogenesis.