Hiroshi Akutsu

Effects of probucol and cilostazol alone and in combination on frequency of poststenting restenosis

The present study was conducted to assess the preventive effect of combined treatment with probucol, an antioxidant, and cilostazol, a phosphodiesterase inhibitor, against poststenting restenosis. Study patients were randomized to 4 modality groups 1 week before stenting: control, probucol (500 mg/day), cilostazol (200 mg/day), and probucol plus cilostazol. Treatment on these modalities was conducted from 5 prestent days until the poststenting follow-up evaluation (6 poststenting months). All patients received aspirin (81 mg/day). The efficacy of each modality against restenosis was evaluated in a total 126 patients with 165 coronary arterial lesions, using a quantitative method. The decrease in luminal diameter at the poststenting follow-up was 1.04 +/- 0.57 mm for controls, 0.88 +/- 0.82 mm for those taking probucol, 0.61 +/- 0.59 mm for those taking cilostazol (p <0.05 vs control), and 0.40 +/- 0.52 mm (p <0.01 vs control) for the combined treatment group. Restenosis rate per segment was 31.7% for controls, 16.7% for the probucol group, 12.5% for the cilostazol group (p <0.05 vs control), and 9.5% for the combined treatment group (p <0.05 vs the control). Neither mortality, myocardial infarction, stent thrombosis, or coronary bypass surgery, nor any serious complications were observed in the combined treatment group. Combined treatment with probucol and cilostazol has thus proved safe and effective in preventing acute poststenting complications and suppressing chronic restenosis.

Effects of the long-term administration of nicorandil on vascular endothelial function and the progression of arteriosclerosis.

This study compared the effects of long-term administration of nicorandil and isosorbide dinitrate (ISDN) on vascular endothelial function and the progression of arteriosclerosis. Forty-two patients with ischemic heart disease were randomly allocated to receive nicorandil (N group; 15 mg/d) or ISDN (I group, 40 mg/d). Twelve normal subjects served as controls. Vascular endothelial function and the progression of arteriosclerosis (intima-media thickness, IMT), as determined by carotid vascular ultrasound, were assessed 1 week before and 3 months after drug administration. Reactive hyperemia was induced in the forearm for 5 minutes, and the percentage change in the diameter of the brachial artery (% change in flow-mediated dilation, %FMD) was calculated. FMD was significantly lower in CAD groups than in controls. The %FMD significantly decreased (7.2 ± 1.9 to 4.2 ± 2.8) in the I group, while rising from 6.8 ± 1.6 to 8.0 ± 2.0 in the N group. IMT increased by 0.036 ± 0.015 mm in the I group but showed no significant change in the N group (−0.01 ± 0.012 mm). Thus, ISDN deteriorates IMT and FMD, whereas a beneficial effect of nicorandil is seen on FMD with no effect on IMT. Long-term treatment with nicorandil may be desirable for prevention of cardiovascular events.

Peptide Inhibitors of the Renin–Angiotensin System

RENIN is said to split a leucyl–leucine bond in alpha 2 globulin substrate—angiotensinogen—to yield a decapeptide, angiotensin I. Angiotensin I is subsequently converted into an octapeptide, angiotensin II, by a converting enzyme contained in plasma. Angiotensin II has a pressor activity. We have studied the effects of synthetic peptides with a leucyl–leucine bond and their derivatives on the activity of renin in the formation of angiotensin. The peptides were di-, tri-, tetra- and pentapeptides with leucyl–leucine bonds at the C-terminal end, in the middle position, at the N-terminal end or with one of the other structures as shown in Table 1.

Purification and properties of endopeptidase from rabbit red cells and its process of degradation of angiotensin

Abstract Endopeptidase, showing angiotensinase activity in rabbit red cells, was purified by fractionation with (NH4)2SO4, DEAE-cellulose column chromatography and Sephadex G-200 gel filtration. The specific activity of angiotensinase on the purified preparation was increased about 8000-fold compared with that of the crude hemolysate. The peptide bonds cleaved by the enzyme preparation in [α- l -Asp1, Ile5]-angiotensin II were Arg-Val, Tyr-Ile and Ile-His. It was demonstrated that hydrolysis of the Tyr-Ile bond with the enzyme was the first step in the inactivation process of angiotensin. The results indicated that the purified so-called angiotensinase might be an endopeptidase without hydrolytic activity on casein, p- toluenesulfonyl - l - arginine methyl ester and acetyl- l -tyrosine ethyl ester.

The immunocytochemical detection of angiotensin-converting enzyme in alveolar macrophages from patients with sarcoidosis

Angiotensin-converting enzyme (ACE) was detected in alveolar macrophages obtained by bronchoalveolar lavage (BAL), but not in lymphocytes and other cells, by immunofluorescence using anti-human ACE antibody. The enzyme was localized on the surface of plasma membrane and cytoplasmic processes of alveolar macrophages, as demonstrated by immunoelectron microscopy. The immunocytochemical staining for ACE in alveolar macrophages from patients with sarcoidosis was intense, which was consistent with the result that ACE activity in BAL cells from patients with sarcoidosis was significantly higher than in cells from normal subjects and from patients with nonsarcoid lung diseases.

