Very little is known of the development of the feedforward postural control mechanism. The purpose of this study was to identify differences in this system between two different stages of development. Two groups of ten children, aged 4- and 5-years old and 10- and 11-years-old took part in this study. Electromyographic (EMG) data from the right anterior deltoid, right and left erector spinae, right and left hamstring muscles and vertical ground reaction force data from the left and right foot as well as the total body, were collected during unilateral rapid forward arm movement about the shoulder in the sagittal plane. EMG and force data were examined for activity 100 ms prior to onset and 70 ms post movement onset. Onset latencies, probability of recruitment and recruitment order were determined for all postural muscles. Onset latencies of changes in the vertical ground reaction forces as well as coefficients of variation were determined for the vertical ground reaction forces. In general, the 4- and 5-year old children demonstrated a similar postural muscle recruitment order as the 10- and 11-year old children. However, the 4- and 5-year old children had a larger proportion of the postural muscles being activated before the movement onset than the 10- and 11-year old children did. The probability of the 4- and 5-year old children recruiting the left erector spinae muscle was significantly less than that of the 10- and 11-year old children. The 4- and 5-year old children demonstrated greater intra-subject variability about the vertical ground reaction forces than did the 10- and 11-year old children. These data suggest that with development, the feedforward postural used in preparation for a unilateral rapid arm raise becomes increasingly consistent. A shift in the feedforward postural adjustment goal from safety to efficiency is proposed.

During exercise, the metabolic rate of muscle increases considerably, and hence the concentration of various metabolites is altered. Surprisingly, the concentration of ATP is not decreased significantly even at exhaustion. This suggests that the muscle may have a safety mechanism that shuts down force generation in order to avoid energy depletion, as the latter causes irreversible damage to the muscle cell. The K+(ATP) channel, which is activated by decreased ATP levels, might be involved in this safety mechanism. According to its postulated mechanism, once activated the channel can contribute to decreasing force generation by decreasing the excitability of the muscle membrane. The scope of this thesis will deal with the physiological role of the K+(ATP) channel in skeletal muscle during fatigue. The main objectives of this study were to understand the physiological role of the K+(ATP) channel and how this role is affected by 1-week denervation in mouse EDL and soleus muscles. K +(ATP) channels were either blocked with 10 muM glibenclamide, or activated with 100 muM pinacidil, while muscles were fatigued by tetanic contractions every sec for 3 min. (Abstract shortened by UMI.)

Teleost fish are very sensitive to changes that occur in their aquatic environment, including those that influence blood acid-base status. The intracellular pH (pHi) of the liver is strongly influenced by the pH of circulating blood and must be able to regulate any changes that occur. The main goal of this thesis was to examine the mechanisms of pHi regulation in hepatocytes (liver cells) isolated from different fish species. Isolated hepatocytes were validated as an appropriate cell model system by examining intracellular and plasma ion levels in three teleost species, rainbow trout, Oncorhynchus mykiss (Walbaum), black bullhead, Ameiurus melas (Rafinesque) and American eel, Anguilla rostrata (Lesueur). Although the electrochemical gradients for Na + and K+ were different in isolated cells as compared to the intact tissue, these gradients were directionally correct. The mechanism of intracellular pH (pHi) regulation was studied in trout, bullhead and eel hepatocytes using the pH-sensitive fluorescent dye BCECF. In the trout and bullhead, recovery to an acid load occurred principally by way of Na+-H+ exchange. In trout hepatocytes, an electrogenic Na+-HCO3- cotransporter also plays a significant role in the maintenance of steady-state pHi and recovery from intracellular acidosis. In eel, recovery to an acid load occurred by a Cl--dependent mechanism. Recovery to a base load in the trout was diminished by blocking the Na+-H + exchanger. Partial sequences of the Na+-HCO3- (NBC) gene were obtained independently from trout liver and gill/kidney cDNA libraries. The fish NBC sequences were identical and showed high homology with mammalian and amphibian sequences. The most important differences between the fish and these other sequences occurred in the large extracellular loop as well as in the DIDS binding motif. Hypercapnia exposure resulting in decreases in blood pH significantly decreases hepatocyte pHi. Chronic in vivo or in vitro hypercapnia did not enhance the ability of hepatocytes to recover from subsequent intracellular acidoses. In summary, hepatocytes of all three teleost species studied appear to have the ability to regulate pHi, though they do not exploit identical mechanisms. In addition to the role of a Na+-H+ exchanger and Cl--HCO3- exchanger, a Na+-HCO3- cotransporter may contribute significantly to hepatocyte pHi regulation. The primary molecular data obtained in this thesis may allow for a more complete and in depth determination of a role of the NBC in regulatory mechanisms in teleost fish.

