Which of the following is one of the ways carbon dioxide is transported by blood?

Carbon Dioxide Transport

Carbon dioxide transport is significantly less complicated than oxygen transport. Carbon dioxide is produced in tissues during the aerobic metabolism of glucose and is transported in the blood to the lungs, where it is exhaled. Eighty-five percent of the carbon dioxide in blood is transported as carbonic acid, 10% is carried by hemoglobin as carbamate, and 5% is transported as either dissolved gas or carbonic acid.19,20 Owing to the equilibrium between dissolved carbon dioxide and the bicarbonate ion, the relationship between the partial pressure of carbon dioxide in the blood (Paco2) and the total CO2 content of blood is essentially linear over the physiologic range (Fig. 10-5).

Because carbon dioxide diffuses rapidly from blood into alveolar gas, the partial pressure of CO2 in blood (PaCO2) leaving the lungs is essentially the same as the partial pressure of CO2 in alveolar gas (Paco2). Thus increasing minute alveolar ventilation decreases the Paco2 and thereby decreases the Paco2. This is the reason Paco2 is dependent on the magnitude of alveolar ventilation.

B Functions of RBCs

The RBC functions of oxygen transport, carbon dioxide transport, and hydrogen ion buffering are interrelated. Each Hb tetramer can bind four molecules of oxygen when fully saturated, forming oxyhemoglobin (OxyHb). Assuming a normal arterial pO2 of 100 mmHg and an Hb concentration of 150 g/l (15 g/dl) in blood, the presence of Hb-containing RBCs increases the oxygen carrying capacity of blood approximately 70 times that which could be transported dissolved in plasma (West, 1985).

Approximately 10% of CO2 is transported dissolved in blood, 5% to 10% is transported bound to amine groups of blood proteins, and 80% to 85% is transported in the form of bicarbonate in normal individuals (Hsia, 1998; Jensen, 2004). Carbonic acid is formed when dissolved CO2 combines with water. This reaction occurs nonenzymatically but is accelerated by the presence of the carbonic anhydrase (CA), also called carbonate dehydratase, enzyme in RBCs. Bicarbonate is formed by the rapid spontaneous dissociation of carbonic acid as shown:

H2O+CO2⟷CAH2CO3⟷H++HCO3-

Hb potentiates the formation of bicarbonate by buffering hydrogen ions and shifting the equilibrium of the reaction to the right. Carbamino groups are formed by the combination of CO2 with the terminal groups of proteins. The globin of Hb is the most important blood protein in this regard. The transportation of CO2 from the tissues to the lungs as carbamino groups is potentiated because deoxyhemoglobin (DeoxyHb) binds twice as much CO2 as OxyHb. The formation of carbamino groups can be represented as follows:

Hb-NH2+CO2↔Hb-NHCOOH↔Hb-NHCOO-+H+

Hb is the most important protein buffer in blood because it occurs in high concentration, has a relatively low molecular weight, and has a large number of histidine residues with pKa values close to 7.4, enabling them to function as effective buffers. It has about six times the buffering capacity of the plasma proteins. An additional factor of importance in contributing to the effectiveness of Hb as a blood buffer is the fact that DeoxyHb is a weaker acid than OxyHb. As a result, most of the H+ produced in the tissues under normal conditions is buffered as a direct result of the H+ uptake by DeoxyHb owing to an increase in effective pKa of Hb following release of oxygen to the tissues (West, 1985).

