25, 70-73 (1978)

Effect of Hypertriglyceridemia on the Hemoglobin-Oxygen Dissociation Curve’ JON D. COOKSEY, M.D., Drpcrrtment

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METHODS The oxygen-hemoglobin dissociation curves and PsOvalues were determined utiliz’ Supported by grants from the Missouri Heart Association and the Lipid Research Center, Washington University (NIH-NHLI-72-2916L). 0022-4804/78/025 l-0070$01.00/0 0 1978 by Academic Press, Inc. of reproduction in any form reserved.


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June 24, 1977

ing an IL (Instrumentation Laboratories) blood gas analyzer (Model 113) and tonometer (Model 237) and a Lex-O-Con (Lexington Instruments). The PsO(7.4) is the partial pressure of oxygen, in millimeters of mercury, required for 50% saturation of hemoglobin at pH 7.4. A 5-ml aliquot of heparinized blood was tonometered against a high-oxygen gas (PO,-31 mm Hg and pC02-39 mm Hg) or a low-oxygen gas (PO*-16 mm Hg and pCO,-39 mm Hg). Simultaneous samples were withdrawn from the tonometer for measuring p02, pCO,, pH, and hemoglobin or hematocrit. Our normal value for PsO in the rabbit is 30.9 -t- 0.9 mm Hg and in normal man 26.9 k 0.5 mm Hg. Previously, we had determined the oxygen saturation of blood using a spectrophotometric analyzer, but found that the turbidity of blood induced by an infusion of soybean oil caused spurious values depending on the degree of turbidity. Subsequently, we have used a method where all oxygen is released from hemoglobin and the volume is determined utilizing a galvanic cell [7]. The rate of release of oxygen from hemoglobin was determined by placing a 5-ml sample of arterial blood in a tonometer perfused with gas having a ~0, of 16 mm Hg and a pCOZ of 39 mm Hg with a flow rate of 400 ml/min through the tonometer. Blood samples of constant volume were withdrawn at 30- or 60-set intervals and the pOZ, &Of, pH, and the oxygen saturation were measured. Six young rabbits weighing 3.2 ? 0.3 kg

It has been suggested that elevated blood lipids, triglycerides or cholesterol, interfere with the blood’s transportation of oxygen [I, 21. Angina pectoris may be precipitated in patients with coronary artery disease following a large fat meal [3, 41. These attacks of myocardial ischemia developed 5 hr after the fat meal, when lipemia was near its peak and they were prevented by the prior administration of heparin, which induced a rapid clearing of plasma by the activation of lipoprotein lipase. It was also demonstrated that post prandial lipemia caused a decreased oxygen tension in the skin of man, which could also be prevented by heparin administration [5]. Other studies have shown that following the intravenous infusion of a lipid emulsion in humans, there is a decrease in arterial oxygen saturation and a decrease in the pulmonary diffusing capacity [ 1,6]. All of these studies suggest that elevated serum lipids interfere with the blood’s transportation of oxygen. To evaluate further these findings, we designed an experimental method to determine if the hemoglobin-oxygen dissociation curve and the rate of oxygen release by blood were altered by the elevation of the serum triglycerides in the experimental animal.

