Tsuneaki Sugimoto

An Experimental Study in Dogs

In order to evaluate a possible therapy for hypersplenism, an experiment with animals was done. In nine dogs, 0.6 ml/kg body weight of 5% ethanolamine oleate was injected percutaneously into the spleen under ultrasound guidance. The injection was repeated three times at intervals of 1 week. Three do

On the mechanism of activation of muscarinic K+ channels by adenosine in isolated atrial cells: involvement of GTP-binding proteins

The molecular mechanisms underlying activation of a K+ channel by adenosine (Ado) and acetylcholine (ACh) were examined in single atrial cells of guinea-pig. Whole cell clamp and patch clamp techniques were used to characterize the K+ channel. In the whole cell clamp conditions, Ado and ACh increased the K+ channel current in a dose-dependent manner. The maximum responses and the apparent dissociation constants were different for Ado and ACh activations of the current. Theophylline blocked activation of the K+ current by Ado, while atropine blocked ACh-activation, indicating that two different membrane receptors were involved. Measurements of the conductance and kinetic properties of both whole cell and single channel currents indicate that Ado and ACh regulate the same K+ channels. In “inside-out” patch conditions, GTP was required in the intracellular side of the membrane for activation of the K+ channel by agonists (present in the patch electrode). The A protomer of pertussis toxin inhibited the channel activation only when NAD was also present. Furthermore, GTP-γS, a non-hydrolyzable GTP analogue, gradually caused activation of the K+ channel in the absence of agonists. Therefore, it was concluded that Ado and m-ACh receptors link with the same population of K+ channels via GTP-binding proteins Ni and/or No in the atrial cell membrane.

Percutaneous ethanol injection therapy for hepatocellular carcinoma. A histopathologic study

Histopathologic examination was done on 18 cases after percutaneous ethanol injection therapy (PEIT) for hepatocellular carcinoma. In eight cases, the lesion was treated by PEIT alone; in the other ten cases, PEIT was combined with transcatheter arterial embolization. The lesion was completely necrotic in 13 cases, 90% necrotic in four cases, and 70% necrotic in the rest. In addition, PEIT seemed to be effective against intercapsular, extracapsular, and vascular invasions. In the four cases of incomplete necrosis, the viable cancer tissue remained in small tumor nodules around the main tumor, in portions isolated by septa, or along the edge of the lesion. Therefore, ethanol should be injected not only into the center of the lesion, but also into sites close to its edge. Ethanol did not damage noncancerous liver parenchyma distant from injected sites. Local dissemination of the cancer cells was not found in any case. Therefore, PEIT seems to be a valuable therapy and may be an alternative to surgery in some cases.

Increased plasma level of endothelin-1 and coronary spasm induction in patients with vasospastic angina pectoris.

To elucidate the pathogenic contribution of a potent vasoconstrictor, endothelin-1, to coronary artery spasm, we provoked spasm with intracoronary administration of acetylcholine or ergonovine and performed sensitive immunoassays of plasma levels of endothelin-1 and atrial natriuretic factor (ANF) in the peripheral vein and coronary sinus of patients with a tentative diagnosis of vasospastic angina (VSA, n = 19). The validity of coronary sinus blood sampling was verified by simultaneous measurement of the ANF level. The plasma endothelin-1 levels in venous and coronary sinus blood of the spasm-provoked patients (n = 12) were 1.71-fold and 2.16-fold higher, respectively, than those of nonprovoked cases (n = 5, p less than 0.01). During left coronary spasm, the endothelin-1 level in coronary sinus transiently decreased from 2.27 +/- 0.14 to 1.76 +/- 0.14 pg/ml (p less than 0.01) and returned to the control level (1.98 +/- 0.20 pg/ml) after the spasm resolved, whereas the change was equivocal during right coronary spasm. In contrast, the patients in whom spasm was not provoked showed no changes and maintained low endothelin-1 levels both before and after the maximal provocation (0.90 +/- 0.13 versus 0.90 +/- 0.13 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Three-year follow-up of patients with right bundle branch block and ST segment elevation in the right precordial leads: Japanese registry of Brugada syndrome

