Hidemasa Okumura

Reduction of size of myocardial infarction with nicorandil, a new antianginal drug, after coronary artery occlusion in dogs

The effects of nicorandil, a new antianginal drug, on size of myocardial infarction were studied in anesthetized, open-chest dogs after left anterior descending coronary artery occlusion. To quantify the extent of the hypoperfused zone.99mTc-albumin microspheres were injected into the left atrium 1 min after occlusion. Fifteen minutes after occlusion, dogs were randomly assigned to a control group or a nicorandiltreated group that received immediately after assignments 100 μg/kg of nicorandil followed by a continuous infusion of 30 μg/kg/min for 6 h. Six hours after occlusion, the left ventricle was cut into 3 mm thick slices for triphenyltetrazolium chloride staining and autoradiography. The extent of the hypoperfused zone (26.1% ± 3.1% of the left ventricle in the control vs. 23.2% ± 3.7% in the treated group, mean ± SEM) was not different between the two groups. The ratio of the extent of myocardial necrosis to the extent of the hypoperfused zone was significantly smaller in the treated group (64.3% ± 7.2%. n = 7, p < 0.05) than in the control group (92.6% ± 9.2%, n = 7). Thus, nicorandil administered early after coronary artery occlusion reduced the size of myocardial infarction by 31%.

A case of Takayasu's arteritis associated with membranoproliferative glomerulonephritis and nephrotic syndrome

We describe a 57-year-old Japanese female who had Takayasus arteritis associated with nephrotic syndrome due to membranoproliferative glomerulonephritis. Although a focal and segmental mesangial proliferative glomerulonephritis associated with Takayasus arteritis has been described, membranoproliferative glomerulonephritis has not been reported previously in this condition.

Quinidine blocks cardiac sodium current after removal of the fast inactivation process with chloramine-T

To determine if the fast sodium current inactivation process is necessary for sodium current (INa) blockade by quinidine, we studied the effects of quinidine on INa in guinea-pig ventricular myocytes treated with chloramine-T, which removes the fast inactivation process of INa. Following exposure to chloramine-T (2 mM), INa amplitude was reduced at all voltages and INa decay was irreversibly prevented. Quinidine (10 microM) produced resting block of INa of 36 +/- 2% (n = 5) at the peak potential of -30 mV in chloramine-T treated myocytes. Quinidine decreased INa in a dose-dependent manner. The half-blocking concentration (KD) was 1.9 +/- 0.2 x 10(-5) M (n = 4). The steady-state inactivation curve (hx) was shifted in the negative potential direction (-5.2 +/- 0.4 mV, n = 4). Even after removal of the fast inactivation process of INa, use-dependent block was observed in the presence of quinidine when various depolarizing pulse durations (5 ms approximately 200 ms) were applied repetitively at intervals of 300 ms approximately 2 s. Longer depolarizing pulses and higher frequency pulse trains produced greater use-dependent block. Use-dependent block was also enhanced at more positive holding potentials. These results suggest that quinidine produces both resting block and use-dependent block of sodium channels in the absence of the fast INa inactivation process.

Long-term haemodynamic effects of a 4-week regimen of nipradilol, a new β-blocker with nitrovasodilating properties, in patients with portal hypertension due to cirrhosis: A comparative study with propranolol

To study the long-term effects of pharmacological combination therapy, a comparison was made of the haemodynamic changes in patients with cirrhosis and portal hypertension following a 4-week treatment of propranolol or nipradilol, a new nonselective beta-blocker with nitrovasodilating effect. Nipradilol (12 mg/dag, n = 12) significantly diminished wedged hepatic venous pressure (WHVP, 25 +/- 16%), the hepatic venous pressure gradient (HVPG, 20 +/- 12%), and estimated hepatic blood flow (EHBF, 18 +/- 16%). Propranolol (30 mg/day, n = 11) also caused a significant reduction in WHVP (22 +/- 21%) and HVPG (24 +/- 21%), but not in EHBF. The percentage of portal pressure reduction and the frequency of nonresponders did not differ between the nipradilol and propranolol groups. Both agents reduced heart rate by approx. 20%. Nipradilol, however, did not cause a significant reduction in cardiac index (CI) versus a 14% reduction by propranolol. Pulmonary capillary wedge pressure and central venous pressure, an index of preload, were decreased slightly in the nipradilol group. When nonresponders were excluded, there was a significant correlation of the percentage of reduction between WHVP and CI or systemic vascular resistance, in the nipradilol group. These results indicate that nipradilol may have potent hypotensive effects on portal hypertension, similar but not superior to propranolol. Nipradilol, at the dosage used in the present study, did not appear to exert a nitrovasodilating effect to enhance the portal pressure reduction induced by beta-blocking action.

Regional Differences in Peripheral Circulation between Upper and Lower Extremity in Patients with Cirrhosis

In 42 patients with compensated cirrhosis and 31 control subjects, blood flow (BF) and vascular resistance (VR) were measured at the forearm and calf, using a pneumoplethysmograph. In some of the subjects deep-body temperature (DBT) was also measured by the zero heat flow method. In cirrhosis, BF and DBT were significantly higher and VR was significantly lower in the forearm than in the calf. Corresponding differences were not observed in control subjects. When these indices of the forearm were compared between cirrhosis and controls, BF and DBT were significantly higher and VR was significantly lower in cirrhosis than in controls. In cirrhotics in whom the gradient between forearm BF and calf BF was 1 ml.dl-1.min-1 or more (forearm greater than calf), the vascular response of the forearm to cold stimulation was reduced, whereas in the remaining patients and in controls the forearm BF and VR responded significantly. These results suggest that there is a regional difference in peripheral circulation in cirrhotics, partly with participation of impaired sympathetic nervous activity, which may account for the selective distribution observed in the clinical manifestations of vascular spider, palmar erythema, and warm hand, inclined toward the upper extremities or the upper part of the body.