Publisher Summary

This chapter describes the oxygen consumption and oxygen and carbon dioxide transport. Oxygen is carried in two ways—dissolved in the plasma and bound to hemoglobin within red blood cells. The arterial blood contains about 20 mL dL−1 O2, and about 98% of this is bound to hemoglobin. Hemoglobin can carry about 1.35 mL O2 per gram, and blood normally contains about 15 g Hb dL−1. Venous blood normally contains about 15 mL O2 dL−1, so the tissues extract at rest about 25% of the arterial O2. This O2 transport matches the metabolic consumption of O2, the amount calculated from the flow of respiratory air, and the difference between inspired air and expired air O2 content. Hemoglobin displays marked cooperativity in O2 binding, so that its O2 dissociation curve is steepest at physiological PO2 levels. There is a continuous gradient of PO2 from about 100 mmHg in the blood to 40 mmHg in the interstitial fluid and 20 mmHg in the cell and about 5 mmHg in the mitochondria. The hemoglobin dissociation curve shifts to the right with increased temperature, increased PCO2, decreased pH, and increased diphosphoglycerate. The Bohr effect describes the decreased affinity for O2 caused by CO2. It is found that dissolved CO2 accounts for about 10% of the total CO2 transport and about 85% of the CO2 transport is carried as HCO3−.

5 BIOLOGICAL ACTIVITY OF LISSOCLINUM PEPTIDE ALKALOIDS

In the previous chapter, a possible link between metal ion chelation properties of lissoclinum peptide alkaloids, carbon dioxide transport and biological function was already mentioned. However, to date the most extensively documented biological effect of these marine natural products is cytotoxicity.

Tables 1-3 summarize the reported cytotoxic activity for 18-, 21-, and 24-membered lissoclinum peptide alkaloids, respectively. Quite frequently, mouse leukemia cells (L1210), SV40 transformed fibroblasts (MRC5CV1), transitional bladder carcinoma cells (T24), and human colon cancer cells (HCT-116) were used in these evaluations. The most active compounds appear to be lissoclinamide 7 and ulithiacyclamide; however, cell types and assay conditions have been widely varied for different natural products and research groups. The presence of contaminating cytotoxic impurities is a major concern with natural product samples. In the absence of any information on the biological mechanism of action of lissoclinum peptides, any conclusions as to the actual potency of these compounds are preliminary at best. The only pharmacological studies that are currently available focus on ulithiacyclamide and ulicyclamide. Ulithiacyclamide was found to have a strong inhibitory effect on protein synthesis and can potentiate the cytotoxicity of anticancer drugs such as bleomycin [102]. Interestingly, ulithiacyclamide self-distructs in the process of inhibiting cell growth. Ulicyclamide, in contrast, was shown to inhibit DNA and RNA syntheses [103].

Table 1. Cytotoxic activity of 18-membered lissoclinum peptides (IC50 [mg/mL]).

Table 2. Cytotoxic activity of 21-membered lissoclinum peptides (IC50[mg/mL).

Table 3. Cytotoxic activity of 24-membered lissoclinum peptides (IC [mg/mL]).

Several lissoclinum peptides show only moderate levels of cytotoxicity in cell assays. In spite of sub-micromolar activity against bladder carcinoma and SV40 transformed fibroblast cells, cycloxazoline (westiellamide) had no activity in solid tumor assays [6].

Nostocyclamide (10) was shown to exhibit growth inhibitory activity against diatoms, chlorophyceae, and cyanobacteria (Anabaena P-9 and others) at 0.1 μM concentration [10]. These data support the notion that chemical defense directed against predators or competitors is a potential biological function of these secondary metabolites. Dendroamide A (but not B and C) was active in reversing multidrug-resistance due to inhibition of drug transport by P-glycoprotein [7]. Patellamide D (26) has also been reported to reverse multidrug-resistance in a human leukemia cell line [104].

A comparison of the cytotoxic effects of naturally occurring lissoclinum peptides, synthetic cyclic peptides and relatively short linear segments served as the basis for the hypothesis that the oxazoline function is essential for cytotoxicity and that a cyclic skeleton might not be needed [105]. While this hypothesis has found considerable support [32], no conclusive evidence for or against it, and no molecular rationalization for an oxazoline-induced cytotoxicity is available to date [106].

7.4.1 Main Functions of the Coagulation System

The liquid tissue blood delivers regularly dioxygen, glucose, and other essential nutrients to all regions of our body and transports carbon dioxide and waste products to the lung, spleen, liver, and kidney. The coagulation system is crucial to minimize blood loss as a result of vessel wall damage and any kinds of injury. In intact vessels, antithrombogenic factors inhibit efficiently any procoagulant activity and ensure thus an undisturbed blood flow. Among these anticoagulant components are heparin, thrombomodulin, tissue plasminogen activator, antithrombin, protein C, protein S, and plasminogen [117].

