**2. Acid-base balance, anesthesia, and circadian rhythms**

To survive, all living organisms need to maintain acid-base balance and oxygenation. The key role of homeostatic maintenance in all living organisms is not at odds with the observation that various biological parameters are dynamic. Rhythmic changes observed in humans that occur regularly play an important role in adaptation to dynamic environments. Chronobiology affects the activities and functions of the organs and tissues and is also a driver of anatomical, physiological, and molecular changes [8]. Control of acid-base balance depends on the concentration of H+ and HCO3 − ions in bodily fluids. In healthy wakeful mammals, including humans, compensatory mechanisms exist for the maintenance of the acid-base balance necessary for normal enzymatic activity, electrolyte diffusion, hemoglobin saturation, and heart contraction, all of which leads to normal functioning of vital organs [9].

The problem of acid-base balance in anesthesia was addressed by several authors in the early decades of the twentieth century. It was then pointed out that patients under general anesthesia experienced metabolic acidosis due to the ineffective metabolism of carbohydrates in states of unconsciousness [10]. However, later works began to report that this acidosis has a respiratory origin due to disordered respiration [11, 12]. In 1955, Lucas and Milne [13] highlighted the respiratory origin of acidosis in 166 patients who underwent surgery. Respiratory acidosis has been shown to be detrimental during surgery, because it predisposes to shock and the occurrence of problem reflexes. It has been shown that in deep general anesthesia with spontaneous breathing, respiratory acidosis invariably occurs regardless of the anesthetic used. If controlled breathing is used, significant respiratory alkalosis is common with a normal arterial CO2 pressure of approximately 20 mmHg. For anesthesiologists, metabolic acidosis associated with hypothermia and circulatory arrest is particularly important in cardiac and peripheral vascular surgery [14]. Monitoring of acid-base balance is recommended, especially for prolonged surgical procedures. There are studies indicating that patients undergoing inhaled anesthesia are affected by metabolic acidosis, which depends not only on the duration of the operation but also on the duration of anesthesia. As the duration of general anesthesia is prolonged, pH decreases significantly [15, 16]. This most likely also applies to animal models involving general anesthesia. Therefore, the choice of anesthetic and its effect on the respiratory and cardiovascular system is critical [17, 18].

only because of their low costs but also for their ability to mimic several human pathologies. These models are used to analyze basic physiological mechanisms, for preclinical and toxicological studies and/or the evaluation of therapeutic approaches [1, 2]. Rats are also useful model animals for studying acid-base balance, especially in relation to the cardiovascular and

The design and development of experimental, in vivo, chronobiological animal models may help reveal some of the relationships between circadian rhythms and biological function, which is sometimes exceedingly difficult to study in humus. Popilskis et al. [3] referred to the fact that "nonhuman primates are important models for a wide variety of biomedical and behavioral research because of their close phylogenetic relationship to humans and they are useful models for experimental surgical studies." However, in the design and development of such chronobiological in vivo rat models, several problems may be encountered. First is the fact that homeostatic regulatory mechanisms are not eliminated; therefore, the responses of the animal as a whole are only a reflection of these mechanisms at a particular time of day. Second is that the circadian rhythms of the observed function itself are not accounted for. Finally, the initial state of the internal environment and the parameters of the function being

In vivo experiments require the use of appropriate anesthesia, which should be selected according to their particular effect on the organism. Moreover, an increasing number of rat and mice studies have acknowledged that the toxicity and efficacy of some anesthetic agents fluctuate in circadian dependence. For example, the toxicity of barbiturates is higher in the early morning [4], and mortality after halothane anesthesia moves from 5% during the day to 76% at night [5]. The toxicity of althesin is highest around 10:00 h [6], and the effective time of althesin anesthesia is 20% longer at 12:00 h than at 06:00 h [5]. Nevertheless, anesthesia has played an important role in ensuring humane surgical/interventions in experimental animals, particularly in long-term in vivo protocols requiring animal survival. Presently, anesthetic practice is primarily based on physiology. The importance of the application of physiological principles in anesthesia has been reaffirmed and emphasizes the need for progress in systemic

To survive, all living organisms need to maintain acid-base balance and oxygenation. The key role of homeostatic maintenance in all living organisms is not at odds with the observation that various biological parameters are dynamic. Rhythmic changes observed in humans that occur regularly play an important role in adaptation to dynamic environments. Chronobiology affects the activities and functions of the organs and tissues and is also a driver of anatomical, physiological, and molecular changes [8]. Control of acid-base balance depends on the

humans, compensatory mechanisms exist for the maintenance of the acid-base balance necessary for normal enzymatic activity, electrolyte diffusion, hemoglobin saturation, and heart

ions in bodily fluids. In healthy wakeful mammals, including

observed―after the induction of general anesthesia―are often not considered.

**2. Acid-base balance, anesthesia, and circadian rhythms**

respiratory systems [1].

108 Circadian Rhythm - Cellular and Molecular Mechanisms

physiology [7].

concentration of H+

and HCO3

−

contraction, all of which leads to normal functioning of vital organs [9].

Changes in the functional efficiency of these systems lead to changes in acid-base balance, and vice versa, changes in acid-base parameters affect the functional state of these systems. Similarly, changes in acid-base balance also reflect 24 h fluctuations in respiratory and cardiovascular functions. Therefore, reference values for acid-base balance can cause problems because the parameters of acid-base balance and ion concentration reflect the current state of the organism at a given time. Results are often compared with average reference values and often regardless of their dependence on the circadian rhythm.

However, rats are typical night animals, which adapt to a natural or controlled artificial lightdark (LD) cycles, which are the strongest synchronizers of endogenous rhythms. This means that their physiological functions exhibit circadian rhythmicity (i.e., fluctuate over a 24 h period).

