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 I1-receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I1-receptors are up-regulated in hamster and human heart failure. Furthermore, cardiac I1-receptor binding decreased after chronic in vivo exposure to moxonidine. These studies implied that cardiac I1-receptors are involved in cardiovascular regulation. The presence of I1-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 microg/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 microg kg(-1) h(-1), sc for 4 weeks) dose-dependently decreased blood pressure, resulted in reversal of LVH and decreased ventricular interleukin 1beta 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.
Highlights
The sympathetic nervous system (SNS) plays an important role in the regulation of blood pressure and cardiac function through the control of vasomotor tone, heart rate and the activity of the renin-angiotensin-aldosterone system
We have identified imidazoline receptors in the heart atria and ventricles, and shown that atrial I1-receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I1-receptors are up-regulated in hamster and human heart failure
Sympathetic nervous activity is regulated in centers in the brain stem and transmitted to organs and blood vessels that are innervated by sympathetic nerve endings, modifying cardiac output, peripheral vascular resistance and renal function
Summary
The sympathetic nervous system (SNS) plays an important role in the regulation of blood pressure and cardiac function through the control of vasomotor tone, heart rate and the activity of the renin-angiotensin-aldosterone system. It appears imperative that selection of vasoactive drugs for the treatment of cardiovascular diseases takes into consideration their effects on the SNS, where ideally treatment should blunt sympathetic activity, or at least avoid activating it. Acting drugs, such as clonidine and αmethyldopa, reduce central sympathetic drive, and maintain cardiac output, arterial tone and body fluid volume. Despite their clinical efficacy, the use of these “first generation centrally acting drugs” was often limited by their side effects, which include, dry mouth, sedation and mental depression. It may be due to this selectivity that moxonidine and rilmenidine have fewer side effects, because imidazoline receptors have been shown to mediate hypotension, while sedation was attributed to α2-adrenoceptors
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Schedule a callMore From: Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
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