Orthostatic intolerance following exposure to simulated or actual microgravity is observed following spaceflight and extended periods of bed rest, and is not always associated with simultaneous hypotension. Differential adaptation of cephalic and caudal arterial vasculatures (as a result of removal of the normal hydrostatic gradient) is proposed as a potential mechanism underlying this phenomenon. A potential role for changes to the L-arginine/nitric oxide pathway in such adaptations has been suggested, predominantly from previous in vitro studies; using an established model of simulated microgravity (head-down tilt; HDT). This thesis investigates whether findings in isolated vessels are reflected by in vivo measurements of cephalic and caudal vascular function. Using carotid or iliac artery flow normalized to mean arterial pressure as an index of cerebral or hind limb vascular conductance, autoregulatory cerebral vasodilatation in response to lower body negative pressure was found to be impaired following HDT. In addition, α¬1-adrenoceptor agonist-mediated vasoconstriction was decreased in the cerebral vasculature and increased in the peripheral and hind limb vasculature. Administration of acetylcholine or the non-selective nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) demonstrated a decreased contribution of NOS to cerebrovascular tone, but an increased contribution of NOS to peripheral vascular resistance and tone of the hind limb vasculature. Together with a lack of difference in the response to the selective inducible NOS (iNOS) inhibitor 1400W, these results suggest that differential adaptation of eNOS may account for the observed differences between control and HDT animals. Further investigation of the changes to the L-arginine/nitric oxide pathway suggest that these changes are not associated with changes in eNOS expression, but may be related to altered activity of eNOS. Furthermore, the bioavailability (as measured by pharmacokinetic half life) or the vascular effector mechanisms (as measured by the haemodynamic response to exogenously administered nitric oxide) responsible for the effects of nitric oxide were also shown to be unaffected by HDT. These findings suggest that differential adaptation of the L-arginine/nitric oxide pathway may contribute to the inability to raise total peripheral resistance and impaired cerebral autoregulation following HDT, thereby representing a mechanism of orthostatic intolerance following exposure to microgravity. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

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Diss. (sammanfattning) Linköping : Univ., 2004. / I publikationen felaktig serie: Linköping studies in health sciences. Härtill 4 uppsatser.

published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Molecular Biology / Doctoral / Doctor of Philosophy

The objective of this research is to investigate both mathematically and numerically the effects of vascular geometry upon the cellular dynamics in the endothelium and its consequence in the localisation of atherosclerosis. It is widely accepted that the formation of atherosclerotic plaques preferentially occurs at specific locations in the vasculature, such as arterial branches and bends. It has also been observed that, at the sites of plaque formation, the physiological functions of the vascular endothelium are impaired due to a defect in the production mechanisms of or diminished activities of endothelial nitric oxide (NO). From these observations, a correlation between the vascular geometry, which is effected via local haemodynamic forces, and local bioavailability of endothelial NO has been postulated. The research areas that have been involved in the investigation of atherosclerosis's localisation in the past, haemodynamics, medicine, calcium dynamics, NO kinetics and endothelial cell biology, have been studied individually, and there appears to be no integrated model to date that allows investigation of coupled haemodynamic and cellular mechanism applied in physiologically realistic model geometries. An integrated numerical model that includes these mechanisms will be developed in this research, which will lead to a further, more comprehensive understanding of the pathogenesis of atherosclerosis.

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Nitric oxide (NO) has been extensively studied due to its importance as a signaling agent. More recently, the pharmacological benefits of nitroxyl (HNO) in the treatment of cardiovascular disease, cancer, and alcoholism have been discovered.That HNO readily dimerizes complicates analysis and necessitates the use of donors. Diazeniumdiolates (NONOates), which can release either NO or HNO, are particularly attractive in this regard. NONOates from primary amines release HNO at physiological pH, and since the few existing examples have relatively short half-lives, a major research goal was to extend the lifetime range. The effect of amine structure on the lifetimes of ionic primary amine NONOates having the general structure Na(RN(H)[N(O)NO]) was unexpectedly small. This prompted the use of O2-protecting group methodology as an alternate method to stabilize donors toward decomposition. A detailed analysis of the decomposition mechanisms of a representative ionic primary amine NONOate and its O2-protected derivative is presented.NONOates were used as analytical tools to compare several commonly-used methods for detection of HNO. While these methods are used routinely for qualitative analysis of HNO, optimization for quantitative measurements was difficult. To improve method sensitivity, an HPLC assay using the fluorogenic reagent o-phthalaldehyde was developed, which may ultimately allow detection of endogenously-produced HNO.HNO donors such as cyanamide have been utilized in the treatment of alcoholism through the inhibition of aldehyde dehydrogenase (AlDH), which is critical for ethanol metabolism. Cyanamide also releases cyanide, and alternate HNO donors are thus desired for this clinical use. The efficacy of NONOates in the inhibition of AlDH was assayed in purified yeast AlDH and in mouse liver homogenate. However, efficacy was limited in a mouse model, perhaps due to a lack of selective delivery. This drug discovery project provided useful information for the future development of potentially liver-selective HNO-releasing NONOates.Together, these studies demonstrate the utility of NONOates as biomedical research tools, with synthetic modifications allowing for the modulation of decomposition profiles. As analytical tools for the development of HNO detection methods and potential pharmaceuticals in the treatment of alcoholism, NONOates provide convenience and control as donors of NO and HNO.