In the present study, the roles of nifedipine-sensitive calcium channels and the endothelium in the potentiating effect of neuropeptide Y (NPY) in the rat tail artery were investigated. Contractile responses to KCl, $\alpha,\beta$-methylene ATP (mATP), and NA were compared. KCl- and mATP-induced vasoconstriction is closely linked to nifedipine-sensitive calcium channels while NA-induced vasoconstriction is not. The role of the endothelium in potentiating effects of NPY was also tested by comparing intact arterial ring segments with denuded arterial ring segments. Freshly isolated single smooth muscle cells in which the influences of the endothelium and the nerves were unequivocally eliminated were examined to verify the results of the ring segments. Contractile responses to KCl and mATP were potentiated by NPY (50 nM) while NA responses were not potentiated at 50 nM but were at 500 nM NPY. The potentiating effect of NPY was antagonized by nifedipine. The intact and denuded arteries responded similarly. The shortening of single smooth muscle cells in response to KCl and mATP was potentiated by NPY (50 nM) while the noradrenaline response was potentiated by NPY at 500 nM but not at 50 nM. (Abstract shortened by UMI.)

The purpose of this study was to determine whether the pressor response to a static handgrip exercise would be blunted if performed during or immediately following dynamic exercise. Male subjects performed one minute handgrip (HG) contractions under three conditions (1) standing at rest, (2) during the 4th to 5th min of treadmill walking exercise and (3) during recovery one min following the combined exercise. The handgrip exercises were performed at 30% and 40% of maximum voluntary contraction (MVC). The results indicated that there was a main effect of intensity, such that HG exercises performed at 40% MVC produced a significantly greater blood pressure response than HG at 30% MVC for all three conditions. The systolic response to static exercise is blunted when a HG at 30% MVC is performed during moderate dynamic exercise but not with HG contractions at 40% MVC. In addition, the systolic response to static exercise is also blunted when HG contractions at both 30% and 40% MVC are performed following dynamic exercise. Also, dynamic exercise augments the diastolic response to static contractions (30% & 40% MVC) performed following dynamic effort. (Abstract shortened by UMI.)

In this thesis we studied the influence of osmotic loading on vasopressin secretion and water intake in experimentally-induced diabetes mellitus, in the insulin deprived state as well as when treated with insulin, in order to investigate whether the osmotic drive for vasopressin release and thirst is altered in the diabetic state. Four dogs were used for the experiments to be reported. They were infused with hypertonic sodium sulfate to investigate the influence of osmotic loading on water intake and vasopressin secretion in the control, insulin-treated diabetic and diabetic conditions. Forty-eight hours of insulin depletion did not produce a change in the basal plasma vasopressin levels, even though there was a significant increase in plasma osmolality. In addition, forty-eight hours of insulin depletion did not alter the sensitivity of the osmoreceptors controlling vasopressin release and thirst. The effect of the diabetic condition on the osmotic threshold is subject to interpretation of the data. If glucose is considered an osmotically effective solute in the diabetic state, there is an upward resetting of the osmostat for vasopressin release and thirst, and a downward or leftward shift of the osmostat when glucose is not considered to be effective osmotically. The results of the present study provide evidence that the osmotic sensitivity of vasopressin release and thirst is not affected by the presence or absence of insulin. However, whether there is a true resetting of the osmostat for vasopressin release and thirst in the diabetic state depends on the assumption mode concerning glucose permeability.

In the present studies, the addition of HOCl to the bathing medium for isometrically contracting papillary rat papillary muscles induced the development of contracture. This was characterized by a decline in developed tension (DT) in combination with a rise in resting tension (RT), a prolongation in relaxation kinetics, and a sensitivity of the muscles to stimulation voltage. This response to HOCl was potentiated by preincubation with low extracellular Ca$\sp{2+}$ or the Ca$\sp{2+}$ channel antagonist nifedipine. Conversely, the response was attenuated by preincubation with high extracellular Ca$\sp{2+}$ concentrations or with the Ca$\sp{2+}$ channel agonist Bay K 8644. The development of contracture was prevented by preincubation with 1 nM ryanodine, an alkaloid compound known to alter Ca$\sp{2+}$ handling by the sarcoplasmic reticulum. In isolated whole-cell clamped cardiac myocytes, using the Ca$\sp{2+}$ fluorescence indicator Fura-2 to monitor (Ca$\sp{2+}$) $\sb{\rm i}$, HOCl induced a steady rise in diastolic (Ca$\sp{2+}$) $\sb{\rm i}$ even in the absence of extracellular Ca$\sp{2+}$. This rise in (Ca$\sp{2+}$) $\sb{\rm i}$ was prevented by pre-exposure of the cell to 5 mM caffeine, a compound known to deplete the SR of stored Ca$\sp{2+}$. In oxalate loaded SR vesicles isolated from rat hearts perfused with HOCl, both the activity of the SR Ca$\sp{2+}$-ATPase (determined by inorganic phosphate production) and the uptake of $\sp{45}$Ca$\sp{2+}$ were significantly depressed as compared to Control. I conclude that the exposure of the rat myocardium to HOCl inactivates the SR Ca$\sp{2+}$-ATPase through the oxidation of protein thiols, leading to a cytosolic Ca$\sp{2+}$ overload and the development of contracture. Cursery evidence also suggests that the Ca$\sp{2+}$ pump of the sarcolemma and the Na$\sp+$/Ca$\sp{2+}$ exchanger may also be inactivated. Subsequent exposure of the HOCl-treated myocardium to the disulfide reducing agent dithiothreitol (DTT) resulted in a restoration of contractile function, characterized by a decline in RT concomitant with a recovery of DT in the isolated papillary model, or a recovery of left ventricular end diastolic pressure and developed pressure in the perfused rat heart. We conclude that DTT was able to cross cellular membranes where it restored cellular protein thiol levels by reducing HOCl-induced disulfide formation. (Abstract shortened by UMI.)

