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Elevated Carboxyhemoglobin in a Marine Mammal, the Northern

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Elevated Carboxyhemoglobin in a Marine Mammal, the Northern © 2014. Published by The Company of Biologists Ltd | The Journal of Experimental Biology (2014) 217, 1752-1757 doi:10.1242/jeb.100677 RESEARCH ARTICLE Elevated carboxyhemoglobin in a marine mammal, the northern elephant seal Michael S. Tift1,2,*, Paul J. Ponganis1 and Daniel E. Crocker2 ABSTRACT storage capacity (decreased arterial O2 content), thus limiting Low concentrations of endogenous carbon monoxide (CO), mitochondrial respiration. However, CO is also generated generated primarily through degradation of heme from heme- endogenously in low concentrations, and functions in proteins, have been shown to maintain physiological function of neurotransmission and in protection of tissues and cells against organs and to exert cytoprotective effects. However, high inflammation, apoptosis and ischemia–reperfusion injuries (Snyder concentrations of carboxyhemoglobin (COHb), formed by CO binding et al., 1998; Kevin and Laffey, 2008; Mustafa et al., 2009; Kajimura to hemoglobin, potentially prevent adequate O2 delivery to tissues by et al., 2010; Prabhakar, 2012). Therefore, low concentrations of CO lowering arterial O2 content. Elevated heme-protein concentrations, can provide beneficial and therapeutic effects up to a specific as found in marine mammals, are likely associated with greater heme concentration, at which elevated CO then leads to detrimental effects degradation, more endogenous CO production and, consequently, from reduced O2 delivery. These relatively recent findings give CO elevated COHb concentrations. Therefore, we measured COHb in a new functional perspective and emphasize the importance of elephant seals, a species with large blood volumes and elevated understanding the biological effects of specific CO concentrations hemoglobin and myoglobin concentrations. The levels of COHb were in the body which can be viewed as therapeutic. positively related to the total hemoglobin concentration. The Ironically, the primary source of endogenous CO comes from the maximum COHb value was 10.4% of total hemoglobin concentration. breakdown of heme, which is an essential component of many heme- The mean (±s.e.m.) value in adult seals was 8.7±0.3% (N=6), while proteins (e.g. hemoglobin, myoglobin and cytochrome c) that juveniles and pups (with lower heme-protein contents) had lower transport O2 or associate closely with aerobic respiration. The mean COHb values of 7.6±0.2% and 7.1±0.3%, respectively (N=9 breakdown of heme-proteins releases heme, which is then and N=9, respectively). Serial samples over several hours revealed enzymatically degraded by heme-oxygenase, resulting in equimolar little to no fluctuation in COHb values. This consistent elevation in production of free iron, CO and biliverdin (Coburn et al., 1963; COHb suggests that the magnitude and/or rate of heme-protein Tenhunen et al., 1968). Biliverdin is then reduced to bilirubin via turnover is much higher than in terrestrial mammals. The maximum biliverdin reductase. These products (biliverdin and bilirubin) and by- COHb values from this study decrease total body O2 stores by 7%, products (CO) of heme degradation have been shown to have a thereby reducing the calculated aerobic dive limit for this species. multitude of beneficial effects including: vasodilatation, antioxidative However, the constant presence of elevated CO in blood may also properties, attenuation of ischemia/reperfusion injury, inhibition of protect against potential ischemia–reperfusion injury associated with apoptosis and downregulation of the inflammatory response (Stocker the extreme breath-holds of elephant seals. We suggest the elephant et al., 1987; Barañano et al., 2002; Mustafa et al., 2009). It is these seal represents an ideal model for understanding the potential properties that have stimulated investigation of CO therapy and the cytoprotective effects, mechanisms of action and evolutionary use of CO-releasing pharmaceuticals for future clinical applications adaptation associated with chronically elevated concentrations of (i.e. sepsis, organ transplants, heart failure, hypertension, endogenously produced CO. inflammation and cancer) (Motterlini and Otterbein, 2010). Considering that heme-proteins are the primary source of KEY WORDS: Calculated aerobic dive limit, Carbon monoxide, endogenous CO production, marine mammals, which have elevated Hemoglobin absorption spectra, Marine mammal, Oxygen stores blood volumes, hemoglobin content and myoglobin concentrations (Ponganis et al., 2011), potentially represent an excellent model for INTRODUCTION investigating elevated endogenous CO production. For example, in Carbon monoxide (CO) is often classified