Katsuyuki Tobise

Enhanced expression of heparin-binding EGF-like growth factor and its receptor in hypertrophied left ventricle of spontaneously hypertensive rats

OBJECTIVES Although heparin-binding epidermal growth factor-like growth factor (HB-EGF) is thought to produce hypertrophy in isolated cardiomyocytes via an autocrine mechanism, the pathophysiological role of HB-EGF, in myocardial hypertrophy in vivo, is not yet known. To investigate the involvement of HB-EGF in cardiac remodeling associated with hypertension in vivo, we assayed the expression of HB-EGF mRNA and protein in the left ventricle (LV) during the development of left ventricular hypertrophy in spontaneously hypertensive rats (SHR). METHODS Prior to sacrifice and assay of HB-EGF and EGF-receptor (EGF-R) mRNA, morphologic and hemodynamic variables were measured in SHR and in age-matched Wistar Kyoto rats (WKY). At 5, 9 and 12 weeks of age, rats were killed, their hearts were removed, and the expression of HB-EGF and EGF-R mRNA and protein were measured. In addition, SHR and WKY were treated with enalapril, atenolol, or both for 4 weeks. RESULTS In untreated SHR, double products (i.e. systolic blood pressure (sBP) multiplied by heart rate (HR), an index of mechanical load, peaked at 9 weeks. Expression of HB-EGF mRNA was also observed to peak in these animals at 9 weeks, while expression of EGF-R mRNA increased from 5 to 9 weeks, but remained constant thereafter. In untreated WKY, double products and EGF-R mRNA expression did not change over time, whereas the level of HB-EGF message increased gradually. Antibody to HB-EGF reacted primarily with myocyte membranes in SHR, whereas antibody to EGF-R reacted mainly with interstitial cells in these animals. The angiotensin-converting enzyme inhibitor, enalapril, markedly decreased sBP in SHR, whereas the beta 1-adrenoreceptor antagonist, atenolol, significantly decreased HR. While neither alone affected the expression of HB-EGF mRNA, their combination significantly reduced the expression of HB-EGF mRNA, as well as double products, in these rats, but had no effect on expression of EGF-R mRNA. CONCLUSIONS The enhanced expression of HB-EGF mRNA and protein in LV of SHR suggest that this growth factor may play an important role during the early development of LV hypertrophy and cardiac fibrosis in SHR. The association between double products and HB-EGF expression suggest that the latter may be induced by increased mechanical load and may contribute, in turn, to cardiac remodeling.

Absence of antioxidant effects of nifedipine and diltiazem on myocardial membrane lipid peroxidation in contrast with those of nisoldipine and propranolol

Both the production of active oxygen species and cellular damage due to concurrent lipid peroxidation are believed to be important factors in the pathogenesis of cardiovascular diseases and the ageing process. Since cardiovascular drugs are often administered over a long term, it might be advantageous if they reduced lipid peroxidation. There have been conflicting reports concerning the antiperoxidant effect of nifedipine. Therefore, we investigated whether nifedipine could inhibit lipid peroxidation in a nonenzymatic active oxygen-generating system, utilizing rat crude myocardial membranes, and compared its effect with those of propranolol, nisoldipine, and diltiazem. Nifedipine and diltiazem had no inhibitory effects on the lipid peroxidation of myocardial membranes. In contrast, nisoldipine and propranolol had a concentration-dependent antiperoxidant effect, with IC50 values of 28.2 and 50.1 microM, respectively. In addition, nisoldipine appeared to possess dual antiperoxidant mechanisms, involving both preventive and chain-breaking properties.

Exertional rhabdomyolysis as a result of strenuous military training

We reviewed biochemical data from 19 soldiers who marched intermittently over 4 weeks, carrying about 45 kg of kit, with a limited intake of food and water. The mean serum creatine kinase activity was higher after the march (p < 0.01), although the subjects did not develop symptomatic rhabdomyolysis. The mean serum potassium level (p < 0.005) and the mean serum sodium level (p < 0.05) were lower after the march. The level of serum osmolality showed no significant changes. Subclinical rhabdomyolysis was not rare among the soldiers. We also report a case of the soldier with exertional clinical rhabdomyolysis.