Severe hepatitis during ketoconazole therapy

SummaryKetoconazole is an imidazole derivative recently developed as an antifungal agent. There have been only a few established cases of hepatotoxicity in the literature. This report describes a case of presumed ketoconazole hepatotoxicity characterized by the development of severe hepatitis with marked centrilobular necrosis. The lack of hypersensitivity reactions in clinical findings and centrilobular location of necrosis suggested a host idiosyncrasy with metabolic abnormality as the effect of ketoconazole in the present case.

Multiple coronary arteriovenous fistulas associated with polymyositis.

We report a case of a 60-year-old female presenting a histologically proven polymyositis with multiple coronary arteriocameral fistulas draining into the left ventricle. The exact pathogenesis of coronary artery fistulas and their relation to polymyositis are not clear.

Primary biliary cirrhosis with fibrosing alveolitis

SummaryA 65-year-old case diagnosed as primary biliary cirrhosis without definite signs of Sjögren’s syndrome at age 62 developed interstitial lung disease, which was clinically, histologically, radiographically, and scintigraphically compatible with fibrosing alveolitis. Analysis of the cells in bronchoalveolar lavage fluid revealed, however, increased proportions of not only neutrophils but also lymphocytic cells, which were predominant. This case should focus attention on the association of primary biliary cirrhosis and fibrosing alveolitis.

Clinical Features and Coronary Backgrounds of Coexistent Peripheral Vascular Disease in Japanese Coronary Artery Disease Patients

By use of noninvasive tests (Doppler segmental pressure study, supraorbital Doppler flow analysis, and segmental plethysmography), coexistent carotid (CTD) or lower extremity peripheral vascular disease (PVD) were diagnosed and cor related with subjective symptoms, coronary risk factors (CRFs), coronary ar teriograms (CAGs), cardiac hemodynamics. and infarct size in 121 consecutive patients with documented coronary artery disease (CAD). PVD was found in 16.5%, CTD in 33.1%, and both PVD and CTD in 9.9% of the patients studied; 20% of PVD patients and 47.5% of CTD patients were asymptomatic with respect to coexistent PVD or CTD. There were no significant differences between the presence or absence of PVD or CTD as regards number of CRFs, Killip classifi cation, cardiac hemodynamics, or number of stenotic coronary arteries. However, serum creatine kinase (CK) and CKMB release curves in the PVD group showed significantly higher peak CK and peak CKMB values than those in the PVD(-) group (4096 ± 5408/282 ± 263 vs 1706 ± 1715/179 ± 186, p < 0.05) because of the higher prevalence (100%) of multivessel disease on CAG. Investigation of the relationship of CRFs to coexistent PVD revealed that the smoking ratio in men (86.7%) and the hypertension ratio in women (80%) were extremely high in PVD patients, and statistically significant differences between PVD( +) patients and PVD(-) groups were found with respect to the obesity ratio (p<0.05) in men and the hyper cholesterolemia ratio (p < 0.05) and obesity ratio (60%, p < 0.05) in women. On the other hand, in CTD patients, the smoking ratio (84%) and hypertension ratio (64%) in men and the hypertension ratio (86.7%) in women were extremely high, and significant differ ences between CTD(+) patients and CTD(-) patients were found with respect to the smoking ratio (p < 0.05) and obesity ratio (p < 0.05) in men and the smoking ratio (p < 0.05) in women. For the entire group of patients, the ankle/brachial pressure index was signifi cantly lower (p<0.05) when CAD patients displayed four or more CRFs, suggesting the progression of PVD with increasing number of CRFs. The incidence and clinical features of coexistent PVD or CTD in Japanese CAD patients were documented in the present study.

Pathophysiology and Epidemiology of Portal Hypertension

SummaryChanges in portal pressure are regulated by changes in hepatic vascular resistance, which is normally under neurohumoral control, and portal tributary blood flow. Two theories on the pathophysiology of portal hypertension have been proposed: the ‘backward flow’ theory, in which portal hypertension is attributable to increased resistance to portal venous flow, and the ‘forward flow’ theory, in which increased splanchnic blood flow maintains portal hypertension despite extreme portal-systemic shunting. The sinusoidal abnormalities caused by an accumulation of collagen in the perisinusoidal space of Disse may induce increased resistance to blood flow in various pathological conditions of the liver. Non-cirrhotic portal hypertension results from not only relatively uncommon disorders prevalent mainly in Asia and tropical countries, but also from acute and chronic phases of relatively common liver diseases. Systemic hyperdynamic circulation, characterised by an increased cardiac output and a reduced peripheral vascular resistance, and splanchnic hyperaemia may develop as consequences of portal hypertension. Although the mechanisms of these changes are not clearly understood, portal-systemic shunting as well as some vasoactive substances, including prostaglandins, may be involved. The erosive and eruptive mechanisms are the two potential explanations for variceal bleeding. In the latter, pressure should not be viewed in isolation and other additive factors such as variceal size may be involved. Several new techniques of measuring variceal pressure and blood flow may improve understanding of the actual pathophysiology of variceal bleeding. Renal haemodynamic alterations secondary to the systemic circulatory changes produced by portal hypertension may occur. The geographical pattern of prevalence in disorders associated with portal hypertension is briefly described in this paper.