Carbon monoxide: from toxin to endogenous modulator of cardiovascular functions

Abstract

Carbon monoxide (CO) is a pollutant commonly recognized for its toxicological attributes, including CNS and cardiovascular effects. But CO is also formed endogenously in mammalian tissues. Endogenously formed CO normally arises from heme degradation in a reaction catalyzed by heme oxygenase. While inhibitors of endogenous CO production can raise arterial pressure, heme loading can enhance CO production and lead to vasodepression. Both central and peripheral tissues possess heme oxygenases and generate CO from heme, but the inability of heme substrate to cross the blood brain barrier suggests the CNS heme-heme oxygenase-CO system may be independent of the periphery. In the CNS, CO apparently acts in the nucleus tractus solitarii (NTS) promoting changes in glutamatergic neurotransmission and lowering blood pressure. At the periphery, the heme-heme oxygenase-CO system can affect cardiovascular functions in a two-fold manner; specifically: 1) heme-derived CO generated within vascular smooth muscle (VSM) can promote vasodilation, but 2) its actions on the endothelium apparently can promote vasoconstriction. Thus, it seems reasonable that the CNS-, VSM-and endothelial-dependent actions of the heme-heme oxygenase-CO system may all affect cardiac output and vascular resistance, and subsequently blood pressure.

Role of the haeme oxygenase/carbon monoxide pathway in mechanical nociceptor hypersensitivity

“…On the other hand, the antimechanical nociceptor hypersensitivity eect of NO does not depend upon CO release. These results are not at all in line with the literature, which suggests that CO inhibits NOS activity by inhibiting all NOS isoforms (Matsuoka et al, 1994;Sato et al, 1998;Johnson et al, 1999;Throup et al, 1999). However, recent evidence has supported the theory that the interaction between the NO and CO pathways is more intricate than envisaged, being not restricted only to the NOS and HO level.…”

“…However, the notion that CO is only a poison has been challenged since 1949 when Sjostrand (1949) reported that CO could be endogenously synthesized, but it was not until 1991 that Marks et al (1991) assumed that CO could have a physiological function. Currently, CO is recognized as an important signalling molecule in cardiovascular system, being a vasoactive substance (Dawson & Snyder, 1994;Johnson et al, 1999) and reducing the expression of endothelin-1 in endothelial cells . CO has also been recognized to act as a neurotransmitter or neuromodulator in the nervous system.…”

“…Three HO isoforms have been identi®ed to date: HO-1, HO-2, and HO-3, among which the isoforms 1 and 2 are the best known (Ewing et al, 1992;Maines, 1997). Both isoenzymes, one of them inducible (HO-1) and the other constitutive (HO-2), have been found in various tissues, including endothelial cells, smooth muscle and neural tissue (Dawson & Snyder, 1994;Maines, 1997;Johnson et al, 1999). The expression of HO-1 is increased in the site of experimental in¯ammation or in¯ammatory diseases such as arthritis and sepsis (Willis, 1999).…”

Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase

“…Until recently, these heme-derived metabolites were considered toxic waste products, but accumulating data suggest they have anti-oxidative, antiinflammatory, antiapoptotic, and signaling properties and possibly immune modulatory functions. [31][32][33][34][35] Therefore, we postulate that, in vivo, large amounts of free heme exert inflammatory actions resulting in the expression of adhesion molecules and the recruitment of leukocytes, whereas HO down-regulates inflammation through a mechanism involving the down-modulation of adhesive properties. To examine this hypothesis, the roles of heme and HO as inflammatory modulators were investigated in a mouse model.…”

Baroreflex function in conscious rats submitted to iron overload

“…Iron has been associated with the modulation of the metabolism and availability of certain chemical mediators such as nitric oxide (9)(10)(11) and carbon monoxide (12), which are implicated in baroreflex function both peripherally and centrally (13)(14)(15). Nitric oxide as well as oxygen-derived free radicals induced by changes in iron concentration are known to suppress baroreceptor activity particularly at high levels of arterial pressure (15).…”