as a strictly toxic gas, an early study by Pugh, there was an unexpected finding of elevated depriving the body of oxygen (O2) by binding to heme-proteins such CO in the blood of Weddell seals (Leptonychotes weddelli) (Pugh, as hemoglobin and forming carboxyhemoglobin (COHb) (Weaver, 1959). This study found mean CO levels in Weddell seal blood that 2009). Deleterious symptoms (e.g. headache, nausea and shortness were over six times the values seen in the blood of human non- of breath) of CO-driven hypoxia are typically seen when COHb smokers (Pugh, 1959). Bilirubin concentration in Weddell seal values reach ≥20% of total hemoglobin concentration, and death is plasma was also elevated approximately threefold to fourfold that of associated with values of 50–80% (Stewart, 1975; Weaver, 2009). human plasma. Similarly, bilirubin and biliverdin have been These COHb values drastically reduce blood-O2 transport and O2 measured in the blood of adult and juvenile northern elephant seals [Mirounga angustirostris (Gill 1866)], yet the values are in the same range as those seen in healthy humans (Thorson and Le Boeuf, 1Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093-0204, USA. 1994; Dennery et al., 2001; D.E.C., unpublished). 2Department of Biology, Sonoma State University, Rohnert Park, CA 94928, USA. Northern elephant seals have some of the highest known mammalian blood volumes (216 ml kg−1) and hemoglobin *Author for correspondence ([email protected]) concentrations (25 g dl−1) in nature, accounting for over 70% of their Received 1 December 2013; Accepted 4 February 2014 total body O2 store (Ponganis, 2011). This elevated blood O2 storage The Journal of Experimental Biology 1752 RESEARCH ARTICLE The Journal of Experimental Biology (2014) doi:10.1242/jeb.100677 0.4 List of abbreviations O2Hb cADL calculated aerobic dive limit HHb CO carbon monoxide COHb COHb carboxyhemoglobin 0.3 HHb deoxyhemoglobin O2 oxygen O Hb oxyhemoglobin 2 0.2 tHb total hemoglobin concentration Absorbance capacity contributes to their ability to perform repetitive dives of 20 to 25 min duration to depths >500 m with only 2–3 min surface 0.1 intervals during foraging trips lasting up to 8 months in duration (Robinson et al., 2012). Additionally, these animals are well known for their extended and repeated breath-holds (up to 25 min) during 0 sleep apnea events on land, which are also usually followed by brief 450 500 550 600 650 700 eupneic periods (Blackwell and Le Boeuf, 1993). Breath-holds of Wavelength (nm) these seals are accompanied by the dive response [bradycardia and Fig. 1. Absorption spectra for oxyhemoglobin (O2Hb), deoxyhemoglobin peripheral ischemia (Andrews et al., 1997; Ponganis et al., 2006)] (HHb) and carboxyhemoglobin (COHb) in northern elephant seals. and routine hypoxemia with arterial hemoglobin saturations Peaks for O2Hb (542 and 577 nm), HHb (555 nm) and COHb (539 and reaching as low as 10% (Stockard et al., 2007; Meir et al., 2009). 569 nm) match those of other mammalian species (human, cow, sheep) The brief periods of eupnea following breath-holds include (from Zijlstra et al., 2000). hyperventilation, tachycardia and vasodilation, which results in reperfusion of tissues with oxygenated blood, thereby increasing the that of pups, but not juveniles (F2,21=6.5, P=0.0066). Mean tHb in potential for exposure of tissues to reactive oxygen species and adults was 24.0±1.0 g dl−1, while juveniles and pups had tHb values damage from oxidative stress. Additionally, a typical elephant seal of 21.7±0.8 and 19.6±0.8 g dl−1, respectively. spends 9–10 months per year at sea with over 90% of its time Adults had significantly higher COHb values (8.7±0.3%) than underwater, and when on land will spend a large portion of time in both juveniles (7.6±0.2%) and pups (7.1±0.3%; Fig. 2). Together, sleep apnea (Blackwell and Le Boeuf, 1993; Robinson et al., 2012). age and tHb explained 80% of the variance in COHb values These life history behaviors drastically limit the amount of time the (F3,20=30, P<0.0001; Fig. 3). Over the course of several hours, animals spend in eupnea. COHb remained elevated and showed no significant variation from Considering endogenous CO is expelled via respiration, the the mean COHb value (F1,801=0.81, P=0.37; Fig. 4). intermittent breathing patterns (sleep apnea and/or diving) of many air-breathing marine divers introduces a potential limitation for DISCUSSION removal of CO. Therefore, increased endogenous CO production The values of COHb found in northern elephant seals from this and delayed removal of CO could elevate COHb content, leading to study are higher than values in humans that smoke ≥40 cigarettes a decrease in blood O2 stores and therefore potentially limiting the per day (Law et al., 1997) and comparable to the highest recorded duration for aerobic
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