The coronary microvascular response during pathological growth is important for the maintenance of adequate myocardial oxygenation. The aim of this research was to examine the coronary microvascular response to hyperthyroidism. Capillary geometry was examined in hyperthyroid, hypothyroid, and hypo-hyperthyroid adult male Sprague Dawley rats. Heart rates increased in hyperthyroid and hypo-hyperthyroid rats but decreased in hypothyroid rats compared to control. Adult-onset hyperthyroidism increased absolute and relative heart mass, whereas hypothyroidism decreased these parameters. In hypo-hyperthyroid rats, heart mass increased compared to hypothyroid rats and relative heart mass increased compared to control. Capillary numerical density was maintained in hyperthyroid and hypo-hyperthyroid rats despite increased LV mass, suggesting capillary proliferation. Hypothyroid rats had a larger than expected increase in capillary numerical density compared to control. In hyperthyroid rats, the area of tissue surrounding an individual capillary (capillary domain) decreased for proximal capillaries, whereas in hypothyroid rats domain areas decreased in both proximal and distal regions compared to control. All groups had shorter capillary segment lengths in proximal and distal regions relative to control. PCNA labelling of endothelial cells was significantly increased only in hypo-hyperthyroid rats. These data suggest that both adult-onset hyper- and hypothyroidism induced capillary proliferation. The effect of altered thyroid hormone status on the developing coronary microvasculature was examined in neonatal rats. Long-term effects of neonatal-onset hyper- and hypothyroidism on coronary microvascular geometry and cardiac function were examined in a subset of adult rats in which euthyroidism had been re-established. Neonatal-onset hyperthyroidism enhanced maturation, while hypothyroidism attenuated maturation. Serum T$\sb3$ levels and heart rates increased in hyperthyroid but decreased in hypothyroid rats compared to control. After discontinuing treatment, heart rates were similar between control and previously hypothyroid rats. Occasionally, heart rates remained elevated in previously hyperthyroid rats compared to control. Hyperthyroidism produced ventricular hypertrophy while hypothyroidism slowed cardiac growth. Both neonatal thyroid conditions induced a long-term deficit in LV growth after euthyroidism was re-established. Capillary and arteriolar numerical density, as well as proximal and distal capillary segment lengths, were maintained in hyperthyroid rats despite LV hypertrophy suggesting enhancement of capillary and arteriolar proliferation. Total arteriolar length was greater in hyperthyroid than control rats. With hypothyroidism, capillary numerical density was either maintained or increased compared to control. Total arteriolar length was significantly lower in hypothyroid rats suggesting slowed arteriolar growth. After cessation of treatment, total arteriolar length in previously hyperthyroid rats did not change despite increased LV mass. Previously hyperthyroid rats had increased RV and LV systolic pressure, LV developed and end-diastolic pressure, and +(dP/dt)max (P 0.05). An increased percentage of small arterioles (i.e. 10-30$\mu$m) was observed in previously hypothyroid rats. (Abstract shortened by UMI.)

The ATP-sensitive potassium (K$\sp+\rm\sb{(ATP)}$) channel is a K$\sp+$ channel which is activated as the energy state of a muscle decreases. It has been hypothesized that once activated, K$\sp+\rm\sb{(ATP)}$ channels decrease the excitability of the cell and cause decreased contractility, such as during fatigue, in order to prevent energy levels from falling to dangerously low levels. The purpose of this study was to test this hypothesis and to determine under which conditions K$\sp+\rm\sb{(ATP)}$ channels can contribute to a decrease in force during a metabolic stress in the sartorius muscle of the frog, Rana pipiens. In the first series of experiments, sartorius muscle fibres were fatigued with 100 msec long tetanic contractions every second for three minutes, a condition known to activate ATP-sensitive potassium channels. So if K$\sp+\rm\sb{(ATP)}$ channels contribute to a decrease in force during fatigue, an activation of K$\sp+\rm\sb{(ATP)}$ channels with channel openers should further decrease membrane excitability and contractility. In a second series of experiments, muscles were subjected to metabolic inhibition which is known to activate a large number of K$\sp+\rm\sb{(ATP)}$ channels in order to better understand the relationship between K$\sp+\rm\sb{(ATP)}$ channel activity, the bioenergetic state, and force. The goal was to determine if K$\sp+\rm\sb{(ATP)}$ channels can contribute to a decrease in force under a bioenergetic state that is within physiological limits. (Abstract shortened by UMI.)

