1. Renin is released from the kidneys (specifically, the juxtaglomerular apparatus) in response to:
   • DECREASE in arterial blood pressure
   • DECREASE in serum [Na+]
   • INCREASE in sympathetic activation (via β1 receptors).
2. Renin converts angiotensinogen (made in the liver) into angiotensin-I.
3. Angiotensin-I is converted into angiotensin-II by angiotensin-converting enzyme (ACE), which is found on the surface of vascular endothelium (and is abundant in the lungs).
4. Angiotensin II causes:
   • VASOCONSTRICTION
     • by binding to AT1 receptors on blood vessels
     • by stimulating secretion of ADH (AKA vasopressin because it is a vasoconstrictor)
     • by stimulating sympathetic activation.
   • Na+ AND H2O RETENTION
     • by stimulating aldosterone secretion, which stimulates renal Na+ (and H2O) reabsorption in the kidneys' distal convoluted tubule
     • by stimulating ADH secretion, which increases H2O reabsorption in the kidneys' collecting ducts.

The renin-angiotensin-aldosterone system ensures that blood pressure is maintained when blood volume is lost, to ensure that vital organs maintain adequate perfusion.

If RAAS is activated inappropriately, it can lead to unnecessarily high blood pressure and fluid retention.

By inhibiting production of angiotensin-II, ACE inhibitors cause:

• VASODILATATION
  • Dilation of systemic arteries decreases arteriolar resistance which therefore reduces cardiac afterload.
  • Dilation of veins increases venous capacity which therefore reduces cardiac preload.
  • Note: Most vasodilating medications (e.g. dihydropyridine CCBs and nitrates) also cause a reflex tachycardia - where heart rate increases in response to a fall in mean arterial pressure. ACE inhibitors do not tend to cause reflex tachycardia because they also decrease sympathetic activity which slows the heart rate.
• DIURESIS AND NATIURESIS
  • By reducing secretion of aldosterone, they reduce retention of Na+ and H2O. This leads to increased renal excretion of fluid which reduces venous congestion and blood pressure.

ARBs have similar effects to those described above, however these work by inhibiting the binding of angiotensin-II at its receptors.