Renin inhibitors - mechanisms of action

Renin inhibitors are antihypertensive drugs which block the first step in the renin-angiotensin system. Their mechanism of action differs from that of angiotensin converting enzyme inhibitors and angiotensin receptor antagonists, but like these drugs, renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion. This increases renin concentrations which may attenuate the inhibition of the renin angiotensin system by these therapies. Renin inhibitors may interfere with measurements of renin in plasma.

Drugs that inhibit the renin-angiotensin system, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists, have proven value for the treatment of hypertension, heart failure and renal disease. They reduce the rates of death, myocardial infarction and stroke in a broad range of patients at high risk, but do not control the blood pressure in all cases. This led to research into inhibiting the renin-angiotensin system at its first step – the production of angiotensin I.

enin is an enzyme produced from the inactive protein, prorenin. The release of renin from the juxtaglomerular cells of the kidney is controlled by several mechanisms. These include the sympathetic nervous system, salt and fluid balance, blood pressure, and negative feedback by angiotensin II. Renin cleaves circulating angiotensinogen to form angiotensin I (Fig. 1). This inactive decapeptide is subsequently cleaved by ACE to produce the octapeptide angiotensin II. Although other bioactive angiotensin peptides are produced from angiotensin I and II, angiotensin II is the main bioactive angiotensin peptide.

Two different receptors mediate the actions of angiotensin II. These are the type 1 (AT₁) and the type 2 (AT₂) receptors (Fig. 1). Stimulation of the AT₁ receptor increases arterial tone and aldosterone secretion. Angiotensin II therefore plays an essential role in blood pressure, and fluid and electrolyte homeostasis. However, this role is much diminished in people consuming a Western diet with an excessive salt content. In these people, even 'normal' concentrations of angiotensin II may play a role in hypertension and in cardiovascular and renal disease.

Angiotensin-(1-7), a heptapeptide, is a metabolite of angiotensins I and II. Both angiotensin-(1-7), acting through its own receptor, and angiotensin II, acting on the AT₂ receptor, may counterbalance some of the effects of angiotensin II stimulating the AT₁ receptor.

The kidney is not the only organ which produces prorenin, and a receptor which binds renin and prorenin has been discovered. The physiological roles of the (pro)renin receptor are unknown, but high concentrations of prorenin predict microvascular complications of diabetes.

Fig. 1 Mechanisms of action of renin inhibitors The renin-angiotensin system can be inhibited by angiotensin converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor antagonists (ARA), renin inhibitors and beta blockers. Also shown is the role of ACE in bradykinin metabolism. ACE also metabolises angiotensin-(1-7).

The therapeutic benefits of inhibiting the renin-angiotensin system are attributed primarily to reduced stimulation of the AT₁ receptor. This can be achieved by either reducing angiotensin II concentrations or blocking the AT₁ receptor, although other mechanisms may contribute (Table 1).

Beta blockers inhibit renin release from the kidney and were the original renin-angiotensin system inhibitors. Reduced renin release leads to reduced concentrations of angiotensin I and II, which may contribute to the benefits of beta blockade in heart failure.¹

In contrast to beta blockers, ACE inhibitors, angiotensin receptor antagonists and renin inhibitors cause an increase in renin release. This is because by reducing AT₁ receptor stimulation they interrupt the negative feedback-mediated regulation of renin release. The combination of an ACE inhibitor, angiotensin receptor antagonist or renin inhibitor with another drug from these groups, or with a diuretic, markedly amplifies the increase in renin concentrations. The increase in renin concentrations may be as much as 100-fold, which then offsets the inhibition of the renin-angiotensin system by these antihypertensive drugs. This may attenuate any reduction in blood pressure.

ACE inhibitors, angiotensin receptor antagonists and renin inhibitors have different effects on the concentrations of angiotensin peptides and bradykinin (a vasodilator) (Table 1). Renin inhibitors reduce the concentrations of all angiotensin peptides, and their effect on bradykinin concentrations is under investigation.

ACE inhibitors block the conversion of angiotensin I to angiotensin II and the metabolism of angiotensin-(1-7). They reduce angiotensin II concentrations and increase the concentrations of angiotensin I and angiotensin-(1-7). In addition, because ACE contributes to bradykinin metabolism, ACE inhibitors increase bradykinin concentrations², which may contribute to the therapeutic benefits of ACE inhibition.