If we focus on the respiratory system, data confirm that ventilation and metabolism in rats exhibit circadian rhythms and rebut the hypothesis that breathing is affected only by the current state of wakefulness or sleeping. The effects of circadian rhythms on breathing in sleep and wakefulness, as well as the rate of metabolism, are additive in the rat [19]. Some measures that reflect the mechanical properties of the lungs, such as functional residual capacity, forced expiratory volume, and respiratory airways resistance, vary periodically with the time of day. Additionally, resting pulmonary ventilation, tidal volume, and respiratory rate are governed by circadian patterns. Circadian oscillations of the respiratory pattern occur independently of the daily rhythms of other activities or states of wakefulness or sleep. Recent measurements of breath patterns over an extended time period in intact animals have shown that circadian changes occur in a close time phase with changes in oxygen consumption, carbon dioxide production, and body temperature. However, none of these variables can fully explain the circadian pattern of breathing, the origin of which remains unclear [20]. Selected parameters of the cardiovascular system (e.g., heart rate, blood pressure) in rats also demonstrate circadian rhythmicity [21, 22], which are regulated by various mechanisms, including those part of the autonomic nervous system [23, 24]. Vulnerability of the rat myocardium to ventricular arrhythmias during normal pulmonary ventilation demonstrates a defined 24-h course, with higher vulnerability during the light period of the day. The acrophase, calculated using the population cosinor test, was 22:53, with a confidence interval from 19:20 to 00:28 [25].

period [42]. Circadian variation of plasma sodium ion (Na+

intestinal clock in coordinating intestinal NaCl absorption is presumed.

/H+

with the physiological state before administration of the anesthetic.

higher during the subjective night than during the subjective day. Transporters and channels operating under the control of NaCl absorption exhibit diurnal regulation, and the role of the

Because the above described events occur primarily in the kidneys, renal function is influenced by circadian clocks through two types of circadian inputs. The first is onset of renal rhythms through external circadian signals such as rhythms of hormones, food intake, activity, and body temperature. The second is the activity of the internal renal circadian clock. For example, Doi et al. [44] reported that the circadian time system controls the reabsorption of sodium in the distal nephron and in the collecting channel via the effect of aldosterone production in the adrenal glands. On the other hand, Rohman et al. [45] reported that internal

that the circadian repressor period 1 is able to regulate expression of epithelial sodium channels in the cells of the collecting channel. A study by Roelfsema et al. [47] reported that the maximum excretion of potassium, phosphate, and magnesium is only slightly affected by the dietary regimen, indicating that it depends mainly on endogenous rhythm. In contrast, the minimum excretion of these ions is determined by food intake. Maximum calcium levels, as well as minimal excretion, correlate with dietary regimen. The sodium excretion pattern differs from the calcium, potassium, phosphate, and magnesium patterns, indicating that it is controlled by another mechanism. Unless this fact is taken into account, we can encounter distortions in which the final results are interpreted from a state that does not correspond

Sodium ions are necessary for the generation of nerve impulses and for the maintenance of electrolyte and fluid balance. In animals, sodium ions are necessary for these functions and for heart activity and certain metabolic functions [28]. Symptoms of hyponatremia can vary from none to severe [48, 49]. Mild symptoms include a decreased ability to process information, headaches, nausea, and poor balance [50]. Severe symptoms include confusion, seizures, and coma [48, 49]. Hypernatremia can evoke a strong feeling of thirst, weakness, nausea, and loss of appetite [51]. Severe symptoms include confusion, muscle twitch, and bleeding in or

Calcium ions also play a vital role in the physiology and biochemistry of organisms and the cell. They play an important role in signal transduction pathways [53, 54], where they act as a second messenger in neurotransmitter release from neurons, in the contraction of all muscle cell types and in fertilization. Many enzymes require calcium ions as a cofactor, those of the blood clotting cascade being notable examples. Extracellular calcium is also important for maintaining the potential difference across excitable cell membranes, as well as proper bone formation. Symptoms of hypercalcemia may include abdominal pain, bone pain, confusion, depression, weakness, kidney stones, or abnormal heart rhythm and cardiac arrest [55]. Hypocalcemia can be associated with disorders of hemocoagulation, numbness, muscle spasms, seizures, confusion, or cardiac arrest [56]. Chloride is an essential electrolyte located in all bodily fluids and is responsible for maintaining acid-base balance, transmitting nerve

in a study by Sotak et al. [43]. Electrogenic Na+

renal clocks directly regulate Na+

around the brain [51, 52].

impulses, and regulating fluid in and out of cells.

) in the rat was also demonstrated

http://dx.doi.org/10.5772/intechopen.75174

111

transport in the rat colon was significantly

Chronobiology of Acid-Base Balance under General Anesthesia in Rat Model

activity in the proximal tubule. Gumz et al. [46] reported

The problem of circadian variation of acid-base balance parameters, therefore, remains. Circadian rhythms of acid-base balance and blood gases have been studied in humans, and the following acrophases were found: pH at 16:05; stHCO3 − at 18:45 h; HCO3 − at 22:55 h; buffer bases (BB) at 19:03; pCO2 at 2:47 pm; pO2 at 04:39 h; HbO2 08: 07 h; and Hb at 2:16 pm [26]. In rats placed in constant darkness, diurnal rhythms were found in glycemia, pH, and pCO2 . Light pulses of 30 min duration increased blood glucose levels but did not affect plasma pH and pCO2 . These circadian rhythms are most likely under the control of the suprachiasmatic nuclei in the hypothalamus, while the hyperglycemic reaction to light is not controlled by circadian clocks and, thus, may involve retinal inputs to areas of the suprachiasmatic nuclei that are not sensitive to visual inputs [27].
