Water and electrolyte changes in skeletal and cardiac muscles of rats during prolonged hypokinesia

The objective of this study was to show that hypokinesia (diminished movement) could affect differently water and electrolyte content in muscles having minimum differences in their function and morphology. To this end, we studied water and electrolyte content in skeletal and cardiac muscles, fluid excretion, electrolyte absorption, and electrolyte levels in plasma, urine and feces of rats during prolonged hypokinesia (HK). Studies were conducted on one-hundred-twenty-six 13-weeks old male Wister rats during a pre-hypokinetic period and a hypokinesia period. Animals were equally divided into two groups: vivarium control rats (VCR) and hypokinetic rats (HKR). Hypokinetic animals were kept in small individual cages which restricted their movements in all directions without hindering food and water intake. Control rats were housed in individual cages under vivarium control conditions. Sodium (Na+) and potassium (K+) absorption, electrolyte and water content in cardiac muscles (right and left ventricle), thigh extensor (quadriceps femoris muscle) and long muscle of the back (biceps femoris muscle), urine volume, and electrolyte levels in plasma and urine and feces did not change in VCR when compared to their pre-hypokinetic levels. The absorption of Na+ and K+, water and electrolyte content in cardiac and skeletal muscles decreased significantly, while urine volume, plasma electrolyte levels and urine and fecal electrolyte excretion increased significantly in HKR compared with their pre-HK values and with their respective vivarium control (VCR). Water and electrolyte content decreased more significantly in skeletal than in cardiac muscles. Water and electrolyte levels decreased more in the thigh extensor and in the right ventricle than in the long muscle of the back, the left ventricle or the septum. Muscles suffering from higher water and electrolyte loss against the background of lower water and electrolyte content show lower water and electrolyte deposition. Lower electrolyte and water content in skeletal than in cardiac muscle shows that water and electrolyte content decreases more in skeletal than cardiac muscles. Skeletal muscle showed lower water and electrolyte content than cardiac muscle indicating that the risk for decreased muscle water and electrolyte content is inversely related to the muscle function and morphology, i.e., the more weight-bearing supporting function and morphology muscles have, the higher the risk for lower muscle water and electrolyte content. It was concluded that the greater muscle function and morphology, the lower electrolyte and water deposition, the higher water and electrolyte losses, and the lower water and electrolyte content.     

Electrolyte changes in plasma and urine of athletes during acute and rigorous bed rest and ambulatory conditions

Rigorous bed rest (RBR) induces significant electrolyte changes, but little it is not known about the effect of acute bed rest (ABR) (i.e., abrupt confinement to a RBR). The aim of this study was to measure urinary and plasma electrolyte changes during ABR and RBR conditions. The studies were done during 3 d of a pre-bed-rest (BR) period and during 7 d of an ABR and RBR period. Thirty male trained athletes aged, 24.4 ± 6.6 yr were chosen as subjects. They were divided equally into three groups: unrestricted ambulatory control subjects (UACS), acute-bed-rested subjects (ABRS), and rigorous-bed-rested subjects (RBRS). The UACS group experienced no changes in professional training and daily activities. The ABRS were submitted abruptly to a RBR regimen and without having any prior knowledge of the exact date and time when they would be subjected to an RBR regimen. The RBRS were subjected to an RBR regime on a predetermined date and time known to them from the beginning of the study. Sodium (Na), potassium (K), magnesium (Mg), calcium (Ca), and phosphate (P) in plasma and urine, plasma renin activity (PRA) and plasma aldosterone (PA), physical characteristics, peak oxygen uptake, and food and water intakes were measured. Urinary Na, K, Ca, Mg, and P excretion and plasma Na, K, Mg, Ca, and P concentration, PRA, and PA concentration increased significantly (p ≤ 0.01), whereas body weight, peak oxygen uptake, and food and water intakes decreased significantly in the ABRS and RBRS groups when compared with the UACS group. However, urinary and plasma Na, K, Mg, P, and Ca, PRA, and PA values increased much faster and were much greater in the ABRS group than in the RBRS group. Plasma and urinary Na, K, Ca, Mg, and P, PRA and PA levels, food and water intakes, body weight, and peak oxygen uptake did not change significantly in the UACS group when compared with its baseline control values. It was shown that RBR and ABR conditions induce significant increases in urinary and plasma electrolytes; however, urinary and plasma electrolyte changes appeared much faster and were much greater in the ABRS group than the RBRS group. It was concluded that the more abruptly motor activity is ended, the faster and the greater the urinary and plasma electrolyte change.     

