Reduced chemosensitivity to hypoxia and blunted perception of dyspnea may predispose patients to fatal asthma attacks.

Heme oxygenase (EC 1.14.99.3) is the rate-limiting enzyme in heme catabolism that cleaves heme at the ␣-methene bridge to form biliverdin IX␣, carbon monoxide, and iron (1, 2). Biliverdin IX␣ is immediately converted by biliverdin reductase to bilirubin IX␣ that is transported to the liver for conjugation and excretion into bile (3). There are two isozymes of heme oxygenase, heme oxygenase-1 (HO-1) 1 and heme oxygenase-2 (HO-2) (4, 5). HO-1 is inducible whereas HO-2 is constitutively expressed in human cells (6). Expression of HO-1 mRNA is highly increased in human cells by the substrate heme (7), heavy metals (8, 9), UV irradiation (10), and nitric oxide donors (11)(12)(13)(14). Because bilirubin IX␣ functions as a natural radical scavenger (15, 16), induction of HO-1 probably represents a protective response against oxidative stress. The physiological importance of HO-1 has been confirmed by the phenotypic consequences of the HO-1-deficient mice (17) and a patient with HO-1 deficiency (18).Induction of HO-1 has been extensively studied for the last few decades by many investigators. In contrast, repression of HO-1 expression has been largely ignored, despite its physiological importance (3). We have shown that HO-1 is not induced or rather reduced by heat shock in human cells (19), whereas rat HO-1 is a heat shock protein (20,21). The expression levels of HO-1 are also decreased in human glioblastoma cells by the treatment with interferon-␥ (22). In addition, hypoxia represses HO-1 mRNA expression in primary cultures of human umbilical vein endothelial cells (HUVECs), human astrocytes, and human coronary arterial endothelial cells (23). On the other hand, hypoxia increased HO-1 expression in rat liver (24) and heart (25) and in various cultured animal cells, including Chinese hamster ovary cells (26), rat ventricular smooth muscle cells (27,28), and rat myocytes (29). These results suggest the inter-species difference in the regulation of HO-1 gene expression by hypoxia between human and animal cells.The inter-species variations in the hypoxic response are of clinical significance because hypoxia is involved in the pathophysiology of various disorders, including ischemic heart disease, cerebrovascular disease, cancer, sleep apnea syndrome, and chronic obstructive pulmonary disease, which account for common causes of death and disability in the developed world. Mammalian cells respond to hypoxia in part by increased expression of several genes coding for erythropoietin (30), vascular endothelial growth factor (31), adrenomedullin (32, 33), and glycolytic enzymes (34,35), all of which cooperate to protect cells and tissues against the hypoxic state. Hypoxia-inducible

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1. An attempt has been made to test the hypothesis that, in the caudal part of nucleus tractus solitarii (NTS) where carotid sinus nerve (CSN) The carotid body is the major peripheral chemoreceptor for hypoxia in humans and other animals, and it plays an important role in augmenting ventilation during hypoxia (Martin-Body, Robson & Sinclair, 1986). In the rat, chemoreceptor afferents from the carotid body travel along the carotid sinus nerve (CSN) and terminate mainly in the caudal nucleus tractus solitarii (NTS; Lipski, McAllen & Spyer, 1977;Donoghue, Felder, Jordan & Spyer, 1984;Housley & Sinclair, 1988). Several neurotransmitters have been found in NTS (Cherniack, Prabhakar, Haxhiu & Runold, 1991). Among them, substance P (Prabhakar, Runold, Yamamoto, Lagercrantz & Euler, 1984;Henry & Sessle, 1985;Lindefors, Yamamoto, Pantaleo, Lagercrantz, Brodin & Ungerstedt, 1986), dopamine (Goiny, Lagercrantz, Srinivasan, Ungerstedt & Yamamoto, 1991) and L-glutamate (Glut; Kazemi, Chiang & Hoop, 1989) are considered to mediate chemoreceptor inputs to NTS. However, which neurotransmitter is released from the CSN in response to peripheral chemoreceptor activation and to what extent it is involved in regulation of respiration has not been determined.In the present study we used unanaesthetized, freely moving rats in which ventilation and in vivo release of Glut in the caudal NTS by microdialysis were measured during peripheral chemoreceptor stimulation by hypoxic hypoxia or doxapram (Dox) infusion in sham-operated and peripherally chemodenervated (carotid body denervated; CBD) rats. Moreover, the effects on ventilation of a local injection of Glut and during hypoxia, of pretreatment with the NMDA-type receptor antagonist MK-801 or the ionotropic receptor antagonist kynurenate into the caudal NTS (Housley & Sinclair, 1988) were investigated. MS 2462, pp. 55-65 55

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