Aldosterone Escape With Diuretic or Angiotensin‐Converting Enzyme Inhibitor/Angiotensin II Receptor Blocker Combination Therapy in Patients With Mild to Moderate Hypertension

Abstract

Renin‐angiotensin‐aldosterone system (RAAS) hyperactivity is implicated in the development of hypertension and progressive damage in target organs. Chronic inhibition of the RAAS or use of thiazide‐type diuretics may trigger an aldosterone escape. The aim of this study was to assess this phenomenon in hypertensive patients treated with thiazide‐type diuretics (hydrochlorothiazide [HCTZ]) or single or double blockade of the RAAS (irbesartan [IRBE], quinapril [QUIN], and IRBE+QUIN). Blood pressure levels were obtained by 24‐hour ambulatory blood pressure monitoring. Plasma renin activity and aldosterone levels were determined by immunoradiometric assay. Blood pressure level was normalized in the 4 treatment groups; the HCTZ and IRBE+QUIN groups showed an increased plasma aldosterone level after 12 weeks (9.1 ±2.2 to 14.1 ±1.4 and 6.9±1.9 to 12.9±2.3 ng/dL, respectively; P<.05), whereas plasma renin activity was increased only in the HCTZ group (0.9 ±0.2‐1.7 ±0.2 ng/mL/h; P<.05). The increase in plasma aldosterone level after 12 weeks of HCTZ and IRBE+QUIN therapy suggests early aldosterone escape.

The renin‐angiotensin‐aldosterone system (RAAs) is an important regulator of the development of hypertension and target organ damage. ¹ Antihypertensive treatment to block this system reduces blood pressure (Bp) levels and protects target organs from damage. ²

The treatment of hypertension by pharmacologic intervention in the RAAs has focused mainly on inhibiting the action of angiotensin II (Ang II) through the use of angiotensin‐converting enzyme inhibitors (ACEIS) or angiotensin II receptor blockers (ARBS). However, the effects of aldosterone on sodium reabsorption, water retention, and the loss of potassium and magnesium are often overlooked with this approach. Recent advances in our understanding of the role of this hormone have highlighted its importance in the development of cardiovascular damage. ^{1 , 3 , 4} Aldosterone interacts with mineralocorticoid receptors to promote endothelial dysfunction, facilitate thrombosis, reduce vascular compliance, impair baroreceptor function, and cause myocardial and vascular fibrosis. ⁵ Ang II has been considered the most important mediator of cardiovascular injury; there is evidence to suggest that aldosterone may mediate and exacerbate the deleterious effects of Ang II. ⁶ Although the use of ACEIs and ARBs may initially decrease plasma aldosterone levels, chronic therapy with these drugs may lead to the phenomenon of aldosterone escape, in which aldosterone levels return to or exceed baseline levels. ^{1 , 5 , 7 , 8} There is also increasing evidence that aldosterone exerts major adverse cardiovascular effects through classical mineralocorticoid receptors in nonepithelial tissues such as the brain and heart. This nonepithelial role of aldosterone has been underscored by the Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Post—Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). These studies showed that when using a mineralocorticoid receptor antagonist as an “organ‐protecting” drug, further organ protection could be derived by the addition of an ACEI or an ARB. The long‐term effect of aldosterone was not inhibited in some patients, so the possibility of organ damage due to so‐called breakthrough aldosterone cannot be ignored. ⁹

In this study, we assessed aldosterone escape in patients with mild to moderate essential hypertension treated for 12 weeks with a thiazide‐type diuretic, an ACEI, or an ARB, with the latter 2 drugs being used alone or in combination.

METHODS

Study Population

The study was performed using a randomized, parallel‐group, open‐label design for each treatment regimen. Volunteers were allocated to a control group or a hypertensive group. The control group consisted of 18 healthy participants (8 men, 10 women; mean age, 46.6±9.0 years) with BP levels <120/80 mm Hg, measured by mercury sphygmomanometer on 3 occasions at 2‐week intervals (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [JNC 7] criterion). ¹⁰ These individuals had no evidence of hypercholesterolemia (low‐density lipoprotein cholesterol ≤ 129 mg/dL; according to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adult Treatment Panel III [NCEP ATP III] guidelines) ¹¹ or diabetes (overnight fasting glycemia <126 mg/dL; according to the American Diabetes Association [ADA] guidelines) ¹² and were nonsmokers. The volunteers provided a complete medical history and underwent a physical examination, electrocardiography, and laboratory analyses to exclude individuals with dyslipidemia, diabetes mellitus, and evidence of hepatic, renal, or hematologic dysfunction.