From bench to bedside--preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A)

Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A) is just the second ruthenium-based anticancer agent after NAMI-A which was developed to the stage of clinical trials. Important steps in the mode of action of KP1019 are thought to be the binding to the serum protein transferrin and the transport into the cell via the transferrin pathway. Additionally, the selective activation by reduction in the tumor might contribute to the low side effects observed in in vivo studies. Apoptosis is induced at non-toxic levels via the mitochondrial pathway. These features distinguish it from the established platinum anticancer drugs and suggest that different types of cancer might be treatable with this drug. Indeed, promising activity against certain types of tumors, which are not successfully treatable with cisplatin, and only a very low incidence of acquired resistance has been observed in in vitro and in vivo studies. Recently, a clinical phase I trial was finished in which none of the treated patients experienced serious side effects, while disease stabilization in five of six evaluable patients was achieved. In this review, the preclinical and early clinical development of KP1019 - from bench to bedside - is recapitulated.     

Bis[platinum(II)] and bis[platinum(IV)] complexes with optically active bis(vicinal-1,2-diamines) and their interaction with DNA.

Bis[platinum(II)] [Cl2Pt(LL)PtCl2] complexes 2,5 and 8 with chiral non-racemic ligands: 1a-c (LL = (R,R), (S,S) and (R,S) N,N'-bis(3,4-diaminobutyl)hexanediamide); 4a,b (LL = (R,R) and (S,S) N,N'-bis[3,4-bis(diaminobutyl)] urea); 7a-d (LL' = (R,R), (S,S), (R,S) and (S,R) 4,5-diamino-N-(3,4-diaminobutyl) pentanamide) and bis[platinum(IV)] complex 10-13 with ligands 1a,b and 4a,b have been prepared and characterized by IR, 1H, 13C and 195Pt NMR spectra. The interactions of 2a-c, 5a, 5b, 8a-d and 10a with dsDNA were investigated with the goal of examining whether the chirality, the nature of the spacer and the oxidation state have an influence on platinum-DNA binding properties. All the bis[platinum(II)] complexes form with dsDNA intra- and interstrand crosslinks and crosslinks over sticky ends, whereas the bis[platinum(IV)] complex 10a only forms intra- and interstrand crosslinks. The platinum-DNA coordination sites were determined by the T4 DNA polymerase footprinting method. The results show that all investigated bis(platinum) complexes have high preference towards distinct purines. All isomeric bis(amide) 2a-c and mono(amide) 8a-d complexes exhibit nearly the same binding pattern, whereas the ureide complexes 5a and 5b have other coordination sites with higher sequence preference. Interestingly, the ureides 5a and 5b differ in their coordination sites not only in comparison to the bis(amides) 2a-c and mono(amides) 8a-d, but also between each other. The bis[platinum(IV)] complex 10a also differs in coordination sites in comparison to all the bis[platinum(II)] compounds.     

Daily hyperhydration effect on electrolyte deficiency of endurance-Trained subjects during prolonged hypokinesia

The aim of this study was to evaluate the effect of a daily intake of fluid and salt supplementation (FSS) on the deficiency of electrolytes, which is characterized by higher rather than lower plasma concentration of electrolytes during prolonged hypokinesia (HK) (decreased number of km taken per day). Forty long distance runners aged 22–25 yr with a peak V0₂ 65.4 mL min^-1 kg^-1 with an average 14.2 km d running distance were selected as subjects. They were equally divided into four groups: 1) unsupplemented control subjects (UCS); 2) unsupplemented hypokinetic subjects (UHS); 3) supplemented hypokinetic subjects (SHS), and 4) supplemented control subjects (SCS). During the investigation of 364 d, groups 2 and 3 maintained an average running distance of less than 4.7 km per day, groups 1 and 4 did not experience any modification in their normal training routines and diets. During the preexperimental period of 60 d and during the experimental period of 364 d urinary excretion of electrolytes and concentrations of sodium, potassium, calcium, and magnesium in plasma were determined. Whole blood hemoglobin, hematocrit index, plasma osmolality, and plasma protein concentration were measured. In the UHS plasma concentration of electrolytes and urinary excretion thereof, fluid elimination, hematocrit, whole blood hemoglobin, plasma osmolality, and plasma protein concentration increased significantly (p < 0.05) when compared with the UCS, SCS, and SHS groups. In the SHS plasma concentration of electrolytes and urinary excretion thereof, fluid excretion, whole blood hemoglobin, hematocrit, plasma osmolality, and plasma protein concentration decreased when compared with the UHS and increased insignificantly when compared with the UCS and SCS groups. It was concluded that FSS may be used to prevent or minimize electrolyte deficiency in endurance-trained volunteers during prolonged restriction of muscular activity.     