Abstract OBJECTIVES We sought to determine the prevalence of right bundle branch block (RBBB) and ST segment elevation in the working Japanese population, as well as the event rate during a three-year prospective follow-up period. BACKGROUND A poor prognosis of RBBB and ST segment elevation has been reported in Europe and South America, even in asymptomatic patients; however, a large population of asymptomatic patients with sporadic RBBB and ST segment elevation has not been studied. METHODS Ten thousand 12-lead electrocardiograms (ECGs) were obtained during annual check-ups of working adults in the Tokyo area. This three-year prospective follow-up study consisted of 105 patients, including 20 with ventricular fibrillation, 18 with syncope and 67 who were asymptomatic. They were registered from 46 institutions in Japan. RESULTS The prevalence of ECG abnormalities in working adults was 0.16%. A coved-type ST segment elevation was related to a history of cardiac events, and 18% of registered patients had PR prolongation and 9.5% had left-axis deviation. The cumulative cardiac event-free rate was 67.6% in the symptomatic group and 93.4% in the asymptomatic group (p = 0.0004) after three years. CONCLUSIONS The recurrence rate of cardiac events in symptomatic patients was similar to that reported previously, but it was very low in sporadic asymptomatic patients. The ECG findings may help us to select patients for further examination and more accurate evaluation of their prognoses.

Role of Nitric Oxide–cGMP Pathway in Adrenomedullin-Induced Vasodilation in the Rat

We previously reported that adrenomedullin (AM), a potent vasodilator peptide discovered in pheochromocytoma cells, stimulates nitric oxide (NO) release in the rat kidney. To further investigate whether the NO-cGMP pathway is involved in the mechanisms of AM-induced vasodilation, we examined the effects of E-4021, a cGMP-specific phosphodiesterase inhibitor, on AM-induced vasorelaxation in aortic rings and perfused kidneys isolated from Wistar rats. We also measured NO release from the kidneys using a chemiluminescence assay. AM (10(-10) to 10(-7) mol/L) relaxed the aorta precontracted with phenylephrine in a dose-dependent manner. Denudation of endothelium (E) attenuated the vasodilatory action of AM (10(-7) mol/L AM: intact (E+) -25.7+/-5.2% versus denuded (E-) -7. 8+/-0.6%, P<0.05). On the other hand, pretreatment with 10(-8) mol/L E-4021 augmented AM-induced vasorelaxation in the intact aorta (-49. 0+/-7.9%, P<0.05) but not in the denuded one. E-4021 also enhanced acetylcholine (ACh)-induced vasorelaxation in the rat intact aorta (10(-7) mol/L ACh -36.6+/-8.4% versus 10(-8) mol/L E-4021+10(-7) mol/L ACh -62.7+/-3.1%, P<0.05). In perfused kidneys, AM-induced vasorelaxation was also augmented by preincubation with E-4021 (10(-9) mol/L AM -15.4+/-0.6% versus 10(-8) mol/L E-4021+10(-9) mol/L AM -23.6+/-1.2%, P<0.01). AM significantly increased NO release from rat kidneys (DeltaNO: +11.3+/-0.8 fmol. min-1. g-1 kidney at 10(-9) mol/L AM), which was not affected by E-4021. E-4021 enhanced ACh-induced vasorelaxation (10(-9) mol/L ACh -9.7+/-1.7% versus 10(-8) mol/L E-4021+10(-9) mol/L ACh -18.8+/-2.9%, P<0.01) but did not affect ACh-induced NO release from the kidneys. In the aorta and the kidney, 10(-4) mol/L of NG-nitro-L-arginine methyl ester, an NO synthase inhibitor, and 10(-5) mol/L of methylene blue, a guanylate cyclase inhibitor, reduced the vasodilatory effect of AM. These results suggest that the NO-cGMP pathway is involved in the mechanism of AM-induced vasorelaxation, at least in the rat aorta and kidney.

Role of sympathovagal interaction in diurnal variation of QT interval.

To elucidate the role of sympathovagal interaction in diurnal variation of QT interval, 24-hour ambulatory electrocardiographic recordings from 56 subjects (23 control subjects, 18 patients with atherosclerotic coronary artery disease, and 15 patients with diabetes mellitus) were studied. The QT interval at a heart rate of 60 beats/min (QT60) was determined for each of the day and night periods by regression analysis. Sympathetic and parasympathetic activities were assessed by spectral analysis of heart rate variability and represented by the low- and high-frequency components, respectively. The proportion of high-frequency component to the sum of low- and high-frequency components was used as an index of sympathovagal balance. The relative increase in QT60 at night (delta QT60 [%]) was larger in control subjects (4.2 +/- 2.1%) than in patients with coronary artery disease (2.2 +/- 1.8%; p less than 0.01) and diabetes mellitus (-1.5 +/- 4.0%; p less than 0.001). When the data from the 3 subject groups were pooled and analyzed, delta QT60 was correlated with the change in the sympathovagal balance (r = 0.554; p less than 0.001). Low-frequency component in the day alone was also related with delta QT60 (r = 0.554; p less than 0.001), but the ratio or difference of the high-frequency component value between day and night was not. These results indicate that although change in sympathovagal balance was responsible for the diurnal variation in QT interval, the enhanced sympathetic activity in the day was a major determinant of this phenomenon.

