Kaplan's Clinical Hypertension by Kaplan Norman M. & Vitor Ronald G

Author:Kaplan, Norman M. & Vitor, Ronald G.
Language: eng
Format: epub, pdf
Publisher: LWW
Published: 2014-09-04T04:00:00+00:00

DIRECT RENIN INHIBITORS

A DRI, aliskerin (Texturna) has been approved for treatment of hypertension. Despite its limited absorption and bioavailability (3%), aliskerin works because of its high aqueous solubility, high specificity for the enzymatically active site of human renin, and long half-life (40 hours) and because it is minimally metabolized (Brown, 2008). Other DRIs are under investigation (Krop et al., 2013).

Mechanism of Action

As detailed in Chapter 3, the renal J-G apparatus secretes prorenin, which is enzymatically converted to the active renin, largely in the kidney. Renin cleaves the 10 amino acid AI from the protein substrate angiotensinogen. Aliskerin blocks renin's catalytic site, reducing the formation of AI and its generation of AII, resulting in a fall of BP. The lower levels of AI and AII remove the normal inhibition of prorenin secretion from the J-G apparatus so that levels of prorenin and renin are markedly increased. According to conventional wisdom, as long as aliskerin blocks the catalytic action of prorenin and renin, the BP will fall.

However, prorenin is now recognized to attach to its own receptor in various tissues where it exerts profibrotic effects, without interference from aliskerin (Schefe et al., 2008).

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