Angiotensin I-Converting Enzyme Inhibition Increases Cardiac Catecholamine Content and Reduces Monoamine Oxidase Activity via an Angiotensin Type 1 Receptor-Mediated Mechanism

Abstract

Antihypertensive and cardioprotective effects of angiotensin I-converting enzyme (ACE) inhibitors are well established and have usually been attributed to the inhibition of angiotensin II (ANG)-mediated effects at vascular or ventricular (angiotensin type 1) AT 1 receptors. One other important mechanism involves ANG-induced interactions with the sympathetic nervous system, which might include alterations of cardiac catecholamine concentrations during ACE inhibition due to a modulation of monoamine oxidase (MAO) activity. Tissue catecholamines were studied in spontaneously hypertensive rats that were long-term treated with captopril (50 or 0.5 mg/kg/day), enalapril (10 or 0.1 mg/kg/day), an AT 1 receptor antagonist (candesartan-cilexetil, 3 mg/kg/day), or a calcium antagonist (mibefradil, 18 mg/kg/day). The kinetic parameters of MAO were then determined in vitro in the presence of ANG, captopril, enalaprilat, or candesartan. Noradrenaline and adrenaline contents were doubled in the left ventricle by captopril, enalapril, or candesartan independently of hypotensive potency but not in liver or cortex. In parallel, cardiac MAO activity was reduced by all doses of captopril (49/29%), enalapril (52/24%), or candesartan (38%). Mibefradil, which does not interact with the renin-angiotensin system, did not alter cardiac catecholamines or MAO activity when an equipotent antihypertensive dose was applied. In vitro MAO activity was not influenced by ANG, enalaprilat, or captopril at concentrations of up to 1 mM. It is concluded that diminished AT 1 receptor stimulation decreases cardiac MAO activity, probably by regulating MAO expression, since ANG, ACE inhibitors, and AT 1 antagonists had no effect on MAO activity in vitro. This action contributes to an increase in cardiac catecholamine content that may improve cardiac sympathetic control during therapy.Angiotensin I-converting enzyme (ACE) inhibitors are well established in the treatment of hypertension and heart failure. They decrease angiotensin II (ANG) generation by blocking the circulating and local renin-angiotensin systems (RAS) and by preventing the degradation of bradykinin. Both mechanisms seem to be involved in the antihypertensive and cardioprotective effects. Both ANG and bradykinin interact with other neurohumoral systems such as the sympathetic system. ANG increases noradrenaline release from sympathetic nerve endings by stimulating presynaptic AT 1 receptors (Brasch et al., 1993). Hence, inhibition of ANG biosynthesis by ACE inhibitors reduces the release of catecholamines (Majewski et al., 1984). In the past, many clinical trials evaluated the pronounced antihypertensive and cardioprotective effects of ACE inhibitors, and in this context, the contributions of diminished plasma noradrenaline levels to their antihypertensive and cardioprotective effects were discussed. The therapeutic significance of this action was revealed for the treatment of heart failure where a pathological sympathetic stimulation was associated with decreased cardiac noradren...

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