Angiotensin receptor antagonist therapies block AT₁, but not AT₂, receptors. This blockade leads to increased renin concentrations and consequently increased angiotensin II concentrations. This causes increased stimulation of the AT₂ receptor. Angiotensin receptor antagonists also increase bradykinin concentrations.³ Stimulation of the AT₂ receptor and increased bradykinin concentrations may contribute to the clinical effects of angiotensin receptor antagonist therapy.

Renin inhibition differs from ACE inhibitor therapy because it reduces angiotensin I and angiotensin-(1-7) concentrations. It differs from angiotensin receptor antagonist therapy because there is reduced stimulation of the AT₂ receptor.

Several renin inhibitors were abandoned because of problems in development. Aliskiren is the first renin inhibitor for which we have extensive information about clinical pharmacology. Other renin inhibitors in clinical development are likely to have different pharmacologies.

Aliskiren is a competitive renin inhibitor which binds to the active site of the enzyme. It is a rather hydrophilic molecule with high aqueous solubility.⁴The distribution volume of intravenously administered aliskiren is 135 L in normal volunteers, indicating extensive tissue uptake of the drug.⁵ The absorbed fraction of orally administered aliskiren is approximately 5%. This low oral bioavailability is compensated for by a long plasma half-life of 34–41 hours, and steady-state plasma aliskiren concentrations are achieved after 5–8 days of daily dosing.⁶ Approximately 90% of the drug is excreted unchanged in the faeces.⁷ The long plasma half-life and very low urinary excretion (< 1%)^6,7 suggest extensive binding of the drug to plasma proteins.⁵

Protein binding accounts for the discrepancy between the concentration of aliskiren required for 50% inhibition of pure renin and that for inhibition of renin in plasma. The concentration (IC₅₀) required was 0.6 nmol/L for pure renin versus 10–14 nmol/L for renin in human plasma.⁵ This suggests that more than 90% of plasma aliskiren is bound to plasma proteins. Extensive binding of aliskiren to plasma proteins reduces the 'free' concentration of aliskiren available to inhibit renin. This, together with the several-fold increase in renin concentrations, accounts for the modest and transient reduction of plasma angiotensin concentrations during aliskiren therapy.⁶ Long-term therapy failed to significantly reduce plasma aldosterone concentrations, although aliskiren did reduce urinary aldosterone excretion.⁶

Renin is measured in the investigation of hypertension. There are two methods – activity assays and immunoassays.⁵ Activity assays measure angiotensin I produced by renin cleavage of plasma angiotensinogen. Immunoassays measure renin concentrations in plasma. Renin inhibitors have different effects on the two methods of renin measurement. Renin inhibitors reduce plasma renin activity, although the reduction in plasma renin activity is attenuated by the rise in renin concentrations. By contrast, renin immunoassay measures both active renin molecules and renin molecules that are inhibited by the renin inhibitor. Consequently, renin immunoassay shows increased renin concentrations because of the increased release of renin that occurs during treatment with a renin inhibitor.

Renin inhibitor therapy can interfere with renin activity assays and immunoassays in other ways. The renin activity assay may overestimate renin inhibition because displacement of the inhibitor from plasma proteins during the assay causes greater inhibition of renin activity in vitro than was present in vivo. During immunoassay, renin inhibitors may cause an artefactual increase in the amount of renin molecules measured as the drug binds to, and causes unfolding of, the prosegment of plasma prorenin. This unfolding causes prorenin to be recognised by the renin immunoassay.

The clinician who wishes to screen for primary aldosteronism or who wishes to investigate hypertensive conditions with high renin concentrations such as renal artery stenosis, in a patient receiving renin inhibitor therapy, needs to cease this therapy for at least two weeks. This allows for clearance of the renin inhibitor before samples are taken for measurement by either activity assay or immunoassay.

Renin inhibitors represent an alternative strategy for inhibiting the renin-angiotensin system. They have a mechanism of action different from that of ACE inhibitors and angiotensin receptor antagonists. Whether renin inhibitors offer therapeutic benefits beyond those provided by ACE inhibitor and angiotensin receptor antagonist therapies will require their direct comparison in clinical outcome studies.

Dr Campbell holds a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC), and has received research grants from the NHMRC and the National Heart Foundation. He has had research contracts with Solvay and Novartis and has been on an advisory board for Novartis.