Transforming growth factor-β1 proliferated vascular smooth muscle cells from spontaneously hypertensive rats

To clarify whether the growth inhibitors, transforming growth factor-β1 (TGF-β1), heparin, and interferon-γ (IFN-γ) contribute to the development of vascular hypertrophy in spontaneously hypertensive rats (SHR), the growth of vascular smooth muscle cells (VSMC) was evaluated both for cell numbers over a period of 4 days, and [3H]thymidine incorporation over 24 h. Heparin and IFN-γ inhibited the proliferation of VSMC from SHR and Wistar-Kyoto (WKY) rats. TGF-β1 enhanced SHR-VSMC proliferation by 16.6 ± 8.9%; in contrast TGF-β1 inhibited WKY-VSMC proliferation by 60.5 ± 7.4%. There was no difference in affinity, number of binding sites, or subtype expression of TGF-β1 receptor between SHR-VSMC and WKY-VSMC. This evidence suggests that the signal transduction system of TGF-β1 either the receptor itself or downstream signaling molecules, may be altered in SHR-VSMC versus WKY-VSMC. This abnormal responsiveness to TGF-β1 is involved in the proliferative characteristics of SHRVSMC. Therefore, TGF-β1 could contribute to the development of hypertension or vascular hypertrophy in SHR.

Prolonged period of global ischemia causes no change in the GTP-binding proteins in the isolated perfused rat heart

The response of the beta-adrenoceptor transduction system to global ischemia for 40 min was investigated in isolated working heart of rat. The enhancement of beta-adrenoceptors was not observed in the ischemic myocardium. A depression of forskolin-stimulated adenylate cyclase enzyme occurred with global ischemia, but no change in Gs or Gi2 was detected. Thus, the present in vitro ischemic heart model may not necessarily reflect the identical milieu induced by the in vivo myocardial ischemia.

Bronchial brushing cytology features of primary malignant fibrous histiocytoma of the lung. A case report.

BACKGROUND Malignant fibrous histiocytoma (MFH) of the lung is rare. Early diagnosis is very important because of its poor prognosis. Long-term survivors of pulmonary MFH are patients who had surgical resection. When the patient can undergo surgery after a prompt diagnosis, the prognosis improves more than with other therapy. However, it is not easy to establish the diagnosis of thoracic MFH. In general, the small fragments from bronchial or percutaneous transthoracic fine needle aspiration (FNA) biopsies are inadequate for cytologic or pathologic analysis. Bronchial brushing cytology is greatly superior to FNA cytology because one can obtain a large amount of cells. Therefore, bronchial brushing cytology may play a useful role in diagnosis when endobronchial involvement is found. CASE A 65-year-old female was admitted with a cough, yellow sputum and exertional dyspnea. A chest roentgenogram showed a 12 x 12-cm mass in the left lung field. Bronchial brushing cytology revealed many fibroblastlike, histiocytelike, bizarre and multinucleated giant cells in a background of necrosis. Atypical mitotic figures were also found. The cytologic findings strongly suggested MFH. Although the pathologic findings from FNA biopsy showed storiform clusters structured by pleomorphic, fibroblastlike cells with bizarre nuclei and mitotic figures, the material was too small to diagnose it definitively. Six months later the patient died. An autopsy confirmed the diagnosis of MFH: the typical storiform clusters were composed of many fibroblastlike and histiocytelike cells that were positive for CD68 (PGM1) antibody. CONCLUSION Bronchial brushing cytology may be a useful method for early, definitive diagnosis of MFH. The presence of pleomorphic, spindle-shaped fibroblastlike and histiocytelike cells with the clusters showing a storiform pattern may permit the diagnosis of MFH.

Transient pulsus alternans induced by isosorbide dinitrate: echocardiographic and hemodynamic evidence of reduced venous return--a case report.

