Aging is associated with increases in regional and systemic vascular resistance and arterial blood pressure. One possible mechanism through which these age-associated alterations occur is enhanced vasoconstrictor responsiveness, or alterations in the structural properties of the resistance vasculature. We hypothesized that stiffness and vasoconstriction would be greater in skeletal muscle arterioles from old rats, and that endurance exercise training would ameliorate the associated with aging alterations. METHODS: Young sedentary (YS; 4 months), old sedentary (OS; 24 months), young trained (YT) and old trained (OT) male Fischer 344 rats were used. Training modality was treadmill exercise at 15 m/min up a 15o incline, 5 days/wk for 12wks. Skeletal muscle first-order arterioles were isolated for in vitro experimentation. Intraluminal diameter was measured in response to the cumulative addition of endothelin-1, norepinephrine, KCl, and isoproterenol. Stiffness was measure by examining the arterioles' stress and strain relation to increased luminal pressure in Ca++ free solution. RESULTS: Skeletal muscle arterioles had augmented vasoconstriction to endothelin-1 and norepinephrine. Adrenergic vasodilation was diminished in aged rat arterioles. Stiffness increased with age. Exercise training ameliorated the age-associated changes in stiffness and norepinephrine vasoconstriction. Exercise training did not alter endothelin-1 vasoconstriction or adrenergic vasodilation. CONCLUSIONS: These findings suggest that enhanced vascular sensitivity to vasoconstrictors and increased arteriole stiffness may play a role in the increase in skeletal muscle and systemic vascular resistance and, thus, contribute to the elevated blood pressure which occurs in aging humans. These results also demonstrate some of the cardioprotective effects of exercise training.

The transport of glucose across the plasma membrane is a fundamental mechanism to provide cells with its basic requirements for energy yielding processes. It is also vital for clearing glucose from blood into tissues, a process normally stimulated by the hormone insulin in mammals. The sympathetic nervous system, normally activated during stress, also regulates glucose transport. The sympathetic neurotransmitter noradrenaline, acts on the family of adrenergic receptors (ARs). An important subtype of the AR family is the β-AR, which is subdivided into the β1, β2, and β3-AR. Glucose is transported across the plasma membrane by the family of glucose transporters (GLUT1-12, and HMIT). In this thesis, I have investigated the β-AR regulation of GLUT1 and 4, and glucose uptake, in skeletal muscle cells and brown adipocytes in culture, model systems which correspond to metabolically active, sympathetically innervated and insulin-sensitive tissues. In brown adipocytes, activation of the β3-ARs induced the expression of GLUT1, resulting in a large increase of glucose uptake. In skeletal myotubes, we postulate there is a possible mechanism where β2-ARs can regulate the intrinsic activity of GLUT1. We found that insulin signaling, but not β-adrenergic signaling, mediated glucose uptake through class I phosphatidylinositol 3-kinase (PI3K). The β-adrenergic signaling to glucose uptake appeared to involve a PI3K related kinase (PIKK), in both skeletal myotubes and brown adipocytes. Furthermore, the increase of glucose uptake by β-ARs in brown adipocytes is partially mediated by AMP-activated protein kinase (AMPK). However, in an artificially constructed system, with cells expressing GLUT4 and β2-ARs, both insulin and β-adrenergic activation translocated GLUT4 and increased glucose uptake. These results show that β-adrenergic signaling increase glucose uptake by regulating glucose transporters through distinct pathways, in skeletal myotubes and brown adipocytes.

Mechanical unloading and food restriction (FR) are leading causes of bone loss, which increase the risk of fracture later in life. Leptin, a 16kDa cytokine like hormone principally produced by white adipocytes, may be involved in bone metabolism with physiological or mechanical changes causing bone loss. The hypotheses of the first study were aimed at determining if serum leptin is reduced by unloading or FR. The serum leptin level reduced by unloading or by global FR, is associated with the decline in bone formation rate. It was conjectured that decreased serum leptin may be due to reduced adipocyte number/size and/or sympathetic nervous system (SNS) activation of betaadrenoreceptors with unloading or FR, inhibiting the release of leptin from adipocytes. In the second experiment, we tested whether leptin or beta-adrenoreceptor blockade attenuates bone loss during unloading and whether such an effect due to beta blockade is associated with changes in serum leptin level. Beta-blockade mitigated unloading induced reduction in serum leptin and also beta blockade was as effective as leptin administration in mitigating a reduction in cancellous bone mineral density with unloading through both stimulation of bone formation and suppression of resorption. It was previously demonstrated that energy restriction (ER) is a major contributor to the bone loss during global FR. In the third study, we tested whether beta- blockade attenuates bone loss during ER and whether such an effect is associated with changes in serum leptin level and leptin localization in bone tissues. Beta blockade attenuated the ER induced reduction in serum leptin level, cancellous bone mineral density and bone formation rate, and also abolished the ER induced increase in bone resorption. Reduction in leptin expression in bone marrow adipocytes observed with ER was attenuated by beta-blockade. Reduction in the number of cells (bone lining cells, osteocytes and chondrocytes in cartilage) which are stained positive for leptin was also attenuated by beta-blockade. Collectively, these data identify circulating leptin effects on preventing bone loss during mechanical unloading or energy restriction. Also beta blockade is associated with mitigating reduction in serum leptin and subsequently with mitigating reduction in bone mass with unloading or ER.

