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Title: The role of nitric oxide in childhood hypertension and a critical analysis of the measurement and interpretation of blood pressure
Author: Goonasekera, Chulananda D. A.
ISNI:       0000 0001 3505 332X
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1997
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Nitric oxide, synthesised continuously from the amino acid L-arginine by the constitutive nitric oxide synthase enzyme of the vascular endothelium maintains a constant vasodilator tone. This basal release of nitric oxide, that help maintains blood pressure at normal level, was believed to be diminished in adults with essential (primary) hypertension but no data was available on its role in childhood hypertension. Raised plasma levels of naturally occurring nitric oxide synthase inhibitors (arginine analogues) had been identified in some cases of pregnancy induced hypertension and in renal failure but their physiological importance was uncertain. Experimentally, however, oral administration of nitric oxide inhibitors was known to produce hypertension. The initial investigations described in Part A of this thesis demonstrate raised plasma levels of arginine analogues, particularly asymmetric dimethyl arginine (ADMA) in children with hypertension. Subsequent experiments in vitro on mice aortic rings confirm that the concentrations of ADMA detected in human plasma may be sufficient to cause an alteration in vascular tone, hence blood pressure. Although a concomitant reduction in nitric oxide generation was expected in these subjects, its assessment indirectly by estimating plasma levels of nitrate appear to suggest otherwise. Additionally higher levels of plasma ADMA was associated with a lower plasma renin activity in these subjects, a possible but hitherto unknown negative feed back mechanism for renin dependent blood pressure control. Furthermore, raised levels of ADMA were shown to be associated with raised plasma levels of the adhesion molecule VCAM-1, a known intermediary in the development of atheroma. This may have wider implications in terms of the development of atheroma in other conditions with raised plasma arginine analogues. Despite the known influence of these plasma agents on blood pressure, none correlated with blood pressure itself in these subjects. On investigation of this observation, a second theme evolved; i.e. factors causing errors in interpretation of blood pressure and its measurement. This is described in Part B that includes a critical analysis of current approved methods of blood pressure measurement and clinical validation of new blood pressure monitors for use in children. This thesis therefore provides the first insight into the role of nitric oxide, in particular its inhibitor ADMA in childhood hypertension especially in the presence of renal impairment. This molecule is at least likely to be involved in modulation of renin angiotensin system and endothelium mediated complications such as atheroma in hypertensive children, besides its prominent role in altering vascular tone and natriuresis. Demonstration of a link between ADMA and blood pressure itself in vivo, however, is difficult due to the complexity of the cardiovascular regulation and covert errors in blood pressure measurement and interpretation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Physiology