Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides

Abstract

Chronic stimulation of sympathetic nervous activity contributes to the development and maintenance of hypertension, leading to left ventricular hypertrophy (LVH), arrhythmias and cardiac death. Moxonidine, an imidazoline antihypertensive compound that preferentially activates imidazoline receptors in brainstem rostroventrolateral medulla, suppresses sympathetic activation and reverses LVH. We have identified imidazoline receptors in the heart atria and ventricles, and shown that atrial I 1 -receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I 1 -receptors are up-regulated in hamster and human heart failure. Furthermore, cardiac I 1 -receptor binding decreased after chronic in vivo exposure to moxonidine. These studies implied that cardiac I 1 -receptors are involved in cardiovascular regulation. The presence of I 1 -receptors in the heart, the primary site of production of natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), cardiac hormones implicated in blood pressure control and cardioprotection, led us to propose that ANP may be involved in the actions of moxonidine. In fact, acute iv administration of moxonidine (50 to 150 µg/rat) dose-dependently decreased blood pressure, stimulated diuresis and natriuresis and increased plasma ANP and its second messenger, cGMP. Chronic SHR treatment with moxonidine (0, 60 and 120 µg kg -1 h -1 , sc for 4 weeks) dosedependently decreased blood pressure, resulted in reversal of LVH and decreased ventricular interleukin 1ß concentration after 4 weeks of treatment. These effects were associated with a further increase in already elevated ANP and BNP synthesis and release (after 1 week), and normalization by 4 weeks. In conclusion, cardiac imidazoline receptors and natriuretic peptides may be involved in the acute and chronic effects of moxonidine. Correspondence S. Mukaddam-Daher

Moxonidine Increases Uptake of Oxidised Low-Density Lipoprotein in Cultured Vascular Smooth Muscle Cells and Inhibits Atherosclerosis in Apolipoprotein E-Deficient Mice

“…We also showed for the first time that moxonidine decreased MCP-1 mRNA expression. Our results and those from the literature [ 14 , 15 ] support the notion that moxonidine has an anti-inflammatory effect, which might play an important role in mediating the anti-atherosclerotic effect of moxonidine.…”

“…It is unknown whether moxonidine (a sympatholytic drug) inhibits atherosclerosis, although the drug has some activities that may be linked to an anti-atherogenic role, such as the inhibition of inflammation [ 14 , 15 ]. This study aimed to investigate the effect of moxonidine on atherosclerosis.…”

Central Sympathetic Modulation Reverses Microvascular Alterations in a Rat Model of High‐Fat Diet‐Induced Metabolic Syndrome

“…Considering that treatment with both clonidine and rilmenidine induced similar effects on systemic hemodynamics and sympathetic activity, a direct cardiac effect could explain this inconsistency. It is already known that cardiac I 1 Rs are involved in the pathophysiology of cardiac diseases and can regulate cell growth and death . Thus, considering that rilmenidine presents a greater selectivity than clonidine for I 1 Rs, compared with α 2 Rs, it is reasonable to suggest that rilmenidine reversed left ventricle capillary rarefaction thorough a direct cardiac effect acting upon I 1 Rs.…”

Effects of moxonidine on sympathetic nervous system activity: An update on metabolism, cardio, and other target-organ protection

“…[ 1 ] Imidazoline I 1 receptors have been localized in the brainstem RVLM, and in peripherical nervous system, including heart-mainly in cardiac atria. [ 22 ] The atria are the primary site of atrial natriuretic peptide (ANP) production. The ANP is involved in blood pressure reduction and volume regulation.…”