Antihypertensive drug treatment is effective in only about 50% of patients. One mechanism
responsible for treatment failure is a drug related stimulation of the
renin-angiotension-aldosterone-system (RAAS). Several classes of medications that treat
hypertension by blocking the RAAS system have been developed. However, the kidney responds
to these drug treatments by producing greater amounts of renin. This high level of renin
can reduce the effectiveness of some of these medications, ultimately causing the blood
pressure to rise. This is one reason why blood pressure can be difficult to control in a
certain percentage of patients.
The hypothesis to be tested in the proposed study is that beta-adrenergic blockade
(β-blockade), when superimposed upon aliskiren, a drug that competitively inhibits plasma
renin activity (PRA) but stimulates the release of renin by the kidneys (plasma renin
concentration [PRC]), can suppress the reactive increase in PRC that occurs during aliskiren
The primary aim of this study is to measure plasma renin concentration (PRC) and plasma
renin activity (PRA) levels during renin inhibition with aliskiren and combined renin
inhibition/β-blocker treatment to determine whether the addition of a β-blocker attenuates
the rise in plasma renin concentration (PRC). A secondary aim is to determine whether
combined treatment further suppresses PRA and blood pressure.
The renin-angiotensin-aldosterone system (RAAS) plays a central role in the maintenance of
normal blood pressure (BP) homeostasis. Derangements in the regulation of this system,
predominantly due to the failure to appropriately suppress renin secretion by the kidney,
contribute to the pathogenesis of hypertension and its cardiovascular, renal and
Several classes of antihypertensive medications that interrupt the RAAS have been developed.
These include agents that block angiotensin II (Ang II) binding to the AT1 receptor (Ang II
receptor blockers [ARB]), inhibit conversion of Ang I to Ang II (angiotensin converting
enzyme [ACE] inhibitors), and suppress renal secretion of renin (beta-adrenergic receptor
blocker). These agents effectively lower BP, particularly in the hypertensive patient with
an unsuppressed plasma renin activity (PRA) level, and significantly improve survival in
cardiovascular diseases in which PRA levels are often elevated (e.g., heart failure,
Renin secretion is regulated, in part, by feedback inhibition due to Ang II binding to the
juxtaglomerular cell (JG). Interruption of Ang II generation or its receptor binding during
treatment with an ACE inhibitor or ARB, respectively, stimulates renin secretion because
feedback inhibition is attenuated and renal perfusion pressure is reduced. The consequent,
reactive rise in PRA that occurs during treatment with these drugs can limit their
antihypertensive efficacy because Ang I and subsequently, Ang II levels increase.
These observations reinforce the theoretical and practical importance of pharmacologic
suppression of renin secretion to prevent the reactive rise in PRA that occurs during
treatment with ACE inhibitors and ARBs. β-blockers suppress renin secretion by inhibiting
β1-adrenergic receptors located on JG cells. PRA and Ang II levels are highly correlated and
these decrease commensurately during treatment with a β-blocker.
Aliskiren is an orally active, non-peptide renin inhibitor. Its antihypertensive efficacy is
due to the competitive antagonism of the renin-mediated conversion of angiotensinogen to Ang
I. During aliskiren treatment, PRA and Ang II levels decrease significantly. Unlike
β-blockade, in which the PRA level decreases as a consequence of reduced renal secretion of
renin, aliskiren treatment decreases PRA in response to the direct, competitive inhibition
of renin. Although PRA decreases, the aliskiren-mediated decrease in plasma Ang II level
stimulates renal renin secretion. Therefore, although aliskiren and β-blockers both decrease
PRA levels, they have divergent effects on the plasma concentration of renin (PRC):
β-blockers decrease it and aliskiren increases it. The reactive rise in PRC has potential
implications regarding the antihypertensive efficacy of aliskiren — high PRC levels
theoretically can overcome the competitive inhibition of renin by aliskiren, thereby
increasing PRA, Ang II, and BP.
Aliskiren has been studied as monotherapy and in combination with other antihypertensive
drugs, including hydrochlorothiazide, valsartan, and amlodipine. It has not been studied in
the presence of a β-blocker. Proposals for future studies include pursuing whether or not
there are hypertensives who are resistant to aliskiren, what the mechanism(s) is for the
resistance and ways to overcome the resistance.
This is a prospective, open-label study of the effect of the sequential addition of a
β-blocker (extended release metoprolol) to aliskiren on the levels of plasma renin activity
and plasma renin concentration in subjects with uncomplicated hypertension.
Twenty subjects with a history of hypertension with the following inclusion criteria will
- Age 18-80 years
- Stage 1 (systolic 140-159 mm Hg or diastolic 90-99 mmHg) or Stage 2 (systolic >160 mm
Hg or diastolic >100 mmHg) or current treatment with antihypertensive medication.
- PRA ≥0.65 ng/ml/h. If PRA is below this level during the screening period, due to
treatment with a beta-blocker or central α2-receptor agonist, the subject may be
enrolled and the PRA level re-checked after treatment is tapered off.
- History of diabetes requiring pharmacologic treatment with an oral or parenteral
hypoglycemic agent, including insulin
- TIA, stroke or myocardial infarction
- History of asthma or COPD
- Cockcroft Gault estimated GFR <60 ml/min/1.73 m2
- Previous adverse events during treatment with a β-blocker or aliskiren
- ALT level twice normal
- Secondary forms of hypertension (e.g., renovascular, primary aldosteronism)
- PRA<0.65 ng/ml/h after discontinuation of antihypertensive medication
- Systolic BP>180 mm Hg, diastolic BP>105 mm Hg
- Pregnant or breastfeeding, or planning pregnancy during the study period