**3. Ion concentrations, anesthesia, and circadian rhythms**

Ion concentrations neither can be neglected nor is there question whether they are affected by anesthesia or whether their circadian rhythm is maintained under anesthesia. These states can change significantly, for example, in myocardial excitability, which also changes over a 24 h period and is dependent on ion distribution. Based on ion status in the body and their particular role, especially in electrophysiological processes occurring in vital tissues, determination is essential. Potassium, for example, is an essential mineral micronutrient and is the primary intracellular ion for all types of cells, providing vital maintenance of fluid and electrolyte balance in humans and animals [28, 29].

There is clear evidence of the presence of circadian rhythm in potassium and sodium concentrations [30–35]. In all the examined species in which these rhythms occur, overlap of the peak excretion of potassium and sodium occurs essentially at the same time during a 24 h period. It is assumed that the peak of sodium excretion corresponds to reduced sodium reabsorption, and the peak in potassium concentration corresponds to an increase in potassium secretion. Studies involving squirrels, monkeys [36], and rats [37, 38] indicate that cyclic changes in potassium excretion are independent of changes in plasma potassium concentration. However, the correlation between plasma potassium and cyclic potassium excretion has been observed in humans [39]. Maintenance of stable plasma potassium ion (K<sup>+</sup> ) concentration is extremely important because K+ controls muscle and nervous activity. In humans, urinary excretion of K+ peaks in the early morning (05:30–07:30 h), with a minimum at night (21:00– 05:30 h) [40]. Circadian rhythmicity has also been demonstrated in thoroughbred racehorses, in which plasma K+ exhibited a significant rhythm, with acrophase during dark periods [41]. Similar results were found in plasma K+ concentration in mice, in which based on measurement of urinary excretion, investigators found that peak excretion occurred in the resting period [42]. Circadian variation of plasma sodium ion (Na+ ) in the rat was also demonstrated in a study by Sotak et al. [43]. Electrogenic Na+ transport in the rat colon was significantly 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 intestinal clock in coordinating intestinal NaCl absorption is presumed.

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

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

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

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

Ion concentrations neither can be neglected nor is there question whether they are affected by anesthesia or whether their circadian rhythm is maintained under anesthesia. These states can change significantly, for example, in myocardial excitability, which also changes over a 24 h period and is dependent on ion distribution. Based on ion status in the body and their particular role, especially in electrophysiological processes occurring in vital tissues, determination is essential. Potassium, for example, is an essential mineral micronutrient and is the primary intracellular ion for all types of cells, providing vital maintenance of fluid and electrolyte bal-

There is clear evidence of the presence of circadian rhythm in potassium and sodium concentrations [30–35]. In all the examined species in which these rhythms occur, overlap of the peak excretion of potassium and sodium occurs essentially at the same time during a 24 h period. It is assumed that the peak of sodium excretion corresponds to reduced sodium reabsorption, and the peak in potassium concentration corresponds to an increase in potassium secretion. Studies involving squirrels, monkeys [36], and rats [37, 38] indicate that cyclic changes in potassium excretion are independent of changes in plasma potassium concentration. However, the correlation between plasma potassium and cyclic potassium excretion has been

05:30 h) [40]. Circadian rhythmicity has also been demonstrated in thoroughbred racehorses,

ment of urinary excretion, investigators found that peak excretion occurred in the resting

observed in humans [39]. Maintenance of stable plasma potassium ion (K<sup>+</sup>

at 04:39 h; HbO2

. These circadian rhythms are most likely under the control of the suprachiasmatic

−

at 18:45 h; HCO3

−

08: 07 h; and Hb at 2:16 pm [26].

at 22:55 h; buffer

) concentration is

controls muscle and nervous activity. In humans, urinary

concentration in mice, in which based on measure-

peaks in the early morning (05:30–07:30 h), with a minimum at night (21:00–

exhibited a significant rhythm, with acrophase during dark periods [41].

.

population cosinor test, was 22:53, with a confidence interval from 19:20 to 00:28 [25].

the following acrophases were found: pH at 16:05; stHCO3

at 2:47 pm; pO2

**3. Ion concentrations, anesthesia, and circadian rhythms**

bases (BB) at 19:03; pCO2

that are not sensitive to visual inputs [27].

110 Circadian Rhythm - Cellular and Molecular Mechanisms

ance in humans and animals [28, 29].

extremely important because K+

Similar results were found in plasma K+

excretion of K+

in which plasma K+

and pCO2

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 renal clocks directly regulate Na+ /H+ activity in the proximal tubule. Gumz et al. [46] reported 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 with the physiological state before administration of the anesthetic.

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 around the brain [51, 52].

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 impulses, and regulating fluid in and out of cells.

What is the effect of anesthetics on ongoing ion-dependent processes? Evidence from voltage-clamp studies of individual nerve fibers suggests that, for example, molecules of local anesthetic interact with sodium channels directly from the inside of the nerve membrane. Anesthetics bind to sodium channels, which open during membrane depolarization and prevent normal sodium flow. Anesthetic molecules can separate from open channels, but not from channels that remain closed when the nerve is kept in the resting state. The "gate" properties, which regulate the opening and closing of sodium channels, are reversibly adjusted during anesthesia [57]. Despite the significant advances in chronobiological studies, the mechanisms of circadian regulation of ion channels remain largely unknown. By exploring and understanding the circadian regulation of the ion channel in detail, progress in the development of therapeutic effective strategies for the treatment of sleep disorders, cardiovascular diseases, and other diseases associated with circadian desynchronization [58] will be developed.