$\sp7$Li NMR spectroscopy has been used to investigate the transsarcolemmal transport mechanisms responsible for the increase in intracellular sodium that occurs during global ischemia in the isolated rat heart. Hearts were perfused with a modified Krebs Henseleit buffer containing 78 mM sodium and 78 mM lithium, lithium being a biological congener for sodium with twice the sodium NMR sensitivity. The NMR relaxation times for lithium were investigated in the perfused heart and buffer solutions. The addition of the shift reagent, DyTTHA$\sp{3-}$, shortened the relaxation times for lithium in buffer and enabled the discrimination of intra- and extracellular lithium. Lithium moved into the myocardial cells with a rate constant (k$\sb{-1}$) of 0.068 min$\sp{-1}$, a t$\sb{1/2}$ of 10.3 min and an initial rate of increase of 5.27 mM/min, while lithium noved out of the heart with a k$\sb{-1}$ of 0.062 min$\sp{-1}$, a t$\sb{1/2}$ of 11.2 min and an initial rate of 4.83 mM/min. Lithium equilibrated in the heart with equal concentrations on either side of the sarcolemma, not in equilibrium with its electrochemical gradient. Perfusion with the low-sodium, lithium-containing buffer had a positive inotropic effect on the heart with no effect on the steady state levels of the myocardial high energy phosphates. The myocardial rate pressure product increased by 114% while the ATP and PCr concentrations, measured using $\sp{31}$P NMR spectroscopy, varied by less than 8%. ICP-AES analysis of hearts showed that as lithium accumulated in the cells, it displaced both sodium and potassium. Finally, intracellular lithium increased during myocardial ischemia with a linear rate of 1.34 mM/min, similar to the rate of increase of intracellular sodium during ischemia. This increase was completely blocked by the Na$\sp+$/ H$\sp+$ exchange inhibitor, amiloride. (Abstract shortened by UMI.)

The metabolic role of chronically elevated cortisol in otherwise unstressed rainbow trout, Oncorhynchus mykiss, was examined. Fish were fitted with mini-osmotic pumps which maintained plasma cortisol levels at approximately 100 or 200 ng $\cdot$ mL$\sp{-1}$ for ten days. Plasma metabolites, liver enzyme activities, liver glycogen content, metabolic flux in isolated hepatocytes and alanine turnover were investigated. Plasma glucose, lactate and protein levels were unaffected by ten days of cortisol administration, despite a significant elevation in plasma cortisol. Plasma amino acids in cortisol treated fish (1023.8 $\pm$ 90.7 $\rm\mu g\cdot mL\sp{-1})$ were significantly elevated compared to shams $\rm(716.7\pm68.5\ \mu g\cdot mL\sp{-1})$ after nine days. Liver glycogen content was significantly reduced by cortisol treatment. The activities of the liver enzymes assayed were unchanged; likewise the fluxes of radioactive substrates to radiolabelled CO$\sb2,$ glucose, and protein in isolated hepatocytes were unaffected in trout with chronically elevated cortisol compared to shams. Both the caloric and water contents of white muscle were unaffected by chronically elevated circulating cortisol levels. The cortisol treatment did not alter the turnover of alanine. These data do not support the purported role of cortisol as a glucocorticoid in rainbow trout. While chronically elevated cortisol may increase the supply of plasma amino acids, the hormone does not appear to alter the manner in which these potential gluconeogenic substrates are metabolized. The absence of other stressors may be partially responsible for the differences between this study and others in the literature.