Heparin is widely used as an anticoagulant drug to prevent clot formation, thrombosis, and embolism in numerous diseases scenarios [118]. It enhances considerably the activity of antithrombin toward thrombin and factor Xa [119].

Owing to bleeding (also known as hemorrhaging), blood escapes from the circulatory system either internally or externally. This activates circulating thrombogenic factors, thrombocytes (also known as platelets), and several vessel wall–specific proteins. The complex interaction of these components is directed to stop bleeding, a process known as hemostasis. This process includes vasoconstriction, temporary formation of a platelet thrombus, and blood coagulation [120]. Vasoconstriction is promoted by vascular smooth muscle cells especially in smaller blood vessels.

Introduction

The hemoglobin (Hb) molecule within the red blood cell (RBC) carries oxygen from the lungs to the tissues, transports carbon dioxide from tissues back to lungs, and helps maintain acid–base balance. Hb is a tetramer consisting of four subunits: α1, α2, β1, and β2. Normally, the two α-chains are identical, as are the two β-chains, and denoted as α2β2.

Sickle cell disease (SCD) is a group of genetic disorders in which two mutant copies of the β-globin gene are inherited (Table 1). One of the mutations must be the sickle Hb (HbS) mutation, a point mutation in the sixth codon of the β-chain gene (GAG to GTG) that results in a hydrophobic valine replacing a hydrophilic glutamic acid. This amino acid substitution decreases a hingelike flexibility of the tetramer that then allows abnormal lateral contacts between HbS-containing tetramers to occur (Table 2).

Table 1. Common hemoglobin patterns of normal and sickle cell–related genotypes

Table 2. Examples of molecules implicated in cell activation or pathogenesis

The other mutation can be another HbS mutation, a HbC mutation, or a β-thalassemia mutation. Table 1 shows typical disease severities, Hb levels, and Hb fractionation patterns of the common SCD genotypes compared to normal Hb (HbAA) and sickle trait (HbSA). Disease severity, however, within each genotype shows wide variability, with known modifiers being β-globin gene cluster haplotypes, concurrent α-gene deletions, and fetal Hb levels.

This article reviews the major pathophysiological aspects of SCD: Hb polymerization and red cell sickling; endothelial and blood cell activation with vaso-occlusion and ischemia–reperfusion injury; and hemolysis with nitric oxide depletion and oxidative damage. The resulting clinical manifestations and their management are wide ranging and beyond the scope of this article. Such information is comprehensively reviewed in the National Heart Lung and Blood Institute guidelines on SCD management, but a concise summary is presented below.

Hemoglobin

Hemoglobin, in the normal adult, is a protein whose main function is to transport oxygen from the lungs to tissues and to transport carbon dioxide from tissues to the lungs. The hemoglobin molecule contains four separate folded peptide chains, which form a hydrophobic or water ‘repelling’ pocket around a heme group. The heme group is composed of a central iron atom complexed to four nitrogen atoms. Oxygen is capable of reversibly binding to the heme unit in a process known as oxygenation. The interactions among the subunits in a hemoglobin molecule are known as cooperativity. There are well-described regulators of the affinity of hemoglobin for oxygen that provide a control mechanism. The S-shaped graph of this oxyhemoglobin relationship is known as the oxyhemoglobin dissociation curve and represents the relationship between the partial pressure of oxygen (PO2) in mm of mercury (Hg) and the oxygen content per 100 ml of blood (Figure 2).

The shape of this relationship is very important since it can be moved to the right, i.e., decreased affinity of hemoglobin for oxygen producing oxygen unloading, or to the left, i.e., increased affinity. These changes are produced by a variety of intracellular cofactors: hydrogen ion (pH), carbon dioxide, and the RBC enzyme 2,3-biphosphoglycerate (BPG). Molecules of 2,3-BPG bind to hemoglobin and decrease the affinity of the molecule for oxygen. This causes enhanced oxygen release, or unloading, and is frequently seen in situations in which the body responds to conditions of low oxygen supply. There are a wide variety of potential diseases and toxic exposures that can impact oxygenation and cooperativity and these will be discussed in subsequent sections.

