Role of Carbon Monoxide in Blood Pressure Regulation

Abstract

C arbon monoxide (CO) is an odorless, colorless, tasteless gas that is generated in the environment as the result of combustion from stoves and engines among other sources. Approximately 500 people per year in the United States are victims of nonfire-associated CO poisoning according to the Centers for Disease Control and Prevention. CO poisoning is often fatal because of its interaction with hemoglobin, which renders it incapable of carrying oxygen-causing organs to become severely hypoxic. CO inhalation is believed to be fatally toxic at concentrations as little as 800 parts per million (ppm) or 0.08% in the air. Despite the lethal nature of this gas, several recent studies suggest that CO inhalation at low doses (Յ250 ppm), as well as increases in CO levels using CO releasing molecules (CORMs), offers protection against ischemic injury in the heart, liver, and kidney. [1][2][3][4] CO is endogenously produced in the body as a result of the metabolism of heme by heme oxygenase (HO), as well as from lipid peroxidation. 5,6 The catabolism of heme by HO also produces an equimolar amount of biliverdin, which is rapidly converted in the cell to bilirubin by the enzyme biliverdin reductase. 7 There are 2 major isoforms of HO responsible for CO production. HO-1 is expressed at very low levels under normal conditions but is highly induced by several stimuli, including heavy metals, ultraviolet light, endotoxin, shear stress, hypoxia, and oxidants. 8 HO-2 is the constitutively expressed form of the enzyme with the highest levels observed in the brain and testes. 9 Experimental evidence has demonstrated that systemic induction of HO has several beneficial actions on the cardiovascular system, including lowering of blood pressure, protection against myocardial infarction, and prevention of atherosclerosis. 10 -12 Although the cardiovascular actions of HO induction have been established, the role of CO in mediating these responses is not clear. The purpose of this review is to outline the potential antihypertensive actions of CO and highlight areas that may pose new opportunities for the development of novel therapeutic targets for the treatment of hypertension. Altering CO Levels In Vivo: Tools of the TradeThere are 3 main approaches that have been used to alter tissue levels of CO in vivo, which need to be briefly discussed. These include inhibition/induction of HO, CO inhalation, and CORMs. Each of these approaches has its own advantages and limitations depending on the specific experimental settings in which tissue levels of CO are to be altered. HO induction/inhibition has been widely used because of the fact that most of the endogenous CO produced in vivo is derived from HO. Given the routine ability to alter HO in a tissue-and temporal-specific fashion either pharmacologically or genetically, this is an attractive option for examining CO in vivo. However, there are several limitations in altering HO levels to examine the role of CO in vivo. First among these is the specificity of the majority of the metalloporphyr...

Heme Oxygenase in the Regulation of Vascular Biology: From Molecular Mechanisms to Therapeutic Opportunities

“…The activation of K þ channels leads to membrane hyperpolarization, which in turn inhibits voltage-gated Ca 2þ channels, causing SMC relaxation (276). HO-derived CO may facilitate the vasodilatory action of NO by stimulating cGMP levels in VSMCs (84,244) (Fig. 13A).…”

Carbon Monoxide–Bound Red Blood Cells Protect Red Blood Cell Transfusion-Induced Hepatic Cytochrome P450 Impairment in Hemorrhagic-Shock Rats

“…Carbon monoxide (CO) possesses anti-inflammatory, antiapoptotic, and antioxidant activities, suggesting that it could be used to prevent organ damage caused by ischemia-reperfusion injury (Otterbein et al, 2000;Brouard et al, 2002;Zuckerbraun et al, 2005;Stec et al, 2008;Motterlini and Otterbein, 2010). Nakao et al, 2008 recently reported an interesting observation, in which the exposure of organ preservation solutions to CO was effective in suppressing the postreperfusion reduction in renal P450 levels in a rat model of kidney transplantation.…”

Activation of Heme Oxygenase and Suppression of cGMP Are Associated With Impaired Endothelial Function in Obstructive Sleep Apnea With Hypertension

“…[10][11][12] CO is predominantly released during heme metabolism by heme oxygenase (HO), generating iron and biliverdin. Biliverdin is further metabolized to bilirubin by biliverdin reductase.…”