Objective. To evaluate the role of $\alpha\sb1$- or $\beta$-adrenoceptors in dietary sodium-induced cardiac hypertrophy, we assessed (1) the effects of high sodium diet (8% NaCl) on the responses of hearts isolated from young WKY rats to $\alpha\sb1$- or $\beta$-adrenergic stimulation after 1, 2, or 6 weeks of high sodium intake and (2) the effects of high sodium diet on responses of hearts isolated from young WKY rats after 2 weeks of high sodium intake to $\alpha\sb1$- or $\beta$-adrenoceptor subtype stimulation. Conclusions. Studies using methoxamine as an $\alpha\sb1$-agonist, as an $\alpha\rm\sb{1a}$-adrenoceptor agonist in the presence of CEC, or as an $\alpha\rm \sb{1b}$-adrenoceptor agonist in the presence of urapidil or the use of isoproterenol as a non-selective $\beta$-agonist revealed no significant differences in the sensitivity of ventricular $\alpha\sb1$-adrenoceptor subtypes or $\beta$-adrenoceptors between hearts from rats on a control or high sodium diet at any duration of feeding. A possible effect of high sodium diet on atrial $\alpha\rm \sb{1a}$- or $\alpha\rm \sb{1b}$-adrenoceptors is suggestive. The unchanged ventricular contractile responses to $\alpha\sb1$ or $\beta$-adrenoceptor stimulation in the hypertrophied hearts suggest that changes in ventricular adrenergic receptors responsiveness do not play a role in dietary sodium-induced left ventricular hypertrophy. One can not exclude a dissociation of intracellular signals linked to $\alpha\sb1$- or $\beta$-adrenoceptors associated with dietary sodium induced cardiac hypertrophy from those associated with contractility. (Abstract shortened by UMI.)

The effects of cardioplegic and reperfusion conditions on energy metabolites and cardiac function were investigated in order to define better conditions for heart preservation (4 or 8 hrs). Myocardial energy metabolites (ATP, PCr and inorganic phosphate), intracellular pH and contractile function were followed using $\sp{31}$P NMR spectroscopy and left intra-ventricular balloon, respectively, during preservation and reperfusion in isolated pig and rat hearts. These hearts were subjected to various conditions of cardioplegia and reperfusion which involved re-arrest perfusion following ischemic preservation, increased concentrations of buffer and Mg$\sp{++}$ in cardioplegic and reperfusion solutions, and an intracellular-type cardioplegic solution. The effect of re-arrest perfusion was tested by comparing the recovery of energy metabolites and contractile function between pig hearts subjected to a secondary cardioplegic solution (S-C-S) prior to Krebs-Henseleit (K-H) solution and those reperfused with K-H solution alone after 8 hours of ischemic preservation at 12$\sp\circ$C. The levels of ATP and PCr during reperfusion in both groups of hearts were comparable whereas the left ventricular developed pressure was significantly higher in the hearts reperfused with S-C-S than in those reperfused only with K-H solution. The reperfusion-induced ventricular fibrillation that occurred in K-H reperfused hearts was prevented by re-arrest perfusion. A cardioplegic solution containing 150 mmol/L MOPS (higher buffer cardioplegic solution) helped to maintain intracellular pH during 8 hours of ischemic preservation. However, it did not affect the levels of energy metabolites during preservation and contractile function during reperfusion. The effects of 16 mmol/L Mg$\sp{++}$ in cardioplegic and reperfusion solution were evaluated using both rat and pig hearts. In working rat hearts, 16 mmol/L Mg$\sp{++}$ in cardioplegic solution did not alter myocardial oxygen consumption and contractile function following 30 minutes of normothermic preservation. Moreover, Langendorff pig hearts preserved with either 0 or 16 mmol/L Mg$\sp{++}$ cardioplegic solution showed similar decrements in energy metabolites during 4 hours of ischemic preservation at 12$\sp\circ$C and recovery of contractile function during reperfusion while 16 mmol/L Mg$\sp{++}$ in K-H solution resulted in a dramatic decline of contractile function. Furthermore, 16 mmol/L Mg$\sp{++}$ in S-C-S also did not affect the levels of high energy phosphates and contractile function during reperfusion. At 4$\sp\circ$C the pig hearts stored with either University of Wisconsin solution (UW, an intracellular-type cardioplegic solution) or St Thomas' solution (an extracellular-type cardioplegic solution) showed comparable changes in energy metabolites during 8 hours of preservation and a similar recovery of contractile function during reperfusion. However, at 12$\sp\circ$C, hearts stored in UW solution showed rapid decrease in ATP and PCr during preservation and significantly poorer functional recovery during reperfusion; four of eight hearts stored in UW solution at 12$\sp\circ$C showed the "stone heart" phenomenon with disappearance of PCr and ATP upon reperfusion. The addition of 0.5 mmol/L Ca$\sp{++}$ to UW solution significantly improved contractile function and prevented the occurrence of the "stone heart" phenomenon with stable levels of high energy phosphates. (Abstract shortened by UMI.)

