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The effect of AT1-receptor blockade on sympathetic activity in healthy humans and in patients with essential hypertension during restrictions in sodium intake.

Henrik Vase

Summary

Blockade of the angiotensin II type 1 receptor (AT1-receptor) has proven beneficial in several cardiovascular diseases. In various animal experiments AT1-receptor blockers possess sympathoinhibitory abilities that may contribute to the benefits of this treatment. This might be the case inessential hypertension as activation of the sympathetic nervous system (SNS) appears to play a role at several stages – from the initiation and sustaining of the elevated blood pressure and induction of insulin resistance to the development of organ damage.

However, in humans this effect of the AT1-receptor antagonists has been far more difficult to demonstrate. Studies evaluating the short term effect of an AT1-receptor antagonist in healthy humans show minimal or absent anti-adrenergic effects or even increased sympathetic outflow. Studies in patients with essential hypertension have also failed to demonstrate this effect. In fact a sympatho-inhibitory effect of AT1-receptor blockade seems only to be present after long term treatment during conditions with high pre-existing levels of sympathetic activity such as heart failure and chronic kidney disease.

Reduction in dietary sodium content is part of the recommended lifestyle changes in the management of arterial hypertension, but moderate sodium restriction may adversely increase the activity of both the renin-angiotensin system and the sympathetic nervous system. Accordingly, sodium restriction is a likely and clinically relevant condition during which blockade of the AT1- receptor might exert anti-adrenergic actions. No human data are available on this issue. The hypothesis tested in the two main studies in relation with the present thesis is therefore that a sympatho-inhibitory effect of AT1 receptor blockade might be present in healthy subjects and in patients with essential hypertension during moderate sodium restriction. All studies were conducted as randomized, double-blinded, placebo-controlled and cross-over studies. Plasma levels of noradrenaline, systemic heamodynamics and renal tubular sodium handling were measured as indices of the activity of the sympathetic nervous system

The purpose of the first study was to evaluate the usefulness of the direct arteriolar dilator dihydralazine for an arterial baroreflex mediated activation of the sympathetic nervous system (that was to be conducted in the two main studies after administration of an AT1-receptor blocker or placebo). Dihydralazine caused dose-dependent decreases in blood pressure and increases in heart rate and plasma levels of angiotensin II, but renal sodium excretion was unchanged and the use ofdihydralazine was also accompanied by considerable adverse effects. It was therefore chosen not to use dihydralazine in the main studies and, despite the potential confounding role of nitric oxide, to use sodium nitroprusside instead.

The purpose of the second study was to test the hypothesis, that very short-term administration of the AT1-receptor blocker eprosartan would inhibit baseline sympathetic activity and the reflex activation of the sympathetic nervous system in sodium restricted healthy humans. Eprosartan had no impact on the indices of sympathetic activity at baseline, but reduced the systemic hemodynamic response during a cold pressor test and increased tubular sodium reabsorption during arterial baroreflex mediated sympathetic activation by nitroprusside infusion. These findings suggest that eprosartan increased the sensitivity of the arterial baroreflex in the control of renal sympathetic activity. Furthermore, the results indicate that eprosartan has a small inhibitory effect on the activation of the sympathetic nervous system during the cold pressor test – a likely indirect effect induced by the increased sensitivity of the arterial baroreflex.

The purpose of the third study was to test the hypothesis, that very short-term treatment with the AT1-receptor blocker eprosartan would inhibit baseline sympathetic activity and the reflex activation of the sympathetic nervous system in sodium restricted patients with essential hypertension. Eprosartan had no impact on the indices of sympathetic activity at baseline and during a cold pressor test, but increased tubular sodium reabsorption and plasma levels of angiotensin II during arterial baroreflex mediated sympathetic activation by nitroprusside infusion. These findings suggest that eprosartan had no direct sympatho-inhibitory abilities, but most likely increased the sensitivity of the arterial baroreflex in the control of renal sympathetic nerve activity. In conclusion, a direct anti-adrenergic effect of eprosartan seems not to be present in healthy humans and in patients with essential hypertension during restrictions in sodium intake. Our findings, however, suggest that eprosartan may increase the sensitivity of the arterial baroreflex in control of renal sympathetic nerve activity.