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Table 1 gives the mean value of the serum cholesterol and triglyceride concentration (mg/dl), total hemoglobin content (gl/dl), and PsO (mm Hg) for the hemoglobinHigh Control triglyceride oxygen dissociation curves both in the congroup (n = 6) Assay group (n = 6) trol group and 25 min after intravenous infusion of the lipid emulsion. The serum 23.9 k 13.2 59 2 15.0 Serum cholesterol triglycerides were significantly elevated folP < 0.001 (mgidl) lowing the lipid infusion (P < O.OOOl),as 50.2 2 22.1 1,033 r 32.3 Serum triglycerides was the serum cholesterol (P < 0.001). P < 0.0001 hddl) The P,, value for the oxygen-hemoglobin 13.6 + 1.0 12.6 2 1.3 Hemoglobin (gidl) dissociation curve was 30.4 t 0.3 mm Hg in n.s. the control period and 28.8 -c 0.5 mm Hg 30.4 + 0.3 28.8 + 0.5 P50 following intravenous infusion of soybean P < 0.001 oil, which is significantly different (P < 0.001). The partial pressure of oxygen in 92.3 _f 8.0 Arterial p0, 105.5 2 5.1 P < 0.01 (mm Hg) arterial blood was also significantly decreased following the lipid infusion (P a n. number of animals; n.s., not significant. < 0.01). The release rate of oxygen by hemoglobin in the control group and following the inwere placed on commercial rabbit chow and fusion of lipid is shown in Fig. 1. When water ad libitum. Arterial blood was with- the hemoglobin’s oxygen saturation was dedrawn from the ear for determination of the creased from 56 to 28% by equilibrating serum cholesterol and triglycerides. The blood with gas having an oxygen partial hemoglobin-oxygen dissociation curve was pressure of 16 mm Hg, the blood released done and the PsOvalues determined. 11.3% of its oxygen in 60 set during the The following day the animals were anesthetized with intravenous methohexital (Brevital). The external jugular vein was isolated and a polyethylene catheter was inserted. After recovery from the anesthesia (30-180 min), a sterile 10% emulsion of soybean oil (6 ml/kg body wt) was infused intravenously over a 3-min period. Arterial blood samples were withdrawn 25 min after the lipid infusion for measuring the cholesterol, triglycerides, hemoglobin, hematocrit, P,,, and the rate of release of oxygen. Serum cholesterol and triglycerides were determined utilizing a Technicon Auto Analyzer [8]. Statistical analysis of the differences beI 2 tween the control animals and following the TIMElMIN) intravenous administration of soybean oil FIG. I. Rate of release of oxygen from hyperwas done by the Student’s t test analysis triglyceridemic rabbit blood and control blood. The and the derived P values less than 0.05 are numbers at the ends of the graphs indicate the rabbit so indicated [9]. numbers.





VOL. 25, NO. 1. JULY


control period and 12.0% of its oxygen in 60 have been due to pulmonary atelectasis set following the lipid emulsion. These following anesthesia in our study. values are not significantly different. The oxygen-hemoglobin dissociation curve showed a “leftward” shift following the intravenous infusion of lipid and resulted in DISCUSSION the P,, value being decreased 1.6 mm Hg. A number of physiological and bio- This finding could not be attributed to a chemical factors are known to alter the change in pH or pCOZ (Bohr effect). This hemoglobin-oxygen equilibrium. Tempera- leftward shift of the oxygen-hemoglobin dissociation curve would result in a maxi2,3-diphosphoglycerate ture, PK PC% (DPG), and adenosine triphosphate (ATP) mum of 3 ~01% less oxygen being liberated most significantly displace the hemoglobinat the same partial pressure of oxygen. Aloxygen dissociation curve and its P,, value though these values are significant, it seems from the normal [lo]. These changes, unlikely that this shift in the hemoglobinparticularly increased erythrocyte concentra- oxygen dissociation would produce any tion of 2,3-DPG, are probably beneficial measurable effect on oxygen utilization. adaptations of the organism to its environ- Recent evidence has shown the following: ment. Abnormalities of hemoglobin-oxy(1) Experimentally reducing 2,3-DPG congen transport may be inherent or acquired centration by 75% and standard P,, by [ 111. Some rare hemoglobinopathies are as- 14 mm Hg in rats did not significantly sociated with increased oxygen affinity and decrease their endurance exercise perresult in marked displacement of the oxy- formance [12]. (2) Chronic depletion of 2,3gen hemoglobin dissociation curve and ele- DPG produced no measurable effects on tisvated P,, values [ 1l]., sue ~0, or oxygen utilization of brain, Clinical studies have suggested that hy- kidney, or muscle tissue in rabbits during perlipidemia may interfere with oxygen acute hypoxic stress [13]. The findings of this experimental study transport in viva [l-3]. Talbott and Frayser [I] noted an acute decrease in the arterial demonstrate that the acute intravenous inblood’s oxygen saturation following the in- fusion of a lipid emulsion causes a small travenous infusion of a 15% emulsion of cot- leftward shift of the oxygen-hemoglobin ton seed oil in humans and suggested that the dissociation curve, but no change in the rate elevated serum lipids produced a decreased of release of oxygen by erythrocytes. It diffusion capacity for carbon monoxide. An- is possible that elevated serum triglycerides other study has reported that following an may interfere with transportation of oxygen intravenous infusion of a 15% emulsion of across the capillary endothelium, as has soybean oil in humans, there was a been demonstrated in the lung [ 1,6, IS]. Our significant decrease in the pulmonary dif- study did not evaluate this possibility. fusion capacity [6]. Our study demonstrated a decrease in the SUMMARY partial pressure of oxygen of arterial blood We have investigated the effect of hyperfollowing the intravenous infusion of a lipid emulsion. This has also been demonstrated triglyceridemia on the oxygen-hemoglobin in humans and attributed to a decreased dissociation curve and the rate of release of pulmonary diffusion capacity due to the ac- oxygen by erythrocytes. Hypertriglycericumulation of lipid along the capillary walls, demia was induced acutely in rabbits by an although increased arterial-venous shunt- intravenous infusion of a soybean emulsion. ing of blood is also a possible explanation The P,, value of blood showed a small [l]. It is also possible that this dif- leftward shift (30.4 + 0.3 mm Hg in control ference in partial pressure of oxygen may and 28.8 t 0.5 mm Hg after infusion) follow-



