Renin Inhibitor - The Renin-angiotensin-aldosterone System

The Renin-angiotensin-aldosterone System

The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathology of cardiovascular disease, hypertension, diabetic kidney disease and heart failure. Under normal conditions, stimulation of the RAAS occurs in response to threats that compromise blood pressure stability, such as hypotension, blood loss and excessive loss of sodium and water. Blood pressure depends on total peripheral resistance and cardiac output.

The highly selective aspartic protease renin is secreted from the juxtaglomerular apparatus, which is the only source of active renin, although its precursor, prorenin, can be secreted by other tissues, such as the salivary glands, brain, heart and blood vessels. Renin is a circulating enzyme that acts on a circulating peptide, angiotensinogen. Renin cleaves the peptide at the Leu10–Val11 bond, and this reaction is the rate-determining step of the RAAS. This leads to the product angiotensin I (Ang I) which is a decapeptide. Ang I is broken down by the angiotensin-converting enzyme (ACE) to the active octapeptide angiotensin II (Ang II), which is the principal effector of the RAAS. Ang II stimulates renal sodium retention; promotes aldosterone secretion; causes vasoconstriction, and increases sympathetic nervous system activity. Ang II also provides a negative feedback to the system by inhibiting renin release by the juxtaglomerular apparatus. Ang II interacts with at least two classes of Ang II receptors, AT1 and AT2. This mechanism, which runs from renin through Ang II and to aldosterone, as well as the negative feedback that Ang II has on renin secretion, is known as RAAS. The net effect is to increase blood pressure, which in normal physiology is necessary in order to maintain homeostasis.

It is suspected that essential hypertension, a heterogeneous disorder whose long-term effects can be end organ damage, can involve at least in some cases an overactivity of this system, which several types of medications attempt to counter. Renin concentration in blood plasma tends to be higher in younger people with hypertension when vasoconstriction may be the main reason for high blood pressure. Conversely, renin is lower in older people or in people of African American or African Caribbean ethnicity when salt retention may contribute more to elevated blood pressure. However, the role of plasma renin levels in the etiology and management of hypertension is disputed.