Thesis (Ph.D.)--University of Delaware, 2009. / Principal faculty advisor: William B. Farquhar, Dept. of Health, Nutrition, & Exercise Sciences. Includes bibliographical references.

Optimal effect of medical treatment requires patients' adherence to those treatments, which plays a even greater role than the medical decision made by physicians. With the epidemiological dynamic evolving, chronic disease becomes the major burden of healthcare, such as AIDS, hypertension, COPD, tuberculosis, asthma, epilepsy, schizophrenia, depression and diabetes, which make the adherence especially medication adherence a sightworthy issue because the risk of poor adherence with the complexity and duration of treatment with both of them are inherent to chronic diseases. Among patients with hypertension, medication nonadherence contributes to poorly controlled blood pressure as an significant yet unrecognized role. With the mediator of negative outcomes of further development of vascular disorders, including stroke, heart failure, renal insufficiency and coronary diseases, medication nonadherence to antihypertensives become the root of all devil in terms of healthcare. In terms of healthcare utilization, it costs approximately 396 to 792 million dollars per year and creates a significant burden. Effect factors for medication nonadherence among hypertension patients include knowledge about hypertension, beliefs about hypertension, perceived beliefs about medication, inadequate self-management behaviors, physician-patient relationship, social support and healthcare policy. The achievements of current single level interventions are not satisfactory, therefore multiple level interventions are calling for attention.Everyone in the healthcare system are responsible to alter the situation. A comprehensive healthcare system that consummates all the effect factors is the effective and efficient solution. / published_or_final_version / Public Health / Master / Master of Public Health

Hypertension is one of the most common chronic medical problems around the world and it is an important public health challenge. Hypertension can lead to cerebrovascular disease, ischemic heart disease, renal failure, myocardial infraction or stroke. According to the statistics from the Census and Statistics Department, it revealed that the ratio of people with known hypertension was about 11.0% in 2011/12. Exposure to stress has been evidenced by different studies as a risk factor for hypertension. Stress included occupational stress, stressful events from the social environment, and low socioeconomic status. Progressive muscle relaxation therapy plays an important role in controlling hypertension apart from the traditional management such as the use of medication or diet control. Objective The objectives of the translational nursing research are to develop an evidence- based guidelines for hypertension patients to maintain an optimal blood pressure level. Methods 5 electronic databases including Medline (Ovid SP) (1950–Aug week 4 2012), Pubmed, ISI web of knowledge (1956- Aug 2012) , The PsycINFO database (1980- Aug 2012) and Cochrane Library (1950- Aug 2012) are used for systematic search of literature. Five suitable are identified while three studies are randomized controlled trials and two are quasi-experimental design. The 5 studies were summarized and a table of evidence is formed. The Scottish Intercollegiate Guidelines Network (SIGN) checklist was used for critical appraisal. The findings indicate that progressive muscle relaxation exercise has significant effects in maintaining optimal blood pressure for hypertension patients. In order to implement the evidence- based protocol, an implementation plan is developed. A pilot test is implemented before the full- scale implementation of innovation. An evaluation plan is developed in order to assess the effectiveness of the program. Conclusion There are all together 8 recommendations are made in this protocol which based on the 5 chosen studies. According to SIGN’s “Grades of Recommendation”, all 8 recommendations in the protocol are graded as “A”. The innovation is proposed to implemented at an outpatient clinic for the hypertension patients. The progressive muscle relaxation exercise would be last for 6 weeks, which is effective in maintaining optimal blood pressure in hypertension patients. In the views of the transferability of the evidences, the feasibility and the cost-effectiveness of the program, the proposed program is considered as rewarding to carry out at the outpatient clinic in Hong Kong. / published_or_final_version / Nursing Studies / Master / Master of Nursing