The hypertensive group consisted of 63 patients with mild to moderate hypertension (29 men, 34 women; mean age, 49.3±7.2 years). Patients were randomized to (1) the diuretic group (n=18) treated with a hydrochlorothiazide diuretic (HCTZ, 25 mg/d), (2) the ACEI group (n=16) treated with quinapril (QUIN, 20 mg/d), (3) the ARB group (n=14) treated with irbesartan (IRBE, 150 mg/d), or (4) a combination group (n=15) treated with a combination of IRBE+QUIN (150 mg/d + 20 mg/d, respectively) when the ambulatory BP monitoring values were >135/85 mm Hg.

All of the participants in the hypertensive group were recruited from the outpatient clinic of the teaching hospital of the State University of Campinas, Campinas, Brazil. The patients were monitored by specialists in the hypertension unit. Patients underwent specific laboratory testing, including abdominal ultrasonography, renal scintigraphy, magnetic resonance imaging, and renal arteriography, when necessary. Exclusion criteria included secondary forms of hypertension, pheochromocytoma, renal artery stenosis, primary hyperaldosteronism, aortic coarctation, impaired renal function, ischemic heart disease, liver diseases, or other major diseases. Patients were also excluded if they had been previously treated with antihypertensive drugs.

In accordance with institutional and Brazilian legislation guidelines, all of the participants were aware of the investigative nature of the study and provided informed written consent before participation. This study was approved by the institutional ethics committee for research.

Study Protocol

Primary hypertensive patients and controls were placed on a regular‐salt diet containing 150 mmol/L/d of sodium chloride for 2 weeks before the study began to allow stabilization of sodium balance.

Baseline blood samples for the quantification of plasma renin activity (PRA) and aldosterone levels were collected into EDTA‐containing tubes from a forearm vein of all participants at 8 AM, after an overnight fast during which the participants were resting in the supine position for 8 hours followed by 1 hour in an upright position in an air‐conditioned room (22‐24°C). The samples were placed on ice and immediately centrifuged, after which the plasma was stored at −80°C until assayed for PRA level (ng/mL/h) and aldosterone (ng/mL) using immunoradiometric assay. PRA and aldosterone levels were measured again in fresh samples collected after 12 weeks of treatment with a hydrochlorothiazide diuretic (HCTZ, 25 mg/d), an ACEI (QUIN, 20 mg/d), an ARB (IRBE, 150 mg/d), or both the ACEI and ARB (IRBE+QUIN, 150 mg/d + 20 mg/d, respectively).

Intermittent 24‐Hour Ambulatory BP Monitoring

Twenty‐four—hour ambulatory BP monitoring (ABPM) was performed with an automatic oscillometric device (Spacelabs 90207, Spacelabs Inc, Redmond, WA). Normal daily activities and BP levels were measured automatically at 20‐minute intervals during the 24‐hour period. Average 24‐hour systolic, diastolic, mean, and pulse (difference between systolic and diastolic) BPs were measured at the beginning of the study and after 12 weeks of treatment.

Statistical Analyses

The results were expressed as the mean ± SD. Statistical comparisons among the 5 groups were performed by 1‐way analysis of variance followed by Bonferroni correction. Two‐tailed paired t test were used to compare the parameters obtained before and after treatment in the hypertensive groups. P values <.05 were considered statistically significant.

RESULTS

Baseline ABPM showed no statistically significant difference (P>.05) in systolic and diastolic BP levels among the hypertensive groups. However, the BP levels were lower in the QUIN and IRBE groups compared with the HCTZ group. Baseline and final office and 24‐hour ABPM BP values are shown inTable I. After 12 weeks of therapy, a significant reduction was noted in systolic and diastolic BP values among the 4 hypertensive groups (P<.001). Baseline and final BP values in the control group showed no significant differences.

Table I.

. Systolic/Diastolic Ambulatory Blood Pressure Monitoring (ABPM) (Week 0 and Week 12)

	Systolic ABPM		Diastolic ABPM
	Week 0	Week 12	Week 0	Week 12
CONT	115±7	114±7	71±4	71±4
HCTZ	136±11.1	128.3±11.1	88±5.9	79.5±11
IRBE	135.4±4.7	122.0±6.9	82.3±2.4	73.8±1.6
QUIN	135.3±8.3	119.8±8.2	82.3±8.7	71.2±5.9
IRBE+QUIN	142.5±4.6	127.3±14	86.5±4.5	78.3±9.4

ABPM; week 0 vs ABPM week 12, P<.001. Abbreviations: CONT, control; HCTZ, hydrochlorothiazide; IRBE, irbesartan; QUIN, quinapril.

There was a significant increase in PRA levels in the HCTZ group compared with the control group at the end of week 12 (P<.05). Plasma aldosterone levels in the HCTZ and IRBE+QUIN groups were also significantly greater than in the control group at the end of week 12 (P<.01). No changes were observed in patients treated with the ACEI or the ARB as monotherapy, however (Table II). One limiting factor was that the dosages of the ACEI and ARB as monotherapy were not at maximum levels.

