Kazutoshi Sugito

Bioactivation of monocrotaline by P-450 3A in rat liver

Monocrotaline (MCT) is bioactivated in liver cytochrome P-450s to MCT pyrrole (MCTP), which primarily injures the lung endothelium to result in the development of pulmonary hypertension (PH) in rats. However, whether there is a relation between the degree of PH and the activity of liver cytochrome P-450 to convert MCT to MCTP remains unclear. To examine the relation between these physiological and biochemical changes, we first measured the severity of MCT-induced (20 mg/kg) PH in male, female, castrated male, and phenobarbital (PB, liver P-450s inducer)-pretreated male rats. The degree of right ventricular hypertrophy was more severe in PB-pretreated male than in control male rats. It was also more severe in male than in either female or castrated male rats, suggesting that sex-specific P-450s could be involved in the metabolic pathways of MCT in the liver. Further to explore which of the isozymes (2A2, 2C11, and 3A) of P-450s in the liver is responsible for the bioactivation of MCT, we measured the rate of MCTP production in hepatic microsomes by a modified Mattocks method. Treatment of male rats with PB and pregnenolone 16alpha-carbonitrile (PCN), which is the specific inducer of P-450 3A, increased the rate of MCTP production, suggesting that P-450 3A may contribute to the conversion to pyrrole. Therefore we measured the amount of P-450 3A protein by immunoblotting and attempted to inhibit MCT metabolism by using antibodies to P-450 3A. P-450 3A was significantly induced by PCN (6.5-fold) and PB (4.6-fold) treatment and reduced by castration (0.38-fold). The amount of P-450 3A was closely correlated with the production of MCTP, and the conversion of MCT to MCTP was strongly inhibited by antibodies against P-450 3A. These results indicated that P-450 3A was predominantly responsible for the metabolism of MCT to MCTP in rat liver and suggested a tight linkage between the degree of PH and the activity of liver P-450 3A.

Role of EDRF in pulmonary circulation during sustained hypoxia.

The pulmonary artery pressure (PAP) response to hypoxia is characterized by an initial vasoconstriction followed by vasodilation. Pulmonary vessels can release endothelium-derived relaxing factor (EDRF), which is considered to be nitric oxide (NO), but the role of EDRF in the regulation of normal and hypoxic pulmonary vascular tone is still uncertain. We designed this study to address the in vivo role of EDRF in vasodilation during sustained hypoxia. We studied the effects of an EDRF-synthesis inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), on the pulmonary vascular response to sustained hypoxia (10% O2, 20 min) in normoxic (N) and chronically hypoxic (CH) rats. Biphasic PAP response was observed in N rats, whereas PAP was unchanged in CH rats during sustained hypoxic exposure. The L-NAME-induced PAP increase during normoxia was greater in CH than in N rats, suggesting that basal EDRF plays an important role in attenuating the severity of pulmonary hypertension in CH rats. Administration of L-NAME increased the initial increment in PAP by acute hypoxia and shifted the PAP response upward throughout sustained hypoxia, while still showing the biphasic pattern, in N rats. In contrast, PAP increased acutely and remained elevated with little recovery in the late phase in CH rats. The inducible NO synthase messenger RNA (mRNA) expression and protein showed greater increases in the lungs of CH than in N rats. These results suggest that EDRF release during sustained hypoxia may partly contribute to the roll-off in PAP response during sustained hypoxia in N rats, and that augmented EDRF may prevent a further increase in PAP during chronic hypoxia.

Effects of inhaled prostacyclin analogue on chronic hypoxic pulmonary hypertension.

Inhaled PGI2 has been reported to elicit pulmonary vasodilation, but whether it is also effective in treating chronic hypoxic pulmonary hypertension is still uncertain. We designed this study to address the in vivo effectiveness of inhaled Beraprost, a stable PGI2 analogue, on pulmonary vascular tone during hypoxic exposure in normoxic (N) and chronically hypoxic (CH) rats. Pulmonary vasodilation was observed by low-dose inhaled Beraprost in N rats, but not in CH rats. It was not until higher doses of Beraprost were given that pulmonary vasodilation was obtained in CH rats. When the agent was continuously administered by an intravascular route at the inhaled dose, it elicited no vasodilation in N rats. On the contrary, it elicited profound vasodilation in CH rats, although a concomitant systemic hypotension was observed. The PGI2 receptor mRNA expression was unchanged in the lungs of CH rats compared with that of N rats. We conclude that low doses of aerosolized Beraprost may reduce pulmonary vascular tone in rats without preexisting lung diseases. In contrast, when hypoxic pulmonary hypertension is present, the threshold of Beraprost inhalation was elevated to provoke pulmonary vasodilation.

