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Oxygen is the essential ingredient for life
WS2-I-2-01
OXYGEN IS THE ESSENTIAL INGREDIENT FOR LIFE Kazuhlro Yamaguchi, M.D. Department of Medicine, School of Medicine, Kelo University, Tokyo 160, Japan As the introductory remarks on the Workshop concerning "Adaptation of Tissue Oxygen Transport to Hypoxia", I would emphasize t h a t oxygen is the fundamental substance to maintain the life in any animals including h u m a n beings. This Implicates that animals exposed to a hypoxic condition will alter the structural, physiological and/or biochemical features o1 varied organisms in the body to survive against the hypoxio stress, the phenomenon being defined as "adaptation to hypoxia". The term "adaptation " has classically referred to the process reducing the physiological strain produced by a stressful component o1 the total environment (acute and/or chronic). Accordingly, "adaptaUon" has been used for describing the phenotypic adaptive process, i.e. changes occurring within the lifetime of the organism. There is another adaptive process which relates to genetically fixed attributes. Here the term "adaptation" is used In a precise Darwinian sense and refers to genotypic adaptation. The comprehensive deliberation on genotyplc adaptation is the scope beyond this Workshop, thereby only the varied aspects of phenotypic adaptation, especially to hypoxic spells will be discussed here. Although adaptation to hypoxia has actively been studied in the field of high alUtude medicine, allowing us to estimate numerous important phenomena In acclimated normal organs, tissues and cells, these arc not sufficient to assess the adaptive process of the organisms exposed to a pathological hypoxic-stress caused by, for instance, decreasing local perfusion as well as tissue injury. In diseased states, adaptation to hyp0xia may qualitatively differ from that observed in the normal organisms exposed to hypoxia such as high-altitude condition, and may, sometimes, fail to occur due to a severe injury existing there. The purpose of this Workshop is, using the newly developed techniques, to clarify the adaptive processes at varied levels in the body including organ, tissue and cell functions responding to hypoxic stress (acute and/or chronic) both in normal and diseased states. Further, it is very much interesting to consider the possible mechanisms on failure in sprouting adaptation to hypoxia in some diseased states.
WS2-I-2-02 ALVEOLAR HYPOXIA: CHANGE IN ACTION OF VASOACTIVE SUBSTANCES AND RESPONSE OF PULMONARY CAPILLARY BED TO INCREASED BLOOD FLOW H. Toga, H. Okazaki, M. Ishigaki, T. Noguchi, M. Matsuda, J. Huang, N. Ohya Department of Pulmonary Medicine, Kanazawa Medical University, Ishikawa, Japan Introduction: One of the most striking effects of hypoxia on the pulmonary circulation is hypoxic pulmonary vasoconstriction (HPV). Hypoxia changes not only the tone of vascular smooth muscle, but also the release and action of vasoactive substances from endothelial cells such as nitric oxide (NO) and arachidonic acid metabolites. However, the site of action of these substances in HPV remains to be elucidated. Alveolar hypoxia in the whole lung induces a marked increase in vascular resistance and a resultant elevation of right ventricular pressure load. In the normal lung, increases in blood flow and resultant elevations of pressure load are compensated in the capillary bed, i.e., capillary dilatation or recruitment. However, it is not known whether hypoxia has effects on the pulmonary microcirculation. The purpose of the present study was, in alveolar hyperoxia and hypoxia, 1) to determine the site of action of NO and thromboxane A2 (TxA2), 2) to compare the magnitude of action of NO and TxA2, and 3) to compare the response of the pulmonary capillary bed to increased blood flow. Materials and Methods: Lungs of 27 adult cats (3.0i-_0.2 kg) were perfused in situ with autologous blood. First, all lungs were ventilated with a gas mixture of 30% 02-6% C02-64% N2 (hyperoxia) and perfused with constant flow (Q1) in zone 3, with pulmonary artery (PPA),airway (PAw) and left atrial pressure (PLA) being 20, 9 and 10 cmH20, respectively. Next, lungs were exposed to hypoxia (2% 02-6% C02-92% N2). The animals were divided into four groups as follows. Group I (n=6) : untreated (control), group II (n=5) : treated with N°-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), a competitive inhibitor of NO synthesis, group III (n=4) : treated with indomethacin (20 I.tg/ml blood) to inhibit cyclooxygenase, and group IV (n=6) : treated with OKY046 (10 mg/kg), a selective inhibitor of TxA2 synthesis. Before and during exposure to hypoxia, we measured PP^ and, by the vascular occlusion technique, venous occlusion pressure (Pvo) to partition the pulmonary circulation