Aldosterone antisecretagogue and antihypertensive actions of adrenomedullin in patients with primary aldosteronism

Abstract

Adrenomedullin (AM) is located in the zona glomerulosa of the adrenal cortex and is considered to suppress aldosterone release. To determine the effect of AM in primary aldosteronism (PA), we infused AM (2.5 pmol kg À1 min À1 ) for 27 h, followed by a 15-h recovery period, in a control group (essential hypertensives with plasma aldosterone levels p100 pg ml À1 , n¼7) and in a PA group (n¼5). The control group was also infused with vehicle. Hemodynamic, hormonal, oxidative and inflammatory responses were studied. AM infusion caused similar and steady decreases in blood pressure and several markers for arteriosclerosis (for example, pulse wave velocity) in both groups. Interestingly, AM infusion suppressed aldosterone release to values within the normal range in the PA group (300.0 ± 58.4 to 111.6 ± 13.5 pg ml À1 , Po0.01). In the control group, aldosterone release suppression was significant but limited (81.7 ± 9.1 to 47.9 ± 9.9 pg ml À1 , Po0.01). The adrenocorticotropic hormone-cortisol system was not changed by AM infusion. Brain natriuretic peptide was cumulatively increased by prolonged AM infusion in both groups, probably because of cardiac overload. AM did not affect oxidative markers. In addition, a mild but significant increase in C-reactive protein (CRP) mediated by interleukin-6 was observed during AM infusion in every participant, without exception. This pathway might participate in CRP elevation in cardiovascular disease. In summary, AM seems to have an essential role in the suppression of aldosterone release in PA. AM may be an important modulator in PA, and intermediate-term Keywords: adrenomedullin; aldosterone; C-reactive protein; humans; primary aldosteronism INTRODUCTION Adrenomedullin (AM) is a potent hypotensive peptide found ubiquitously in tissues and organs, especially in cardiovascular tissues, the kidneys, lungs and endocrine glands. AM has multiple functions in a wide range of tissues and acts mainly as a vasodilatory and proliferation-inhibitory factor. 1 AM was initially identified in the adrenal medulla, but similar densities of AM were detected in the zona glomerulosa of the adrenal cortex, where AM suppresses aldosterone release. 2,3 In addition, expression of AM and its receptor was detected in Conn's adenoma cells, and AM exerted aldosterone antisecretagogue action and proliferative effects on cultured Conn's adenoma cells. 4 These findings suggest that endogenous AM may be an important modulator of aldosterone release in normal and pathogenic hyperaldosteronism. In addition, AM antagonized aldosterone-induced vascular or cardiac remodeling 5,6 and suppressed aldosterone-induced oxidative stress in a malignant hypertensive model. 7 The characteristics that define this compound, from its release to alterations in target organs, suggest that AM may be an endogenous anti-aldosterone factor, especially in the cardiovascular system.

<p>Safety, Tolerability, and Pharmacokinetics of Adrenomedullin in Healthy Males: A Randomized, Double-Blind, Phase 1 Clinical Trial</p>

“…20 Furthermore, the prolonged infusion of AM at a dose of 15 ng/kg/min for 27 h decreased the BP of patients in a previous report, especially late at night. 21 Based on these results, we chose the upper limit of AM administration as 15 ng/kg/min for 12 h, allowing the infusion to be terminated before midnight. Indeed, the safety of hemodynamic parameters was confirmed in a previous exploratory clinical study, where AM was infused at a dose of 9 ng/kg/ min for 8 h in patients with UC.…”

Adrenomedullin Therapy in Patients with Refractory Ulcerative Colitis: A Case Series

“…We used a relatively low dose of AM (1.5 pmol/kg/min), and it was infused for only 8 h daily for 14 days. We previously characterized the hemodynamic and hormonal effects of exogenous AM in humans and showed that prolonged administration elicited a strong and steady reduction in blood pressure with significant increases in the plasma AM concentration [ 17 , 21 ]. In patients with essential hypertension, for example, continuous AM infusion at 2.5 pmol/kg/min (15 ng/kg/min) for 27 h safely caused a significant reduction in blood pressure.…”

Adrenomedullin 2/Intermedin in the Hypothalamo–Pituitary–Adrenal Axis

“…Mazzocchi et al concluded that AM and CGRP stimulated rat adrenals in vivo to release corticosterone by raising blood flow rate, whereas AM and CGRP enhanced aldosterone secretion via an indirect mechanism probably requiring the release of catecholamines by medullary chromaffin cells. Furthermore, Kita et al (2010) have recently shown that intravenous infusion of AM suppressed plasma aldosterone levels to values within the normal range in patients with aldosterone-secreting adrenocortical adenoma (primary aldosteronism).…”