Renin inhibitor and angiotensin
September 10 2017 by
Ray Sahelian, M.D.

Renin is also known as angiotensinogenase, an enzyme released mainly by cells in kidneys in response to low blood volume. Although it has hormone-like actions, it cleaves a protein precursor in the circulation rather than working on a cellular target.

The renin-angiotensin system (RAS) is well-recognized as one of the oldest and most important regulators of arterial blood pressure, cardiovascular, and renal function. New frontiers have recently emerged in the RAS research well beyond its classic paradigm as a potent vasoconstrictor, an aldosterone release stimulator, or a sodium-retaining hormone. First, two new members of the RAS have been uncovered, which include the renin/(Pro)renin receptor (PRR) and angiotensin-converting enzyme 2 (ACE2).

Numerous clinical studies have been conducted to analyze the ability of renin-angiotensin system blockade to lower blood pressure and to reduce end-organ damage. In addition to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, direct renin inhibitors emerged as an attractive option to inhibit the renin-angiotensin system and thus to prevent cardiovascular damage.

Regulators of kidney function
The renin - angiotensin - aldosterone system plays an important role in regulating blood volume, arterial pressure, and cardiac and vascular function. While the pathways for the renin - angiotensin system have been found in a number of tissues, the most important site for renin release is the kidney.
   Chronic kidney disease and cardiovascular disease share many risk factors, including hypertension, obesity, and insulin resistance. All of these are associated with increased risk of morbidity and mortality. One mechanism that links renal injury with these symptoms and signs is activation of the renin-angiotensin system. Chronic angiotensin II activation promotes development of renal disease through blood pressure effects and up-regulation of inflammatory cytokines and growth factors. Inhibition of the renin-angiotensin system delays progression of renal disease and improves renal function. Higher doses of renin-angiotensin system inhibitors may provide greater protection to kidneys. Inhibition of the renin-angiotensin system in patients with risk factors or vascular disease with or without recognized blood sugar abnormalities may be a useful strategy for preventing the progression of chronic kidney disease in patients with vascular disease.

Stimulation of Renin Release
Sympathetic stimulation (acting via b1-adrenoceptors), renal artery hypotension, and decreased sodium delivery to the distal tubules stimulate the release of renin by the kidney.

How Renin works, mechanism of action
Renin is an enzyme that acts upon a circulating substrate, angiotensinogen, that undergoes proteolytic cleavage to from the decapeptide angiotensin I. Vascular endothelium, particularly in the lungs, has an enzyme, angiotensin converting enzyme (ACE), that cleaves off two amino acids to form the octapeptide, angiotensin II (AII).

Renin Blocker
Treatment with aliskiren, the first of a new class of agents that block renin, provides steady 24-hour blood pressure control in patients with hypertension. When lowering blood pressure, smooth control is important because variability has been linked to adverse outcomes and to diminished end-organ protection. This new renin blocker is designed to provide steady control of blood pressure for longer than 24 hours. Although a renin inhibitor is now poised to hit the market, researchers have been attempting to block this enzyme since the 1960s. It is possible that this renin blocker, aliskiren may work with existing therapies. Novartis Pharmaceuticals, which plans to market aliskiren as Rasilez, filed a new drug application with the US Food and Drug Administration in 2006.

March 2007 - The U.S. Food and Drug Administration (FDA) announced the approval of Tekturna ( aliskiren ) tablets for the treatment of high blood pressure, or hypertension. Tekturna, a new molecular entity, is the first high blood pressure drug approved by FDA that inhibits renin, a kidney enzyme associated with the regulation of blood pressure. Tekturna acts at the beginning of the blood pressure regulation process, while other available high blood pressure medications act at later stages. The effectiveness of Tekturna in lowering blood pressure has been demonstrated in placebo-controlled eight-week clinical trials, which studied more than 2,000 patients with mild to moderate hypertension. The effect was maintained for up to one year. Tekturna was effective across all demographic subgroups, but African American patients tended to have smaller reductions in blood pressure than Caucasians and Asians, as is generally true for drugs that affect the renin - angiotensin system, a component of blood pressure regulation. When Tekturna was used in combination with hydrochlorothiazide, a diuretic, further reductions in blood pressure were achieved.

Tekturna side effects
Tektuma common side effect include diarrhea diarrhea, allergic reactions with swelling of the face, lips or tongue and difficulty breathing.

Renin inhibitor Tekturna for hypertension
Aliskiren (Tekturna, Rasilez), the first renin inhibitor for treating hypertension, is no better than older, less expensive agents for reducing blood pressure. Aliskiren may actually increase blood pressure in patients with highly reactive renin systems. Dr. Jean E. Sealey and Dr. John H. Laragh, from Cornell University in New York, found that aliskiren was no more effective than ACE inhibitors, angiotensin receptor blockers, or diuretics in reducing blood pressure. While aliskiren blocks renin activity, it causes greater reactive increases in renin levels than other antihypertensives, which could be a problem for patients who have highly reactive renin systems, the researchers note. Moreover, this reactive increase in renin levels may offset the drug's ability to lower blood pressure. American Journal Hypertension 2007. Tekturna is manufactured by Novartis Pharmaceuticals Corp., East Hanover, N.J.

Tektuma for pregnancy
Tekturna and other drugs that act directly on the renin - angiotensin system should not be used during pregnancy because they can cause injury and even death to the developing fetus.