Blood urea content changes in man under hypokinesia

It has been demonstrated that hypokinesia (diminished muscular activity) leads to an increase in blood urea content in man. Against this background the objective of this investigation was to determine blood urea content under hypokinesia (HK) on 17 physically healthy men aged 19-23 yr. They were divided into three groups: the 1st group (5 men) was examined under HK, the 2nd group (4 men) was studied during the background period (BGP) as well as in the readaptation period (RTP), and the 3rd group (8 men) was placed under ordinary conditions and served as control. For the simulation of the hypokinetic effect the men were kept under a rigorous bed rest regime for 16 days. Blood urea, blood creatinine, urine urea, and urine creatinine were measured. The results were processed statistically. The most pronounced increased urea content was observed in the men with an initial low concentration (3.3-4.2 mmole/liter). Variations in the urea concentration were analogous and manifested a reduction during the initial days and an elevation thereafter. Creatinine excretion and clearance were reduced uniformly and significantly during the initial 10 days of HK. It was concluded that diminished muscular activity induced an increase in urea content and a decrease in creatinine clearance in man.     

Calcium supplementation effect on calcium balance in endurance-trained athletes during prolonged hypokinesia and ambulatory conditions

Calcium (Ca) supplements may be used to normalize Ca-balance changes but little is known about the effect of Ca supplements on Ca balance during hypokinesia (decreased kilometers per day). The aim of this study was to evaluate the effect of daily intakes of Ca supplements on Ca balance during hypokinesia (HK). Studies were done during 30 d of a pre-HK period and during 364 d of a HK period. Forty male athletes aged 23–26 yr were chosen as subjects. They were divided equally into four groups: unsupplemented ambulatory control subjects (UACS), unsupplemented hypokinetic subjects (UHKS), supplemented hypokinetic subjects (SHKS), and supplemented ambulatory control subjects (SACS). The SHKS and UHKS groups were kept under an average running distance of 0.7 km/d. In the SHKS and SACS groups supplemented with 35.0 mg Ca lactate/kg body weight. Fecal Ca loss, urinary excretion of Ca and phosphate (P), serum concentrations of ionized calcium (Ca_I) total Ca, P, and Ca balance, intact parathyroid hormone (iPTH) and 1,25 dihydroxyvitamin D (1,25(OH)2D), anthropometric characteristics and peak oxygen uptake were measured. Fecal Ca excretion, urinary Ca and P excretion, serum Ca_I, total Ca, and P concentration, and negative Ca balanced increased significantly (p ≤ 0.01) in the SHKS and UHKS groups when compared with the SACS and UACS groups. Serum, urinary, and fecal Ca changes were much greater and appeared much faster in the SHKS group than in the UHKS group. Serum iPTH and 1,25 (OH)2 D, body weight, and peak oxygen uptake decreased significantly (p ≤ 0.01) in the SHKS and UHKS groups when compared with the SACS and UACS groups. In contrast, the corresponding parameters remained stable in the SACS and UACS groups when compared with the baseline control values. It was concluded that during prolonged HK, urinary and fecal Ca excretion and serum Ca concentration increased significantly despite the presence of a negative Ca balance; thus, Ca supplements cannot be used to normalize negative Ca balance during prolonged HK.     

Serum, urinary, and fecal calcium changes in trained and untrained subjects during prolonged hypokinetic and ambulatory conditions