Inhibition of aldosterone production by α-human atrial natriuretic polypeptide is associated with an increase in cGMP production

Synthetic alpha-human atrial natriuretic polypeptide caused rapid and marked inhibition of aldosterone production in dispersed rat adrenal capsular cells. The polypeptide also slightly, but significantly, decreased cAMP production in the adrenal dispersed capsular cells, while markedly stimulating cGMP production. The cGMP production was accelerated at the concentration of alpha-human atrial natriuretic polypeptide lower than the threshold level to stimulate aldosterone production. These findings suggest that alpha-human atrial natriuretic polypeptide possibly plays a regulatory role in aldosterone production and an additional role in natriuresis through inhibition of aldosterone production. The stimulation of cGMP production by alpha-human atrial natriuretic polypeptide may be involved in the inhibitory effect of this peptide on aldosterone production.

Short-term desensitization of muscarinic K+ channel current in isolated atrial myocytes and possible role of GTP-binding proteins

The short-term desensitization of the acetylcholine (ACh)-induced K+ channel current was examined in single atrial cells of guinea-pig heart. The tight-seal whole cell voltage clamp technique was used. The solution in the pipettes contained GTP or guanosine-5′-O-(3-thiotriphosphate) (GTP-γS, a non-hydrolyzable GTP analogue). In GTP-loaded cells, ACh evoked a specific K+ channel current via GTP-binding proteins (G) in a dose-dependent manner. The K+ current showed agonist-dependent desensitization similar to those reported in other cardiac tissues (Nilius 1983; Carmeliet and Mubagwa 1986). The cellular response to ACh was also desensitized by activation of P1-purinergic receptors with adenosine (Ado). In GTP-γS-loaded cells, the K+ current was gradually induced even in the absence of agonists, probably due to direct activation of G proteins by GTP-γS. In the early phase of the spontaneous current increase, ACh evoked a large current transiently. As the GTP-γS-induced activation of the current progressed, the magnitude of the ACh-evoked current transient became smaller and finally negligible. Similar results were obtained when Ado was used as an agonist instead of ACh to induce the K+ current. Therefore, it is indicated that the agonistreceptor interaction may not be essential for the desensitization of ACh-induced K+ current in atrial myocytes.

Plasma concentrations of α-human atrial natriuretic polypeptide and cyclic GMP in patients with heart disease☆

Plasma concentrations of immunoreactive α-human atrial natriuretic polypeptide (iα-hANP) and cyclic guanosine monophosphate (cGMP) were measured in 70 patients with heart disease. Plasma concentrations of iα-hANP were directly related to the severity of heart disease (F = 29.61, p < 0.001). Plasma concentrations of iα-hANP were well correlated with pulmonary capillary wedge pressure (PCWP; r = 0.64, p < 0.001), mean pulmonary arterial pressure (PAP; r = 0.62, p < 0.001), and mean right atrial pressure (RAP; r = 0.75, p < 0.001). Plasma concentrations of cGMP were also directly related to the severity of heart disease (F = 13.61, p < 0.001) and highly correlated with plasma concentrations of iα-hANP (r = 0.73, p < 0.001). Plasma concentrations of cGMP were also closely correlated with PCWP (r = 0.69, p < 0.001), mean PAP (r = 0.61, p < 0.001), and mean RAP (r = 0.60, p < 0.001). The iα-hANP concentrations of plasma samples obtained from the coronary sinus were approximately fourfold higher than those of samples obtained from the pulmonary artery, whereas cGMP concentrations were comparable in plasma samples obtained from either site. Elevation of cGMP concentrations following intravenous infusion of synthetic α-hANP was comparable in plasma samples obtained from the coronary sinus and the pulmonary artery. These findings suggest that elevated plasma concentrations of iα-hANP in cardiac patients result from an increase in the secretion of ANPs, which is probably accelerated by elevation of right or left atrial pressure, and that plasma concentrations of cGMP reflect circulating levels of α-hANP.