The purpose of this study was to determine if the training effects on lactate threshold (LT) and maximal oxygen consumption (VO$\sb2$max) are specific to musculature involved in training or if there is evidence of a general training effect, such that adaptations are also found during exercise with untrained muscle groups. Seven moderately active male students participated in an eight week progressive endurance training program that involved leg cycling at specific intensities above and below the pre-training LT to give a total of 30 minutes of training above LT three times per week. All subjects were tested before and after training for LT and VO$\sb2$max while performing leg cycling and arm cranking exercises. VO$\sb2$max showed a significant increase during both leg cycling and arm cranking exercise following training. Conversely, increases in both absolute and relative LT were confined to leg cycling exercise only. It is suggested that peripheral adaptive responses of oxidative capacity within the trained muscles are primarily responsible for the specificity of the LT response, while cardiovascular adaptations were beneficial to VO$\sb2$max of both of the muscle groups tested. Furthermore, the significant improvement in relative LT during leg cycling and of VO$\sb2$max to both arm and leg exercise suggests that adaptive responses of LT and VO$\sb2$max to training are not governed by the same physiological processes. Therefore, it was concluded that, for the conditions of this experiment, the concept of specificity of training applies to LT but not to VO$\sb2$max when comparing exercise modalities which involve separate musculature.

Ferrets received whole-body irradiation (5 Gy, gamma). At different times post-irradiation (PIRR, 2, 24, and 48 hours), measurements of fluid and electrolyte fluxes, and of the blood-to-lumen clearance of $\sp{51}$Cr-EDTA, were compared between in situ perfused loops of jejunum and ileum. Intestinal permeation of $\sp{51}$Cr-EDTA was increased (4x control) in both the jejunum and ileum at 2 hours PIRR. At 24 hours PIRR, $\sp{51}$Cr-EDTA permeation was the same as control. At 48 hours PIRR, jejunal permeation of $\sp{51}$Cr-EDTA was not statistically different from control animals, whereas in the ileum, $\sp{51}$Cr-EDTA permeation was increased 10x control. Absorption of luminal fluid was abolished 2 hours PIRR in the ileum. Sodium and chloride fluxes were unaffected by radiation exposure, but at 48 hours PIRR there was a significant secretion of potassium in the ileum. Diarrhea rarely occurred after the first hour post-irradiation. Serotonin, acting via 5-HT$\sb3$ receptors, was investigated as a possible mediator of radiation-induced alterations in intestinal permeability. Pretreatment with the 5-HT$\sb3$ antagonist and anti-emetic BRL 43694 significantly reduced the severity of radiation-induced vomiting. It offered some therapeutic benefit to radiation-induced diarrhea. However BRL 43694 pretreatment had no effect on intestinal permeability. (Abstract shortened by UMI.)

The purpose of this study was to compare the effects of acute exercise on plasma testosterone, LH, FSH and prolactin. In addition, the effects of LH, FSH, Prolactin and physical fitness on testosterone levels were investigated. The serum levels of testosterone, LH, FSH and prolactin were measured at rest, immediately after, 30 minutes and 60 minutes after acute exercise, which comprised of running on a treadmill at 70% of the subjects' previously determined MVO$\sb2$ for 20 minutes. Trained (n = 12) and untrained (n = 9) male subjects were tested. Mean testosterone levels increased significantly (p 0.01) in both groups immediately after cessation of exercise, independent of the effects of LH, FSH and prolactin. Testosterone responses to exercise were significantly (p 0.01) greater in trained (45% increase) than in the untrained (19.5% increase) group. In addition, basal levels of testosterone were significantly lower (p 0.01) in the trained group compared to the untrained group.

In the present work, a reproducible cell culture system using adult rat atrial cardiocytes was developed to study ANF processing. Freshly isolated atrial cardiocytes stored high molecular weight ANF (38.0 $\pm$ 4.5 pg/$\mu$g of DNA) and released almost exclusively (83.3% $\pm$ 6.7%) low molecular weight ANF, at an average rate of 12 pg/hour/$\mu$g of DNA. The cell content and the rate of release of ANF decreased over 15 days in culture to 3.9 $\pm$ 1.2 pg/$\mu$g of DNA and 0.32 pg/h/$\mu$g of DNA $\pm$ 0.08 respectively and 62.7% $\pm$ 6.3% of the released peptide was of a low molecular weight. Cultures of non-cardiocytes, superfused with exogenous proANF, did not process the peptide. There was no correlation between the changes in cell population and the reduction in processing. Therefore, atrial non-cardiocytes are not involved in ANF processing. The results presented in this work vary from other reports which found that ANF processing in cultures is absent. The discrepancies may be due to differences related to serum-free culture conditions versus serum supplemented cultures. This suggests that factors present in the serum may be responsible for maintaining ANF processing activity in culture. (Abstract shortened by UMI.)