into the upstream (arteries and capillaries) and downstream (venous) segments. In other 6 untreated lungs, before and during exposure to hypoxia, we increased blood flow from Ql to the double of Q1 (Qx) by every one fourth of Q1. At each blood flow, we measured PP^ and, by the micropipette/servonull methods, pressures in subpleural arterioles (Pmv(a)) and venules (Pmv(v)) of 30-60 I.tm in diameter to partition the pulmonary circulation into the arterial, microvascular and venous segments. Results and Discussion: Hypoxia increased the resistance in the upstream segment in untreated lungs. Both L-NAME and indomethacin induced a minimum elevation of baseline tone during hyperoxia, while OKY046 had no effects on baseline tone. The increases in arterial and venous resistnaces during hypoxia were significantly greater in L-NAME treated lungs than those in untreated lungs, indicating that NO attenuates I-IPV in the arterial and venous segments. In indomethacin treated lungs, the increase in total resistance was also greater than that in untreated lungs. In contrast, the increase in arterial resistance daring hypoxia was smaller in OKY046 treated lungs. These results indicate that products of the cyclooxygenase pathway attenuate HPV as a whole, but that HPV in the arterial segment is partly dependent on TxA2. Under the condition of hyperoxia, with increased blood flow from Q~ to Q2, total resistance increased significantly, and resistance in the arterial and venous segments also increased significantly. In contrast, microvascular resistance remained unchanged. Under the condition of hypoxia, not only resistance in the arterial and venous segments but also that in the microvascular segment showed a significant increase with increased blood flow from Ql to Q2. These results indicate that capillary resistance decreases with increased blood flow in hyperoxia, but that in hypoxia, the compensatory decrease in capillary resistance is attenuated. Conclusion: Compared with hyperoxia, hypoxia augmented the release or action of NO, resulting in attenuation of HPV especially in the venous segment, Products of the cyclooxygenase pathway as a whole also attenuated HPV in the arterial and venous segment. Hypoxia induces the release of TxA2, resulting in augmentation of HPV in the arterial segment. The compensatory decrease in capillary resistance with increased blood flow is attenuated in hypoxia.
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OXYGEN IS THE ESSENTIAL INGREDIENT FOR LIFE Kazuhlro Yamaguchi, M.D. Department of Medicine, School of Medicine, Kelo University, Tokyo 160, Japan As the introductory remarks on the Workshop concerning "Adaptation of Tissue Oxygen Transport to Hypoxia", I would emphasize t h a t oxygen is the fundamental substance to maintain the life in any animals including h u m a n beings. This Implicates that animals exposed to a hypoxic condition will alter the structural, physiological and/or biochemical features o1 varied organisms in the body to survive against the hypoxio stress, the phenomenon being defined as "adaptation to hypoxia". The term "adaptation " has classically referred to the process reducing the physiological strain produced by a stressful component o1 the total environment (acute and/or chronic). Accordingly, "adaptaUon" has been used for describing the phenotypic adaptive process, i.e. changes occurring within the lifetime of the organism. There is another adaptive process which relates to genetically fixed attributes. Here the term "adaptation" is used In a precise Darwinian sense and refers to genotypic adaptation. The comprehensive deliberation on genotyplc adaptation is the scope beyond this Workshop, thereby only the varied aspects of phenotypic adaptation, especially to hypoxic spells will be discussed here. Although adaptation to hypoxia has actively been studied in the field of high alUtude medicine, allowing us to estimate numerous important phenomena In acclimated normal organs, tissues and cells, these arc not sufficient to assess the adaptive process of the organisms exposed to a pathological hypoxic-stress caused by, for instance, decreasing local perfusion as well as tissue injury. In diseased states, adaptation to hyp0xia may qualitatively differ from that observed in the normal organisms exposed to hypoxia such as high-altitude condition, and may, sometimes, fail to occur due to a severe injury existing there. The purpose of this Workshop is, using the newly developed techniques, to clarify the adaptive processes at varied levels in the body including organ, tissue and cell functions responding to hypoxic stress (acute and/or chronic) both in normal and diseased states. Further, it is very much interesting to consider the possible mechanisms on failure in sprouting adaptation to hypoxia in some diseased states.