INTRODUCTION

The general performance requirements for blood oxygenators have been known for many years (Galletti & Brecher, 1962, and references therein). They can be summarised:

Oxygen and carbon dioxide transport of up to 300 ml/min at blood flow rates of up to 5 litres/min.

The prime volume of the device should be small.

The blood handling should cause minimum trauma both to formed elements and to plasma proteins.

The device should be easily sterilised and reliable so as to allow routine safe use over short or prolonged periods.

Bubble oxygenators have achieved widespread use for short perfusions by meeting all of these criteria, except for minimising blood trauma. For longer term use, where bubble oxygenators would produce unacceptable levels of blood damage, membrane oxygenators are the devices of choice (Hill et al., 1975). For membrane oxygenators, in addition to the general requirements above, additional requirements met inherently by bubble oxygenators require specific attention. These are:

The pressure difference required to drive blood flow through the oxygenator should not be excessive.

Gas transfer must be adequate at low blood flow rates, so that the oxygenator can safely be used at less than its maximum capacity.

It is not unfair to say that at present no commercially available device can meet all these requirements. The cause for this is the compromises which are necessary in design. The requirements for moderate pressure drop and for even perfusion of a multichannel device at low flow rates require relatively wide blood channels or many very short channels. On the other hand, the low solubility and diffusivity of oxygen in blood means that, to achieve high oxygen transport, blood channels should be as narrow as possible, and blood flow rate as high as possible. The necessity to minimise trauma to blood means that materials for membranes and other blood contacting parts must be ‘compatible’, and that blood should not be subjected to stasis or to high shear stress.

The most common design choice has been a multichannel flat plate arrangement with silicone rubber membranes. Silicone co-polymer and more recently micro-porous hydrophobic membranes have also been used. Other blood channel geometries have been multiple hollow fibres and coiled flat tubing. Blood flow has been essentially steady, driven by conventional roller pump.

Oxygen transfer under these conditions is blood film limited, particularly so at low flow rate, and the overall transfer is typically about one tenth of the transfer capabilities of 0.05 mm thick silicone rubber. Carbon dioxide, however, because of its higher solubility in plasma is transferred with considerably more efficiency.

Systemic anticoagulation has been used to prevent clotting within the oxygenator. Under these circumstances, clotting and haemolysis are not normally problems, but reduction in the level of circulating platelets and loss of platelet function occur (Fong et al., 1974).

It is apparent that improvements in gas transfer membranes and in haemodynamics are still necessary in membrane oxygenators.

20.3.6 Hemoglobin

Hemoglobin (Hb) is an iron-containing metalloprotein in the red blood cells of all vertebrates. The main function of hemoglobin is to carry oxygen to different tissues of the body for energy metabolism, and then transport carbon dioxide back to the lungs. It can also scavenge nitric oxide [101]. Moreover, α- and β-globin have been found in mesencephalic dopaminergic neurons and glial cells, suggesting their physiological mitochondrial functions [102]. Selenotrisulfide can bind to a β subunit of hemoglobin via selenotrisulfide [103], although the physiological significance is unclear.

Carbon Dioxide Diffusion/Transport.

The diffusion of carbon dioxide is similar to the process that occurs with oxygen transfer. As mentioned earlier, carbon dioxide diffusion across the alveolar-capillary membrane is more rapid than oxygen diffusion due to the greater solubility of carbon dioxide. Carbon dioxide transport is dependent upon a variety of interactions in the red blood cell and plasma. The amount of carbon dioxide carried by the blood is dependent on its partial pressure and the presence of oxyhemoglobin. In the presence of oxyhemoglobin there will be a lower carbon dioxide content for a given partial pressure of oxygen. This results in the improved carbon dioxide removal as capillary blood becomes oxygenated. As blood is transported to peripheral tissues, carbon dioxide is taken up from the peripheral tissues and transported to the alveolus for gas exchange.