Calver, Alison Louise; (1993) Manipulation of the L-arginine: Nitric oxide pathway in health and disease. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Nitric oxide (NO) is a potent, newly discovered, endogenous vasodilator, synthesized stereospecifically from L-arginine in a process inhibited by NG-monomethyl-L-arginine (L-NMMA). The work described in this thesis was designed to examine the role of the L-arginine: NO system in the control of vascular tone in healthy humans, to investigate whether the L-arginine: NO system was abnormal in patients with essential hypertension or insulin dependent diabetes mellitus, and to examine the possibility that derangement of the L-arginine: NO system might contribute to the secondary hypertension associated with chronic renal failure. In the bulk of the studies, drugs were given by local infusion and responses measured in a single dorsal hand vein or in the forearm arterial bed. In the study involving patients with end stage renal failure drugs were administered systemically. In healthy volunteers, NO mediated vasodilatation accounts for approximately 40% of basal vascular tone, since L-NMMA caused a maximum fall in forearm blood flow of approximately 40%. In addition, although L-arginine at calculated plasma concentrations above 4-5mmol/l is a vasodilator, this action is shared by D-arginine. Hence the mechanism of L-arginine induced vasodilatation is unlikely to be via activation of the NO pathway through the provision of excess substrate for NO synthase. NO plays a part in the physiological response to acute increases in plasma volume, since acute plasma expansion in healthy subjects caused an increase in forearm blood flow which was abolished by local administration of L-NMMA. An endogenous inhibitor of NO synthase, asymmetric dimethylarginine, is active in the human vasculature in vivo and caused forearm blood flow to fall by approximately 40%. In patients with essential hypertension or insulin dependent diabetes the NO pathway is abnormal, since the forearm blood flow response to L-NMMA was reduced in both disorders. However, in hypertensive patients whose blood pressure had been controlled with medical therapy, the L-NMMA response was restored towards normal. The forearm response to acetylcholine was not augmented by supplying excess local L-arginine substrate in either healthy controls, or patients with hypertension or diabetes mellitus. However, in patients with end stage renal failure, a preliminary investigation showed that systemic L-arginine caused a small fall in diastolic blood pressure. Thus the supply of L-arginine may be more critical for NO synthesis in patients with renal failure than in those with essential hypertension or diabetes mellitus. The work in this thesis confirms and extends the observation that NO contributes to the control of resting vascular tone in healthy humans. In addition, it shows that abnormalities of the NO system are present in vivo in patients with a variety of human diseases. It is possible that derangements of the NO pathway may provide a mechanism to explain the development of cardiovascular complications in essential hypertension and insulin-dependent diabetes, and partly explain the mechanism behind the secondary hypertension associated with renal impairment.

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