Effects of insulin-like growth factor on weight gain in chronic hypoxic rats.

Chronic hypoxemia has been suggested as the cause of weight loss in malnourished patients with chronic obstructive pulmonary disease. Insulin-like growth factor I (IGF-I) is believed to improve nitrogen balance and have anabolic effects, and it has been proposed as one of the mediators of vascular smooth muscle proliferation. The aim of this study was to assess the effects of IGF-I administration on the nutritional status and pulmonary vasculature in normoxic and chronic hypoxic rats. Twenty rats were randomly assigned to the normoxic (n = 10) and chronic hypoxic groups (n = 10). They received daily subcutaneous injections of either 3.2 mg/kg of recombinant human IGF-I (rhIGF-I) or isotonic saline (control group) for 3 weeks. Body weight was greater in IGF-I-treated rats compared with vehicle-treated rats, especially during the early and late stages of chronic hypoxic exposure, whereas similar weight gain was observed between IGF-I- and vehicle-treated normoxic rats. In addition, IGF-I treatment increased serum total protein and albumin at the end of hypoxic exposure. However, IGF-I had no additive effects on the degree of pulmonary hypertension. These results indicated that IGF-I promoted anabolism under chronic exposure to hypoxia, whereas no adverse effect was observed in the development of pulmonary hypertension.

Role of carotid body in pressure response of pulmonary circulation in rats.

We investigated how signals arising from peripheral chemoreceptors could affect pulmonary vasculature in rats. Effects of the hypoxic exposure (10%) on mean pulmonary arterial pressure (mPAP), abdominal aortic flow (Q) and the estimated total pulmonary vascular resistance (mPAP/Q) were determined in anesthetized, artificially ventilated, carotid sinus nerve intact or chemodenervated rats. The pressor response of PAP to hypoxia seen in intact rats changed to the depressor response after chemodenervation. Hypoxia elicited a decrease in Q and an increase in mPAP/Q in both intact and chemodenervated rats. Selective carotid body stimulation by the intra-carotid injection of sodium cyanide (NaCN) in normoxia elicited an immediate but transient increase in PAP and Q before and after bilateral vagotomy. The peak change in PAP slightly preceded that in Q. These responses to NaCN were completely abolished by chemodenervation. These results indicate that the immediate chemoreflex contributes to the short-term regulation of pulmonary vasculature in rats.

Home oxygen therapy in pulmonary tuberculosis and pulmonary atypical mycobacteriosis during chemotherapy

During the period of eight years from 1985 to 1992 we had sixteen patients (pulmonary tuberculosis: 6, atypical mycobacteriosis: 10) who had been under the treatment for tuberculosis and on whom home oxygen therapy (HOT) was started. Of sixteen patients twelve had history of antituberculous therapy in the past. There were nine chronic active or persistently sputum positive patients of whom three were pulmonary tuberculosis and six atypical mycobacteriosis. The duration of illness was long in these patients and it was more than ten years in tuberculosis patients. Four cases died, two cases of pulmonary tuberculosis died from hemoptysis, and two cases of atypical mycobacteriosis died from respiratory failure.

A Case of Invasive Thymoma with Pure Red Cell Aplasia After Anti cancer Chemotherapy.

症例は68歳, 女性で, 咳嗽を訴え, 当科に入院となった. 胸部エックス線写真で前縦隔に腫瘍を認めた. CT写真上, 前縦隔腫瘍の他に, 後胸膜面に一カ所と, 他に肋骨転移を疑わせる腫瘍を認めた. 経皮生検で胸腺腫と診断した. 臨床病期はIVb期であった. 抗癌剤を投与したが腫瘍は縮小しなかった. 3カ月後, 息切れ, 呼吸困難を訴え, 緊急入院となった. 血液データから赤芽球癆と診断し, 輸血, 副腎皮質ステロイド剤によるパルス療法を施行したが, 改善せず, 心不全で死亡した.