The renin-angiotensin system : interaction with other homeostatic systems in upper limb resistance vessels in man
The thesis is concerned with the interaction of the renin-angiotensin system (RAS) with other homeostatic systems in the peripheral circulation of man. The activity of the RAS and is relationship to vascular tissue ACE, the arginine-nitric oxide system, the kallikrein-kinin system and the sympathetic nervous system are examined. The activity of a new orally active angiotensin (AT1) receptor antagonist and the regulation of AT receptors in response to low circulating angiotensin II concentrations are also assessed. Forearm venous occlusion plethysmography with mercury-in-silastic strain gauges was used to define the actions of drugs and investigational agents on forearm resistance vessels. Direct infusion of agents into the left brachial artery of hypertensive patients and normal volunteers using fine-gauge steel cannulas was employed. Information on the reproducibility of this technique is detailed. The effect of antihypertensive therapy on nitric oxide dependent vasorelaxation in untreated hypertensive patients is described. Forearm arterial responsiveness to increasing doses of intra-arterial L-NMMA was assessed before and after treatment with oral enalapril, amlodipine or placebo. Normalisation of blood pressure by these antihypertensive drugs with different modes of action returns L-NMMA mediated vasoconstriction to normal. A putative neuromodulary role for angiotensin II in adrenergic neurotransmission is examined. The vasoconstrictive action of intra-arterial angiotensin II in forearm resistance vessels, predilated with phentolamine was contrasted with its effect on nonadrenergically predilated resistance vessels, with an equivalent dose of sodium nitroprusside.