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The Renin-Angiotensin System and Autoregulation of Cerebral Blood Flow

Sigur ١r Sigur­sson

Summary

The aim of this PhD-thesis was to elucidate the role of the renin angiotensin system (RAS) and bradykinin on autoregulation of cerebral blood flow (CBF), which keeps CBF constant during wide fluctuations in systemic blood pressure. Both experimental and clinical studies have indicated that the RAS plays a role in the modulation of this system, presumably by an effect on the larger resistance vessels. The thesis is based on two original research papers. The studies were carried out in anesthetized Sprague-Dawley (SPRD) rats , and CBF was measured by the laser-Doppler technique. The lower limit of autoregulation was calculated by a computer program. In the first study the effect of the angiotensin converting enzyme inhibitor (ACEi) enalaprilat, the ARB candesartan, and the bradykinin 2 (B2) receptor blocker Hoe 140 given intravenously on the lower limit of CBF autoregulation was studied. While ACEis cause systemic bradykinin accumulation, ARBs have no such effect, but may activate a local bradykinin system in the vessel wall. 

The following observations were made: 

1. Both the ACEi and the ARB shifted the lower limit of CBF autoregulation towards lower blood pressure levels whereas the B2 receptor blocker in itself had no effect on autoregulation. 

2. The B2 receptor blocker abolished both the effect of the ACEi and the ARB on the lower limit of CBF autoregulation. 

The conclusion of this study is that the effects of both ACEi and ARB on the lower limit of CBF autoregulation is dependent on bradykinin release. While ACEis cause systemic bradykinin accumulation, ARBs have no such effect, but may activate a local bradykinin system in the vessel wall. 

In the second study we evaluated the effect of the ARB candesartan on the modulation of CBF autoregulation in animals fed either high or low sodium diet. In this study SPRD rats were fed with chow containing either 4% sodium or 0,004% sodium for one week. All the animals had access to water ad libitum. High sodium diet would expectedly suppress the renin levels in the rats whereas low sodium intake would expectedly stimulate renin. Both the high sodium and low sodium groups were given either the ARB candesartan intravenously, or were controls. 

In this study the following observations were made: 

1. The effect of the ARB candesartan on the lower limit of CBF autoregulation seen with normal sodium chow (0,25% Na+) was not present in animals on high or low sodium chow and there was no difference in the lower limit of CBF autoregulation between the 4 groups of animals. 

2. Plasma renin concentration (PRC) as expected was raised in animals fed low sodium chow compared to the animals fed high sodium chow.

3. Under anesthesia the initial blood pressure levels surprisingly was higher in the animals fed low sodium chow than in the animals fed high sodium chow, despite signs of a reduced extracellular volume in the former group. 

The conclusion of this study is that both high- and low sodium diet annuls the effect of the ARB candesartan on the lower limit of CBF autoregulation. During anesthesia the blood pressure levels were elevated in the low sodium animals. It may be speculated that in the low sodium animals, sympathetic nervous activation overrides blockade of the RAS and its modulation on the lower limit, while in the high sodium animals, the suppressed RAS is not responsive to blockade with the ARB. A small additional study was made to demonstrate the hypotensive effect of intravenous enalaprilat and candesartan. Both drugs caused an abrupt similar fall in blood pressure below the lower limit of CBF autoregulation. This illustrates the necessity of transiently giving norepinephrine to demonstrate the autoregulatory plateau. Based on these studies it is conclude that the RAS influences autoregulation of CBF and bradykinin is involved in both the response that the ACEis and the ARBs have on the lower limit of autoregulation. The effect of the ARB candesartan on the lower limit of CBF autoregulation is annulled in rats on both high and low sodium chow.