Glucagon-like peptide-1 (GLP-1) has been shown to improve tolerance to glucose. It has been suggested that this could be mediated by an incretin effect--the enhancement of insulin secretion in response to glucose, as well as by alterations in the sensitivity of the body to insulin. In order to evaluate the effect of GLP-1 on the improvement of glucose tolerance, the systemic as well as tissue-specific (the liver, intestine and muscle) effects of this hormone have been determined. The study has been conducted on animal model (the pig). Following an overnight fast and baseline measurements, glucose was infused (set point = 150 mg/dl), alone or supplemented with GLP-1 (4 ng/kg/min) and GLP-1 (8 ng/kg/min) in 90 min steps. The levels of metabolites (glucose, lactate) and hormones (insulin, glucagon, GLP-1) were then determined in arterial blood as well as in portal, hepatic and femoral venous blood. Tissue balances were then calculated. Levels of metabolites and hormones, glucose infusion rates and tissue balances were compared using statistical analysis (general linear models procedure, SAS Institute). (Abstract shortened by UMI.)

Theoretical studies have demonstrated a pronounced effect of red blood cell (RBC) spacing on tissue oxygen supply. In spite of this, realistic values for RBC spacing and related capillary hematocrit (Hct) are not known in the heart. One of the possible reasons is the lack of proper methodology. Thus, the goal of this research study was twofold: (i) to develop a method to rapidly freeze rat heart in situ, following which RBCs and capillary walls could be simultaneously visualized, and (ii) to apply this methodology in rat hearts to establish whether differences exist in capillary Hct and RBC spacing in two distinct locations within the capillary bed, in the subendo- and midmyocardium, during diastole or systole. The results of this study suggest that different geometrical conditions (e.g. RBC spacing and capillary Hct) exist at the two distinct locations of the capillary bed studied. Presumably, the oxygen supply conditions in distal portions of the capillary bed are improved by these geometrical adjustments, preventing hypoxic or anoxic conditions in the tissue, which would be detrimental to cardiac function. (Abstract shortened by UMI.)

This study has concentrated on evaluating the possible contributions of changes in liver uptake to glucose intolerance. Insulin secretion was simultaneously monitored. The level of hepatic uptake of insulin during basal conditions and after glucose loading was assessed in non-obese subjects with mild diabetes and compared to that of a healthy control group. It was demonstrated that metabolic clearance of insulin was identical under basal conditions (13.1 $\pm$ 1.5 ml kg$\sp{-1}$ml$\sp{-1}$--controls and 13.6 $\pm$ 2.0 ml kg$\sp{-1}$ml$\sp{-1}$--subjects with mild diabetes). Both the metabolic clearance rate and hepatic extraction of insulin fell by 20% in the control group following the glucose load (10.5 $\pm$ 1.5 ml kg$\sp{-1}$ml$\sp{-1}$ 139 $\pm$ 9%, n.s). However, the decrease in the group of subjects with mild diabetes was found to be approximately 50% (p 0.05). The ratios of the integrated insulin to C-peptide concentrations (in arbitrary units) showed a close relationship to the decline in the fractional hepatic extraction after glucose loading. It was found to be 0.21 $\pm$ 0.03 for the control group and 0.38 $\pm$ 0.05 for the subjects with mild diabetes (p 0.05). These ratios also demonstrated a correlation with a degree of glucose intolerance expressed as the integrated glucose concentrations for each subject (r = 0.6). The increase in the levels of circulating insulin resulted primarily from the fall in the hepatic insulin extraction, because based on the C-peptide data, there was no significant increase in the insulin secretion. The integrated insulin concentrations were 100% greater in the glucose intolerant group when compared with controls (137 $\pm$ 24 vs. 73 $\pm$ 12), while there was no significant difference in the integrated C-peptide concentrations (369 $\pm$ 51 vs. 340 $\pm$ 28). It is suggested, therefore that the decrease in insulin removal by the liver, and not hypersecretion can explain the hyperinsulinemia seen in the patients with mild diabetes which were studied here and therefore could be one of the early defects in this disease. (Abstract shortened by UMI.)