Studies on the Effects of Ageing on the Physiology and Pharmacology of the Autonomic Nervous System

[摘要] The work described in this thesis involved investigations into the effect of ageing on the physiology and pharmacology of the sympathetic nervous system. Noradrenaline is the principal neurotransmitter of the peripheral sympathetic nervous system. It is found in increased concentration in the plasma of elderly people. The reasons for this increase could be: [1] An increase in the spillover of noradrenaline from the nerve terminal, [2] A reduction in clearance of noradrenaline from the plasma, and [3] a combination of both. The rates of noradrenaline release into, and clearance from the circulation were measured in two groups of young and elderly volunteers. The resting noradrenaline concentrations were higher in the elderly subjects. There was no change in the rate of clearance of noradrenaline between the groups but the elderly had a higher rate of noradrenaline spillover into the circulation. The activity of the cardiac beta-1-adrenoceptor reduces with age. There was no corresponding information concerning the activity of the alpha-1-adrenoceptor. The second study described in this thesis examined the responses of human isolated arteries to noradrenaline. This provided evidence of the sensitivity of the alpha-1-adrenoceptor free from the complicating influence of the baroreceptors. There was no change in the sensitivity of this receptor across a wide age range. Prazosin is an alpha-1-adrenoceptor antagonist. It has been used in the treatment of hypertension, heart failure and prostatism. The third study examined the pharmacokinetics of prazosin in two groups of young and elderly volunteers. Prazosin was administered intravenously and orally on two separate days. By this means, a measure of the drug bioavailability and clearance may be measured. In the elderly, there was no change in the rate of clearance of prazosin but there was a reduction in bioavailability. The fourth study reported in this thesis concerned a combined examination of the pharmacokinetics and pharmacodynamics of three antihypertensive drugs: Trimazosin, an alpha-1-adrenoceptor antagonist; acebutolol, a beta-1-adrenoceptor antagonist; and tolmesoxide, a non-specific vasodilator. This study not only provided information about the relative effect of age on the clearance of these drugs but also on the effect of age on the sensitivity to the drugs (as measured by fall in systolic blood pressure per unit of plasma drug concentration). There was an increased effect of trimazosin with increasing age. This was due to a reduction in drug clearance. The sensitivity of the alpha-1-adrenoceptor remained unchanged. There was a reduced effect of acebutolol with increasing age. This was due to an decrease in the sensitivity of the beta-1-adrenoceptor, the drug clearance remaining unchanged. There was no change in the sensitivity or clearance of tolmesoxide with age. The increase in the plasma concentration of noradrenaline and the lack of change in the sensitivity of the alpha-1-adrenoceptor provides evidence for the suggestion that alpha-1-adrenoceptor antagonists might be useful in the treatment of hypertension in the elderly. Prazosin is limited by a short duration of action and by a first dose hypotensive effect. Doxazosin, which is chemically related to prazosin, has a longer half life, and the potential for once daily dosing. The last study in this thesis describes the effect of doxazosin on elderly hypertensive patients. Doxazosin produced statistically significant, but modest, falls in diastolic pressure 24 hours post dose. There was no change in systolic pressure.

[发布机构] University:University of Glasgow

[关键词] Neurosciences, Pharmacology, Physiology