Fosinopril Pathway


The renin-angiotensin-aldosterone system (RAAS) is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to angiotensin I (ATI), which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II (ATII). ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. ATII also stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption in the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Second, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of angiotensin I to angiotensin II and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and sustains its effects causing increased vasodilation and decreased blood pressure (mechanism not shown).

Fosinopril, an ACE inhibitor, is a prodrug that is hydrolyzed in vivo by esterases to its active form, fosinoprilat. Fosinoprilat competes with angiotensin I for binding to ACE and effectively inhibits the conversion of angiotensin I to angiotensin II. This results in lower concentrations of angiotensin II and reductions in blood pressure. Increased bradykinin levels resulting from decreased bradykinin inactivation may also contribute to the effects of fosinopril. Fosinopril may be used to treat hypertension, congestive heart failure and chronic renal failure.

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References

  1. Bader, M. (2004). Renin-angiotensin-aldosterone system. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (pp. 810-814). Berlin, Germany: Springer.
  2. Monopril. (2009). [Electronic version]. e-CPS. Retrieved August 22, 2009.
  3. Peters, J. (2004). ACE inhibitors. In S. Offermanns, & W. Rosenthal (Eds.). Encyclopedic reference of molecular pharmacology (pp. 2-5). Berlin, Germany: Springer.
  4. Stanfield, C.L., & Germann, W.J. (2008). Principles of human physiology (3 rd ed.). San Francisco, CA: Pearson Education, Inc.