Angiotensin I-converting enzyme inhibition increases cardiac catecholamine content and reduces monoamine oxidase activity via an angiotensin type 1 receptor-mediated mechanism.
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.
Raasch
Walter
W
Institute of Experimental and Clinical Pharmacology and Toxicology, Medical University of Lübeck, Germany.
Bartels
Torsten
T
Gieselberg
Annabella
A
Dendorfer
Andreas
A
Dominiak
Peter
P
D000804:Angiotensin II / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001923:Brain Chemistry / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002395:Catecholamines; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D008995:Monoamine Oxidase; C081643:candesartan