Inhibition of angiotensin I converting enzyme and kininase in rabbit plasma by bradykinin potentiating peptide B (Pyr-Gly-Leu-Pro-Arg-Pro-Lys-Ile-Pro-Pro).

Das Bradykinin-potenzierende Peptid B (Pyr-Gly-Leu-Pro-Pro-Arg-Pro-Lys-Ile-Pro-Pro) verhindert in vitro und in vivo die Aktivität der Plasmakininase und des «converting»-Enzyms.

The influence of left ventricular geometry on coronary vasomotion in patients with essential hypertension

The objective of this study was to assess the influence of left ventricular (LV) geometric pattern on coronary vasomotion in patients with essential hypertension. We studied 34 hypertensive patients, who had never been treated, with angiographically normal coronary arteries. Patients were classified into four LV geometric patterns by echocardiography: normal, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. The responses of coronary vasomotion in left anterior descending artery to vasoactive agents (acetylcholine, isosorbide dinitrate, adenosine triphosphate) were examined using a Doppler guidewire and quantitative coronary angiography. The percent increase in coronary blood flow evoked with acetylcholine (endothelium-dependent vasomotion) showed lowest in concentric hypertrophy, followed by eccentric hypertrophy, concentric remodeling, and normal geometry. The significant linear relationship between acetylcholine-induced coronary blood flow and LV mass was noted. There was no difference in the percent increase in coronary blood flow evoked with isosorbide dinitrate (endothelium-independent vasomotion of conduit vessel) among the four groups. The percent increase in coronary blood flow evoked with adenosine triphosphate (endothelium-independent vasomotion of resistant vessel) was significantly lower in patients with concentric hypertrophy than in the other three groups. The results in this study suggest that coronary vasomotion may be associated with LV geometry in patients with hypertension. The endothelium-dependent vasodilation is impaired progressively as LV hypertrophy advances. The endothelium-independent vasodilation of microvessels is impaired only in concentric hypertrophy. This advanced abnormality of coronary vasomotion may contribute to the high cardiovascular morbidity and mortality in patients with concentric hypertrophy.

Direct radioimmunoassay of angiotensin-converting enzyme in sera from patients with pulmonary diseases

The concentration of angiotensin-converting enzyme (ACE) was measured in the sera of 47 normal subjects and 108 patients with various pulmonary diseases by radioimmunoassay (RIA) using antiserum to human kidney ACE and homogeneous human kidney ACE as a tracer. The immunologic identity of ACE in the sera from a normal subject and a patient with active sarcoidosis was demonstrated by parallel logit-log transformation of displacement curves in the RIA. The activity and the enzyme concentration in normal and clinical samples correlated well (r=0.78,P<0.001). The mean concentration of ACE in normal serum was 320.9±105.2 ng/ml (mean ±1 SD, n=47). Serum ACE concentration in patients with active sarcoidosis (823.4±209.7, n=13) and in patients with silicosis (569.5±183.8, n=21) was significantly higher than in normals, and the ACE activity in the serum of both groups increased parallel to the concentration. In contrast, patients with active pulmonary tuberculosis (508.5±159.4, n=11) and with lung cancer (481.1±169.5, n=12) had significantly higher serum ACE concentrations (P<0.005) although the serum ACE activity did not increase. The specific activity of both groups (40.4±7.0 and 39.6±7.1 µmol/min/mg, respectively) was lower than that of normal subjects (50.0±12.8). A low ACE activity and a normal ACE concentration in patients with diffuse panbronchiolitis (n=8) and chronic bronchitis (n=6) resulted in a significantly low specific activity (37.4±13.0 and 36.2±7.3, respectively).

Antiphospholipid Syndrome With Acute Myocardial Infarction and Portal Vein Occlusion

A 62-year-old woman was admitted to hospital because of chest oppression and abdominal discomfort. Coronary arteriography revealed that the proximal left anterior descending artery had a large thrombus with TIMI (Thrombolysis in Myocardial Infarction) Grade 3 flow. On the second hospital day, she had sudden hematemesis because of esophageal varices. Her general condition became stable with conventional therapy. On the 20th hospital day, coronary arteriography and arterial portography showed that the thrombus had diminished. Arterial portography also revealed total occlusion of the portal vein as well as giant gastric varices. She was diagnosed as antiphospholipid syndrome, based on the presence of lupus anticoagulant. The treatment of this case was very complicated because of the bleeding from the esophageal varices induced by the anticoagulant therapy for the thrombus. Prednisolone was administered for 1 month, but no remarkable effects were observed. Therefore, she was treated with endoscopic sclerotherapy for the esophageal varices and anticoagulant therapy for prevention of thrombosis.

Antihypertensive effect of purified enzyme showing angiotensinase activity from rabbit red cells in rats

In der akuten Phase der Goldblatt-Hypertonie der Ratte verhinderte die Injektion von reiner Angiotensinase ein Aussteigen des Blutdruckes. Die Behandlung war unwirksam bei chronischem Hochdruck.