Table II.

. Markers of Renin‐Angiotensin‐Aldosterone System

	Week 0		Week 12
	Plasma Renin Activity	Plasma Aldosterone	Plasma Renin Activity	Plasma Aldosterone
CONT	0.7±0.1	6.7±1.4	0.8±0.2	7.6 ±2.3
HCTZ	0.9±0.2	9.1±2.2	1.7±0.2 a	14.1±1.4 a , b
IRBE	0.8±0.2	8.0±2.4	1.0±0.3	7.8±1.3
QUIN	0.8±0.2	7.6±2.5	1.0±0.2	6.4±2.2
IRBE+QUIN	0.9±0.2	6.9±1.9	0.9±0.4	12.9±2.3 a , b

^a P<.05 vs week 0.

^b P<.01 vs control (CONT) (week 12). Abbreviations: HCTZ, hydrochlorothiazide; IRBE, irbesartan; QUIN, quinapril.

DISCUSSION

In this study, patients in the 4 treated groups (HCTZ, QUIN, IRBE, and IRBE+QUIN) showed a similar reduction in BP levels. No additive antihypertensive effect was seen with the combination of an ACEI and an ARB (IRBE+QUIN group) compared with treatment with a single agent (IRBE or QUIN), in contrast with the findings of other studies. ^{8 , 13 , 14} Baseline BP levels were higher in this group in one study. ⁹ An increase in the PRA and plasma aldosterone concentrations in HCTZ‐treated hypertensive patients was observed; an increase in plasma aldosterone concentration was also seen in patients treated with combination IRBE+QUIN.

The results of this study indicate that although RAAS inhibition can normalize BP, there may be an aldosterone escape in some patients. The increased plasma aldosterone concentration seen in patients who received a thiazide‐type diuretic may involve mechanisms such as the thiazide‐sensitive Na⁺/Cl⁻ cotransporter of the distal convoluted tubule, the epithelial Na channel of the collecting duct, and the protein responsible for Na⁺/H⁺ exchange in the apical portion of the proximal tubule. ^{8 , 15}

When aldosterone levels are elevated under inappropriate circumstances (ie, under conditions of normovolemia or hypervolemia), the kidney can overcome the sodium chloride—retaining action of aldosterone by activating the aldosterone escape mechanism in which renal tubule Na⁺ reabsorption decreases, despite the continued presence of aldosterone. ¹⁶

Acute treatment with an ACEI can virtually eliminate Ang II from the plasma, while chronic treatment has been associated with the reappearance of measurable Ang II in some patients and also an increase in PRA/aldosterone serum levels. This has been labeled Ang II reactivation. ⁶ Thus, it is possible that the reductions in Ang II and aldosterone levels may not be maintained with chronic ACEI treatment. This is one explanation for our findings at 12 weeks. Although a combination of an Ang II antagonist and an ACEI results in a more complete and sustained blockade of both circulating and tissue renin‐angiotensin system, alternative mechanisms involving bradykinin and Ang (1–7) accumulation and angiotensin II type 2 (AT2) receptor stimulation, and consequently nitric oxide release, may come into play. Stimulation of AT2 receptors per se could trigger a vasodilator and natriuretic cascade involving bradykinin, nitric oxide, and cyclic guanosine monophosphate. ^{9 , 17 , 18} Finally, in contrast with the plasma renin, prorenin, and angiotensin I increases, no major additive effect on the decrease in plasma aldosterone of the combined RAS blockade has been detected, especially in the long term. This is especially true in clinical settings other than with congestive heart failure, probably because of the multiplicity of factors regulating aldosterone secretion, particularly plasma potassium. ^{19 , 20}

The findings suggest that aldosterone antagonists may represent appropriate therapy in many patients in whom BP is not controlled by a diuretic or RAAS inhibition.

CONCLUSIONS

Our results show that combined therapy with an ACEI and an ARB or the use of a thiazide‐type diuretic alone induces aldosterone escape in patients with mild to moderate hypertension after 12 weeks of treatment but that the use of an ARB or an ACEI alone does not. This phenomenon was unrelated to the decrease in BP level, since all of the treated groups had Bp changes that were not significantly different throughout the study. Our results also suggest that aldosterone escape may occur earlier than with the conventional association with chronic therapy. ²¹ Finally, the clinical extrapolation is that this escape could contribute to target organ damage in patients with mild to moderate hypertension and that aldosterone antagonist therapy should be considered in patients receiving diuretics of combined RAAs blockade.

• 1Disclosure: This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo a Ensino e Pesquisa da Universidade Estadual de Campinas (FAEP‐UNICAMP).