Electrolyte metabolism undergoes significant changes in trained subjects, but it is unknown if it undergoes significant changes in untrained subjects during hypokinesia (decreased movement). The aim of this study was to measure calcium (Ca) changes in trained and untrained subjects during prolonged hypokinesia (HK). Studies were done during 30 d of a pre-HK period and 364 d of a HK period. Forty male trained and untrained volunteers aged 23–26 yr were chosen as subjects. All subjects were equally divided into four groups: trained ambulatory control subjects (TACS), trained hypokinetic subjects (THKS), untrained hypokinetic subjects (UHKS), and untrained ambulatory control subjects (UACS). The THKS and UHKS groups were kept under an average running distance of 0.7 km/d. Fecal Ca excretion, urinary Ca and magnesium (Mg) excretion, serum ionized calcium (Ca_I), Ca, Mg, intact parathyroid hormone (iPTH) and 1,25 dihydroxyvitamin D [1,25 (OH)2 D] concentration, body weight, and peak oxygen uptake were measured. Fecal Ca loss, urinary Ca and Mg excretion, and serum Ca_I, Mg, and Ca increased significantly (p ≤ 0.01), whereas serum iPTH and 1,25 (OH)2 D concentration body weight and peak oxygen uptake decreased significantly (p ≤ 0.01) in the THKS and UHKS groups when compared with the TACS and UACS groups. The measured parameters were much greater and much faster in the THKS group than in the UHKS group. By contrast, the corresponding parameters did not change significantly in the TACS and UACS groups when compared with the baseline control values. It was concluded that prolonged HK induces significant fecal, urinary, and serum Ca changes in the hypokinetic subjects when compared with control subjects. However, fecal, urinary, and serum Ca changes were much greater and appeared much faster in the THKS group than the UHKS group.     

Urinary excretion of microelements in endurance-trained volunteers during restriction of muscular activity and chronic rehydration

The objective of this investigation was to determine the effect of daily intake of fluid and salt supplementation (FSS) on increased urinary losses of microelements that developed during hypokinesia (decreased number of walking steps/d). The studies were performed on 30 endurance-trained male volunteers aged 23–26 yr, with an averaged maximum oxygen uptake of 65 mL/kg/min during 364 d of hypokinesia (HK). All volunteers were divided into three equal groups: Ten volunteers were placed continuously under an average of 10,000 running steps/d (14.2 km/d) (control subjects), ten volunteers subjected continuously to HK without the use of FSS (hypokinetic subjects), and ten volunteers were continuously submitted to HK and consumed daily FSS (hyperhydrated subjects). For the simulation of the hypokinetic effect the hypokinetic and hyperhydrated volunteers were kept under an average of 3,000 walking steps/d (2.7 km/d) for 364 d. Prior to their exposure to HK the volunteers were on an average of 10,000 running steps/d (14.2 km/d). During the prehypokinetic period of 60 d and during the hypokinetic period of 364 d were determined renal excretion of microelements responses of endurance-trained volunteers. In the hyperhydrated volunteers urinary excretion of iron, zinc, copper, manganese, cobalt, nickel, lead, tin, chromium, aluminum, molybdenum, and vanadium decreased, whereas in the hypokinetic volunteers it increased significantly. It was concluded that chronic hyperhydration may be used to attenuate urinary excretion of microelements in endurance-trained volunteers during prolonged restriction of muscular activity.     

Blood plasma concentrations of microelements in endurance trained volunteers during hypokinesia and chronic hyperhydration

The objective of this investigation was to determine the effect of daily intake of fluid and salt supplementation (FSS) on increased urinary losses of microelements that developed during hypokinesia (decreased number of walking steps/d). The studies were performed on 30 endurance-trained male volunteers aged 23–26 yr, with an averaged maximum oxygen uptake of 65 mL/kg/min during 364 d of hypokinesia (HK). All volunteers were divided into three equal groups: Ten volunteers were placed continuously under an average of 10,000 running steps/d (14.2 km/d) (control subjects), ten volunteers subjected continuously to HK without the use of FSS (hypokinetic subjects), and ten volunteers were continuously submitted to HK and consumed daily FSS (hyperhydrated subjects). For the simulation of the hypokinetic effect the hypokinetic and hyperhydrated volunteers were kept under an average of 3,000 walking steps/d (2.7 km/d) for 364 d. Prior to their exposure to HK the volunteers were on an average of 10,000 running steps/d (14.2 km/d). During the prehypokinetic period of 60 d and during the hypokinetic period of 364 d were determined renal excretion of microelements responses of endurance-trained volunteers. In the hyperhydrated volunteers urinary excretion of iron, zinc, copper, manganese, cobalt, nickel, lead, tin, chromium, aluminum, molybdenum, and vanadium decreased, whereas in the hypokinetic volunteers it increased significantly. It was concluded that chronic hyperhydration may be used to attenuate urinary excretion of microelements in endurance-trained volunteers during prolonged restriction of muscular activity.