This thesis investigates the involvement of the non-neuronal cholinergic system in endothelium-dependent relaxations and the impact of hypertension on the function of this system. In Study1 the contribution of nicotinic receptors (nAChRs) to endothelium-dependent relaxations evoked by acetylcholine was examined. Both muscarinic (mAChRs) and nAChR were expressed in the aortic endothelium of spontaneously hypertensive (SHR)and Wistar-Kyoto rats (WKY). However, isometric tension measurements showed that, the muscarinic antagonist atropine abolished the relaxations to acetylcholine in WKY aortae, but only partially inhibited those in SHR aortae. While the nicotinic antagonist mecamylamine inhibited the remaining response in SHR aortae, it did not significantly affect the response solely in either SHR or WKY preparations. Hence, nAChRs mediate endothelium-dependent relaxations to the acetylcholine only in the SHR aorta and only when mAChRs are inhibited. Nicotine, the prototypical nicotinic agonist, also induced endothelium-dependent relaxations in both SHR and WKY aortae which were due to activation of α7-nAChRsbut not by mecamylamine-sensitive α3-nAChR. The acetylcholine-induced, atropine-insensitive relaxations and that to nicotine both involve the PI3K pathway. Thus, activation of nAChRscan contribute to acetylcholine-induced endothelium-dependent relaxations via PI3K signaling pathway in aortae of hypertensive animals. Study 2 examined the involvement of non-neuronal cholinergic system in endothelium-dependent relaxations. Isometric tension measurements showed that mild hypothermia (37℃–31℃) induced endothelium-dependent relaxations, which were reduced by atropine, tubocurarine, acetylcholinesterase (enzyme responsible for acetylcholine degradation), bromoacetylcholine (inhibitor of acetylcholine synthesis), hemicholinium-3 (inhibitor of choline uptake) and vesamicol (inhibitor of acetylcholine release) in SHR but not in WKY aortae, indicating that the non-neuronal cholinergic system is involved in mild hypothermia-induced endothelium-dependent relaxations. Compared with WKY, SHR preparations expressed similar levels of acetylcholinesterase and choline acetyltransferase, but lesser vesicular acetylcholine transporter, located mainly in the endothelium. A choline/acetylcholine assay showed that, mild hypothermia increased the uptake of choline by the endothelium of SHR,but not WKY, aortae from extracellular environment for acetylcholine production. To define possible different mechanisms employed by SHR and WKY endothelial cells, the involvement of transient receptor potential (TRP)channels in mild hypothermia-induced response were examined using selective pharmacological inhibitors of different subtypes of TRP channels, namelyAMTB (TRPM8 antagonist),HC-030031 (TRPA1 antagonist)and HC-067047 (TRPV4 antagonist).The results suggest that both TRPM8 and TRPA1 play a role in the response to mild hypothermia in the WKY aorta; however, in the SHR aortaTRPV4,but not TRPA1, channels are activated by mild hypothermia. Moreover, the observation that the mild hypothermia-induced increases in cyclic guanosine monophosphate (cyclic GMP)and choline uptake were inhibited by HC-030031 in WKY but by HC-067047 in SHR aortae further indicate that in the hypertensive strain compensatory TRPV4 activation can make up for the loss of TRPA1-mediated NO production, and that the endothelial cells of the hypertensive animal utilize TRPV4 channels to activate the production of endogenous acetylcholine in response to mild hypothermia. Taken in conjunction, the results reported in this thesis together suggest that hypertension alters the function of the non-neuronal cholinergic system (e.g. n-AChR sensitivity or acetylcholine production) to modulate endothelium-dependent relaxations. / published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

Hypertension leads to vascular complications including endothelial dysfunction, heart failure and stroke. The purpose of the present studies was to investigate the chronic and acute impact of high pressure on vascular responsiveness. In Study I, isometric tension measurements demonstrated that contractions to phenylephrine, in the presence of indomethacin (inhibitor of cyclooxygenase), were smaller in aortae of spontaneously hypertensive rats (SHR) with, than in those without, endothelium, while they were comparable in such preparations of normotensive Wistar-Kyoto rat (WKY); the difference in SHR aortae was not affected by L-NAME [inhibitor of nitric oxide synthase (NOS)]. This endothelium-dependent, NOS-independent inhibition of phenylephrine-induced contraction was greater in older SHR (36 versus 18 weeks), and abolished by NO scavengers and ODQ (inhibitor of soluble guanylyl cyclase). It was observed not only in the presence of indomethacin but also apocynin (antioxidant), but inhibited by diphenyleneiodonium (inhibitor of cytochrome P450 reductase). These results suggest that the endothelium-dependent, eNOS-independent inhibition is caused by NO produced by cytochrome P450 reductase in the endothelium of the SHR aorta. Study II investigated the mechanisms underlying the reduced contractions to prostaglandin E2 [agonist of prostaglandin E2 and thromboxane-prostanoid (TP) receptors] by a previous exposure to phenylephrine (agonist of α1-adrenoceptor) in the aortic smooth muscle of the SHR. This inhibition induced by the pre-activation of α1-adrenoceptor was augmented in aortae of older SHR (36 versus 18 weeks) and was not present in WKY preparations. Pre-exposure to the protein kinase C (PKC) activator, phorbol 12,13-dibutyrate, also inhibited subsequent contractions to prostaglandin E2 in SHR aortae. Inhibition of PKC by calphostin C abolished the effect of pre-exposure to phenylephrine. The mRNA expressions of PKC isoforms differed in WKY and SHR smooth muscle. These experiments suggest that in the SHR but not the WKY aorta, α1-adrenergic activation causes heterologous desensitization of TP receptor through activation of a specific PKC isoform(s). In Study III, experiments were performed in a pressure myograph to determine whether or not acute elevation of transmural pressure in the isolated carotid artery of adult mouse (10-12 weeks) impairs endothelium-dependent dilatation by increasing angiotensin II expression or by directly activating AT1 receptors. Transient exposure of arteries to increased pressure (150 mmHg, three hours) inhibited endothelium-dependent, NO-mediated dilatations to acetylcholine, but did not affect responses to the NO donor DETA-NONOate. Inhibiting angiotensin II signaling or angiotensin converting enzyme prevented the impairment of endothelium-dependent dilatation by elevated pressure. Elevated pressure increased the expression of angiotensinogen [precursor of angiotensin II]. Thus, exposure of carotid arteries to elevated pressure leads to local release of angiotensin II, which activates AT1 receptors to cause endothelial dysfunction. In summary, chronic increased pressure increased the endothelial NO release produced by cytochrome P450 reductase from nitrate and developed the heterologous desensitization of TP receptor caused by PKC in SHR aorta. Acute increased pressure impaired endothelium-dependent NO-mediated vasodilatation by activation of local angiotensin system in adult mouse carotid artery. These processes likely contribute to the pathogenesis of hypertension-induced vascular dysfunction and organ injury. / published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

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published_or_final_version / Medicine / Master / Master of Research in Medicine

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