Hypertension Knowledge Centre
Angiotensin II Antagonists
Role played by angiotensin II and the sympathetic nervous system in determining systolic blood pressure
The classical ‘blood pressure equation’ states that mean blood pressure is the product of peripheral resistance multiplied by cardiac output. It follows that an increase in peripheral resistance will lead to an increase in systolic and diastolic blood pressure.
However, another major factor contributing to raised SBP is a decrease in arterial compliance, associated with alterations in aortic wave travel and reflection.16,21 Reduced arterial compliance is caused by arterial stiffening, a consequence of aging and atherosclerosis, thus helping explain why hypertension in older people is predominantly systolic.
The renin-angiotensin system (RAS) and sympathetic nervous system (SNS) play important interlinked roles in the control of systolic blood pressure (figure 4).16 Angiotensin II and norepinephrine are both powerful vasoconstrictors with direct effects on peripheral resistance. They also appear to affect vascular growth, which contributes to arterial stiffening and compliance.
Figure 4: Impact of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) on systolic blood pressure and cardiovascular disease. (Abbreviations: HTN, hypertension; CHF, congestive heart failure; ESRD, end-stage renal disease; CAD, coronary artery disease; LVH, left ventricular hypertrophy. Adapted from16
Interactions between the RAS and SNS occur on several levels. The SNS can affect the release of renin and the subsequent formation of angiotensin II, whilst angiotensin II may alter sympathetic outflow within the brainstem and can modulate the release of norepinephrine from presynaptic neurones.
There is growing evidence supporting the concept that angiotensin II can regulate the amount of norepinephrine released from peripheral sympathetic neurones.16,22,23 Animal studies indicate that it does this by stimulating angiotensin II ‘type 1’ (AT1) receptors located on the presynaptic nerve terminal of sympathetic neurones,22 and this triggers enhanced release of norepinephrine into the synapse. This is in addition to its effects on AT1 receptors located postsynaptically on blood vessels, which triggers its direct vasoconstrictor effects.
Figure 5: Angiotensin II ‘type 1’ receptors (AT1) and the sympathetic neuro-effector junction. Adapted from16.
The introduction of ACE inhibitors and angiotensin II antagonists (AIIAs) has been an important development in the management of essential hypertension. ACE inhibitors block activation of the renin-angiotensin system by restricting the conversion of the precursor angiotensin I to angiotensin II. However, alternative pathways can also convert angiotensin I to angiotensin II; ACE inhibitors may, therefore, only cause a partial blockade of the actions of angiotensin II.
AIIAs compete with angiotensin II for binding sites on AT1 receptors on blood vessels, which appear to mediate the majority of the deleterious effects of angiotensin II on blood pressure.
Figure 6: Renin-angiotensin system – formation and action of angiotensin, and sites of action of ACE inhibitors and AIIAs.
Increased awareness of the interplay between angiotensin II and sympathetic nervous system in patients with systolic hypertension is especially relevant for eprosartan. Uniquely amongst AIIAs, eprosartan has been shown to inhibit the presynaptic effects of angiotensin II, giving eprosartan a dual mechanism of action.10,11