Transient pulsus alternans was induced by isosorbide dinitrate (ISDN) in a patient with postmyocarditis congestive heart failure under diuretic therapy. The severity and duration of pulsus alternans depended on the dose of ISDN. According to the echocardiographic and hemodynamic examinations, the superimposed preload reduction caused by ISDN combined with decreased blood volume owing to diuretic therapy most likely contributed to the development of pulsus alternans.

Effect of β-adrenoceptor antagonist and angiotensin-converting enzyme inhibitor on hypertension-associated changes in Adenylyl cyclase type V messenger RNA expression in spontaneously hypertensive rats

Adenylyl cyclase (AC) messenger RNA (mRNA) expression is decreased in failing hearts. Diminished expressions are accompanied by desensitization of &bgr;-adrenergic signal transduction. Factors contributing to such changes in mRNA expression for the major myocardial isoform AC V are not well established. To assess the contributions of hypertension, left ventricular hypertrophy (LVH), the renin-angiotensin-aldosterone system (RAS), and the sympathetic nervous system to these changes, ventricular expression of AC V mRNA was measured at different ages in spontaneously hypertensive rats (SHRs). In addition, the effects on them of angiotensin-converting enzyme inhibitor and &bgr;-adrenoceptor antagonists were determined. Prior to quantitative Northern blotting at ages 5, 9, or 12 weeks, hemodynamic and morphologic variables were measured in SHRs and Wistar-Kyoto rats (WKYs). The SHRs and WKYs were treated with an angiotensin-converting enzyme inhibitor, enalapril (10 mg/kg/d), or a &bgr;1-adrenoceptor antagonist, atenolol (100 mg/kg/d), for 8 weeks preceding Northern analysis. Myocardial AC V mRNA expression increased from 5–12 weeks in both SHRs and WKYs. Expression of AC V mRNA in SHRs increased somewhat less than in WKYs at 9 weeks and significantly less at 12 weeks. This was accompanied by development of LVH and hypertension in SHRs. Blood pressure and left ventricular weight relative to body weight were markedly decreased by enalapril and were moderately decreased by atenolol. Expression of AC V mRNA in SHRs at 12 weeks was normalized equally by enalapril and atenolol to the level of WKYs. Thus AC V mRNA expression increases are blunted in the early stages of LVH in SHRs under the influences of &bgr;1-adrenergic signal transduction and the RAS.

A CASE OF PULMONARY ALVEOLAR PROTEINOSIS

症例は, 47才,男性,教員.主訴は,労作時息切れ,咳嗽,喀痰. 28才頃より慢性気管支炎と言われていたが,最近息切れが増強し受診した.理学的所見では,胸部で両下肺野後面に少数の捻髪音が聴かれ,軽度のばち状指趾が認められた.胸部写真では,左右両下肺野に淡い微細粒状影を,呼吸機能検査では,拘束性障害と拡散能力の低下を,動脈血ガス分析では,低酸素血症と過換気の状態を認めた.開胸肺生検により組織学的に肺胞蛋白症と診断された. L-シスチン内服で若干の改善が認められたが, Ramirez-Rらの方法に準じて病変の高度な左肺の肺洗浄を施行し,自覚的および他覚的症状は著明に改善された.肺洗浄液の分析では,蛋白と燐脂質は正常であり,燐脂質ではレシチンとスフィンゴミエリンが主であつた.レシチン画分では,パルミチン酸が高値を示し,洗浄液脂質の主成分はlung surfactantと近似していた.肺胞蛋白症は,血清とII型肺胞上皮細胞に由来する物質が,何らかの原因により肺胞クリアランス機構が障害されるため肺胞内に異常に蓄積し,さらに悪循環を形成するために生ずると考えられる.従来は死亡率がかなり高いとされたが,肺洗浄などの積極的な治療で著明な改善を期待できる疾患であるので,早期発見および治療が重要である.疑わしい症例に対しては,積極的に喀痰の分析,肺生検などの確診の得られる検査を行なう必要がある.