| Summary: | The work embodied in this thesis was designed to explore the interaction between the renin -angiotensin -aldosterone system (RAAS) and the autonomic nervous system. It was stimulated by the observations that the neurohormonal suppression of the RAAS by ACE inhibitors in chronic heart failure (CHF) is inadequate, and that high residual levels of circulating aldosterone have been shown to have detrimental autonomic modulating effects independent of angiotensin II in experimental models. The effects of aldosterone blockade with spironolactone therapy were examined in CHF patients already established on ACE inhibitors. It was observed that spironolactone has beneficial parasympathomimetic properties, improving heart rate variability and reducing heart rate, particularly during the early morning hours of the day when ACTH -induced aldosterone secretion is maximal. The interaction between the RAAS and the parasympathetic tone was explored further in a series of normal volunteer studies. Although the effects of ACE inhibitors are well recognised, not much is known about the parasympathomimetic properties of direct angiotensin II or aldosterone receptor antagonism. In this thesis, it was demonstrated that losartan, an angiotensin II receptor antagonist, and enalapril, an ACE inhibitor, were equally effective in improving the vagally-mediated baroreflex response in salt depleted normotensive subjects. It was also demonstrated that direct intravenous aldosterone administration impaired the baroreflex response to vasopressor agents in healthy subjects. The observed vagomimetic effects of aldosterone blockade may have important therapeutic implications, suggesting the possibility that spironolactone may have anti -ischaemic or anti -arrhythmic properties. However, aldosterone blockade did not appear to have any significant impact on either autonomic tone or ischaemic events when administered to patients with ischaemic heart disease but preserved LV function. The reasons for the latter remain unclear but may reflect differences in disease -state (less neurohormonal activation, and a larger proportion of these patients was established on beta -blockers -which may influence autonomic tone - and only a minority was taking concomitant ACE inhibitors, compared to the CHF cohort). In CHF however, spironolactone was shown to improve QT dispersion, a surrogate marker of arrhythmic activity and sudden cardiac death. Mechanisms in which aldosterone may contribute towards dispersion of the QT intervals on the electrocardiogram are probably multifactorial. Aldosterone increases cardiac afterload (by increasing vascular tone and potentiating vascular smooth muscle hypertrophy) and it is demonstrated that cardiac afterload would increase QT dispersion through mechano- electrical feedback. Vagal tone modulation itself however did not contribute towards QT dispersion. These studies demonstrate how inextricably linked the RAAS and the autonomic nervous system is. In particular, the detrimental autonomic effects of aldosterone in CHF have been highlighted. The findings of these studies highlight possible mechanisms and provide valuable insights as to why further therapeutic mileage is gained by the addition of an aldosterone antagonist in CHF patients who have already been established on ACE inhibitors.
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