Lipopolysaccharide (LPS) is the toxic chemical component of the cell wall in all gram-negative bacteria which can activate NF-£eB, also stimulate immune cells to release cytokines. These pro-inflammatory mediators induce systemic acute inflammation, multiple organs dysfunction syndrome¡]MODS¡^and sepsis. LPS could increase the permeability of capillary, and cause the acute formation of numerous endothelial gaps among venular endothelial cells that result in extensive plasma leakage in the inflammatory tissues. Plasma leakage from microvasculature is a hallmark of inflammation. Mammalian intestines have many goblet cells that synthesize mucus and discharge it into the intestinal lumen. The mucus film that covers the surface epithelium facing the lumen of digestive system, is an immune defense that can prevent gastrointestinal epithelium from chemical and physical damage and act as a lubricant. Goblet cells can discharge mucins in response to a wide variety of stimuli, including irritant gases, nerve activation, reactive oxygen species, inflammatory mediators. This study was aimed to investigate : (1) The degree of plasma leakage and goblet cell secretion in the small intestine of rats after an intravenous injection of a high dose of LPS (15 mg/kg), (2) The effect of £\2-adrenergic receptors antagonist, urethan, on endotoxin-induced plasma leakage and goblet cell secretion. For the study of plasma extravasation in small intestine during endotoxemia, India ink was used as the tracer to mark the inflamed leaky microvessels. The sections of the small intestine 3£gm in thickness were stained with Alcian blue and periodic acid-Schiff reagent to detect glycoproteins of goblet cells. Our results showed that LPS not only caused an increase in plasma leakage but also triggered degranulation of many goblet cells in the small intestine. LPS augment the expression of plasma leakage and mucus secretion for three times. A large amount of extracellular mucus was accumulated between intestinal villi after LPS stimulation. Pretreatment with urethan, the £\2-adrenergic receptor antagonist, significantly inhibited plasma leakage by 40-50% and goblet cell secretion by 25-30% induced by endotoxin. It is concluded that the plasma leakage and goblet cell hypersecretion induced by endotoxin shock was outstanding and associated with activation of £\2-adrenergic receptors.

Aging is associated with increases in regional and systemic vascular resistance and arterial blood pressure. One possible mechanism through which these age-associated alterations occur is enhanced vasoconstrictor responsiveness, or alterations in the structural properties of the resistance vasculature. We hypothesized that stiffness and vasoconstriction would be greater in skeletal muscle arterioles from old rats, and that endurance exercise training would ameliorate the associated with aging alterations. METHODS: Young sedentary (YS; 4 months), old sedentary (OS; 24 months), young trained (YT) and old trained (OT) male Fischer 344 rats were used. Training modality was treadmill exercise at 15 m/min up a 15o incline, 5 days/wk for 12wks. Skeletal muscle first-order arterioles were isolated for in vitro experimentation. Intraluminal diameter was measured in response to the cumulative addition of endothelin-1, norepinephrine, KCl, and isoproterenol. Stiffness was measure by examining the arterioles' stress and strain relation to increased luminal pressure in Ca++ free solution. RESULTS: Skeletal muscle arterioles had augmented vasoconstriction to endothelin-1 and norepinephrine. Adrenergic vasodilation was diminished in aged rat arterioles. Stiffness increased with age. Exercise training ameliorated the age-associated changes in stiffness and norepinephrine vasoconstriction. Exercise training did not alter endothelin-1 vasoconstriction or adrenergic vasodilation. CONCLUSIONS: These findings suggest that enhanced vascular sensitivity to vasoconstrictors and increased arteriole stiffness may play a role in the increase in skeletal muscle and systemic vascular resistance and, thus, contribute to the elevated blood pressure which occurs in aging humans. These results also demonstrate some of the cardioprotective effects of exercise training.

Thesis--M.D., University of Hong Kong, 1982.

Thesis--Ph. D., University of Hong Kong.

No description available.

No description available.

No description available.