ing the lipid infusion. The rate of release of oxygen by erythrocytes was unchanged by the lipid infusion. These experimental findings indicate that the acute intravenous administration of a lipid emulsion produces a minimal change in the hemoglobin-oxygen reaction. REFERENCES 1. Talbott, G. D., and Frayser, R. Hyperlipidemia: A cause of decreased oxygen saturation. Nature (London)

200: 684, 1963.

2. Steinbach, J. H., Blackshear, P. L., Varco, R. L., and Buchwald, H. High blood cholesterol reduces in vitro blood oxygen delivery. .I. Surg. Res. 16: 134, 1974. 3. Kuo, P. T., and Joyner, C. R. Angina pectoris induced by fat ingestion in patients with coronary disease .I. Amer. Med. Assoc. 158: 1008, 1955, 4. Kuo, P. T., and Joyner, C. R. Effects of heparin on lipemia-induced angina pectoris. J. Amer. Med. Assoc. 163: 727, 1957. 5. Joyner, C. R., Howritz, O., and Williams, P. G. The effect of lipemia upon tissue oxygen tension in man. Circulation 22: 901, 1960. 6. Sundstrom, G., Zayber, C. W., and Arborelius, M. Decrease in pulmonary diffusing capacity during lipid infusion in healthy men. J. Appl. Physinl. 34: 816, 1973.

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7. Valeri, C. R., Zaroulis, C. G., Marchionni, L., and Patti, K. J. A simple method for measuring oxygen content in blood. .I. Lab. Clin. Med. 79: 1035, 1972. 8. Manual of laboratory operation, Lipid Research Clinics Program, Vol. I, DHEW No. (NIH) 75628. 9. Snedcor, G. W., and Cochran, W. G. Statistical Methods. Iowa State Univ. Press, Ames, Iowa, 1967. 10. Bunn, H. F., and Jandl, J. H. Control of hemoglobin function within the red cell. N. Engl. J. Med. 282: 1414, 1970. Il. Finch, C. A., and Lenfant, C. Oxygen transport in man. N. Engl. J. Med. 286: 407, 1972. 12. Woodson, R., Wranne, B., and Detter, J. Effect of erythrocyte 2,3-DPG and hemoglobin concentration on 0, delivery. Clin. Res. 20: 628, 1972. 13. Rand, P. W., and Norton, J. M. Effect of 2,3diphosphoglycerate (DPG) on tissue oxygen availability. Clin. Res. 20: 876, 1972. 14. Nicolson, P., and Roughton, F. J. W. A theoretical study of the influence of diffusion and chemical reaction velocity on the rate of exchange of carbon monoxide and oxygen between the red blood corpuscle and the surrounding fluid. Proc. Roy. Sot. London Ser. E 138: 241, 1951. 15. Green, H. L. Effects of intralipid on the lung. In R. W. Winters and E. G. Hasselmeyer (Eds.) Intrawnous


in the High

Wiley, New York, 1973.

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Effect of hypertriglyceridemia on the hemoglobin--oxygen dissociation curve.

JOURNAL OF SURGICAL RESEARCH 25, 70-73 (1978) Effect of Hypertriglyceridemia on the Hemoglobin-Oxygen Dissociation Curve’ JON D. COOKSEY, M.D., Dr...
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