WS2-I-2-02 ALVEOLAR HYPOXIA: CHANGE IN ACTION OF VASOACTIVE SUBSTANCES AND RESPONSE OF PULMONARY CAPILLARY BED TO INCREASED BLOOD FLOW H. Toga, H. Okazaki, M. Ishigaki, T. Noguchi, M. Matsuda, J. Huang, N. Ohya Department of Pulmonary Medicine, Kanazawa Medical University, Ishikawa, Japan Introduction: One of the most striking effects of hypoxia on the pulmonary circulation is hypoxic pulmonary vasoconstriction (HPV). Hypoxia changes not only the tone of vascular smooth muscle, but also the release and action of vasoactive substances from endothelial cells such as nitric oxide (NO) and arachidonic acid metabolites. However, the site of action of these substances in HPV remains to be elucidated. Alveolar hypoxia in the whole lung induces a marked increase in vascular resistance and a resultant elevation of right ventricular pressure load. In the normal lung, increases in blood flow and resultant elevations of pressure load are compensated in the capillary bed, i.e., capillary dilatation or recruitment. However, it is not known whether hypoxia has effects on the pulmonary microcirculation. The purpose of the present study was, in alveolar hyperoxia and hypoxia, 1) to determine the site of action of NO and thromboxane A2 (TxA2), 2) to compare the magnitude of action of NO and TxA2, and 3) to compare the response of the pulmonary capillary bed to increased blood flow. Materials and Methods: Lungs of 27 adult cats (3.0i-_0.2 kg) were perfused in situ with autologous blood. First, all lungs were ventilated with a gas mixture of 30% 02-6% C02-64% N2 (hyperoxia) and perfused with constant flow (Q1) in zone 3, with pulmonary artery (PPA),airway (PAw) and left atrial pressure (PLA) being 20, 9 and 10 cmH20, respectively. Next, lungs were exposed to hypoxia (2% 02-6% C02-92% N2). The animals were divided into four groups as follows. Group I (n=6) : untreated (control), group II (n=5) : treated with N°-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), a competitive inhibitor of NO synthesis, group III (n=4) : treated with indomethacin (20 I.tg/ml blood) to inhibit cyclooxygenase, and group IV (n=6) : treated with OKY046 (10 mg/kg), a selective inhibitor of TxA2 synthesis. Before and during exposure to hypoxia, we measured PP^ and, by the vascular occlusion technique, venous occlusion pressure (Pvo) to partition the pulmonary circulation into the upstream (arteries and capillaries) and downstream (venous) segments. In other 6 untreated lungs, before and during exposure to hypoxia, we increased blood flow from Ql to the double of Q1 (Qx) by every one fourth of Q1. At each blood flow, we measured PP^ and, by the micropipette/servonull methods, pressures in subpleural arterioles (Pmv(a)) and venules (Pmv(v)) of 30-60 I.tm in diameter to partition the pulmonary circulation into the arterial, microvascular and venous segments. Results and Discussion: Hypoxia increased the resistance in the upstream segment in untreated lungs. Both L-NAME and indomethacin induced a minimum elevation of baseline tone during hyperoxia, while OKY046 had no effects on baseline tone. The increases in arterial and venous resistnaces during hypoxia were significantly greater in L-NAME treated lungs than those in untreated lungs, indicating that NO attenuates I-IPV in the arterial and venous segments. In indomethacin treated lungs, the increase in total resistance was also greater than that in untreated lungs. In contrast, the increase in arterial resistance daring hypoxia was smaller in OKY046 treated lungs. These results indicate that products of the cyclooxygenase pathway attenuate HPV as a whole, but that HPV in the arterial segment is partly dependent on TxA2. Under the condition of hyperoxia, with increased blood flow from Q~ to Q2, total resistance increased significantly, and resistance in the arterial and venous segments also increased significantly. In contrast, microvascular resistance remained unchanged. Under the condition of hypoxia, not only resistance in the arterial and venous segments but also that in the microvascular segment showed a significant increase with increased blood flow from Ql to Q2. These results indicate that capillary resistance decreases with increased blood flow in hyperoxia, but that in hypoxia, the compensatory decrease in capillary resistance is attenuated. Conclusion: Compared with hyperoxia, hypoxia augmented the release or action of NO, resulting in attenuation of HPV especially in the venous segment, Products of the cyclooxygenase pathway as a whole also attenuated HPV in the arterial and venous segment. Hypoxia induces the release of TxA2, resulting in augmentation of HPV in the arterial segment. The compensatory decrease in capillary resistance with increased blood flow is attenuated in hypoxia.
156