Every metabolite in AQIX® RS-I has a specific synergistic role in maintaining the functional integrity of normothermically, perfused isolated organs and all organ systems during hypovolemic replacement.
Current perfusates or plasma replacement fluids very rarely contain substrates to support intermediate metabolism.
Glucose, Glycerol and Insulin
Allows for the regeneration of the energy levels within of tissues and organs, even when they are not the preferred substrate for the organ in question, e.g. heart, by the inclusion of physiological levels of insulin. Glycerol and glucose also have free radical scavenging and membrane stabilizing properties, which is extremely important in maintaining the viability of tissues and organs. Glycerol sustains the glycerol phosphate shuttle and, along with the aspartate-malate shuttle, ensure optimal NAD/NADH balance within the mitochondria of individual cells.
Insulin is further involved in cellular regeneration through:
- Enhancement of intracellular glucokinase activity and amino-acid incorporation into protein
- Stimulation of DNA (deoxyribonucleic acid) translation into proteins
- Increased lipid synthesis
- Stimulation of sodium, potassium and inorganic phosphate transport across cell membranes.
Insulin is a major operand in all cell functions at all levels of cell development by facilitating optimum usage of glucose and glycogen and in several other metabolic processes. Erroneously, when included in phosphate-buffered solutions it has been at a concentration 10,000 times higher than that measured in the serum of 24-hour fasting individuals, namely, 25-28 mIU/L, which leads to the formation of ‘inactive’ globular aggregates. AQIX® RS-I, has been formulated to include a tertiary AOF recombinant human insulin at serum levels in the ‘active’ monomer/dimer form, to avoid any antigenicity issues and adverse reactions or inhibition of the mechanistic actions of insulin.
Aspartate and Glutamate
Enhance oxidative metabolism by replenishing tricarboxylic acid (TCA) cycle intermediates, thereby maintaining high energy phosphate (ATP) levels even during ischemic insult. Similarly, glutamate is involved in maintaining intracellular oxidation-reduction potentials. By restoring the aspartate-malate and glycerol phosphate shuttles, cells will maintain an optimal NAD/NADH balance and thereby sustain adenine nucleotide levels.
Glutamate and Glutamine
Act as intermediary metabolites to form pyroglutamate and participate in the gamma-glutamyl cycle to synthesise glutathione, a beneficial agent in preventing the generation of toxic oxygen radicals associated with the incidence of reperfusion injury. Glutamine is an essential amino acid for cell development and numerous cellular functions, e.g. smooth muscle viability in vitro, kidney re: acid-base balance.
Plays an important role in the oxidation of α-keto acids and prevents the accumulation of pyruvate and toxic pyruvate aldehyde, thereby reducing cellular apoptosis and accompanying necrosis of tissues and associated organs. Thiamine pyrophosphate is involved in regenerating numerous interrelated biochemical pathways, especially those of the Pentose Phosphate and Glycolytic pathways and acts as the sole energy substrate for transketolase activity in red blood cell metabolism.
Choline is an essential component in mammalian serum for the sustained manufacture of Acetylcholine at all cholinergic central, ganglionic and peripheral neuromuscular synapses. It is also a basic component in phosphatidyl moieties that make cell membranes and the enzymes that keep cells active and responsive to electrical and drug receptor stimulation.
Multiple effects in restoring cardiac function, it is required to optimise oxidative metabolism, leading to the reversal of fatty acid inhibition of glucose oxidation and promoting the utilization of alternative substrates to restore and improve coronary blood flow and is a factor in preventing heart dysfunction and arrhythmias.
The inclusion of ‘colloidal’ or ‘plasma expanders’ in preservation and perfusion solutions may be unnecessary if it is considered that each and every cell membrane in the human body lies in continuity with a 99% viscous gel interstitial phase. Therefore, each cell has a natural colloidal, buffering mechanism to prevent adverse movement of extracellular ions and water, which, in tandem with a medium of correct ionic conductivity, will subtend the cellular integrity of each cell in a tissue or organ via the natural processes of autoregulation. The majority of the osmotic pressure is provided by the sodium cations and accompanying anions and only a small component (ca. 0.5%) can be attributed to plasma proteins.
AQIX® RS-I is isosmotic to human serum (ca. 280 ± 10 mOsmoles) and has not appeared to necessitate the inclusion of colloids as demonstrated by the fact that only minor changes (ca. 3-12%) in hydration (oedema) occur during long term periods, 4-52 hrs of either hypothermic or normothermic preservation/perfusion of isolated tissues and organs.