Angiotensin converting enzyme inhibition improves cardiac neuronal uptake of noradrenaline in spontaneously hypertensive rats.
OBJECTIVE
It has been shown that a diminished sympathetic activity contributes to the hypotensive and cardioprotective actions of angiotensin converting enzyme (ACE) inhibitors (ACEI). Besides an inhibition of central sympathetic tone and peripheral noradrenaline release, we hypothesized that the interactions of ACEI with the sympathetic system may include a modulation of neuronal catecholamine uptake by peripheral nerves.


METHODS
We investigated the influence of fosinopril on noradrenergic uptake into cardiac neurones in vitro and in vivo in acute and chronic models.


RESULTS
Acute administration of fosinoprilat to isolated perfused rat hearts increased the extraction of [3H]-noradrenaline from the perfusate by 39%. Treatment (14 days) of spontaneously hypertensive rats (SHR) with fosinopril (20 mg/kg per day) enhanced the cardiac uptake of i.v. administered [3H]-noradrenaline by 28%. The endogenous left ventricular content of noradrenaline was increased by 49% after an antihypertensive treatment of SHR with fosinopril (20 mg/kg per day). Identical increases in cardiac noradrenaline stores (53%) were observed in SHR treated with a blood pressure ineffective dose of fosinopril (0.2 mg/kg per day). The myocardial content of adrenaline was increased in parallel to noradrenaline after both dose regimes.


CONCLUSIONS
It is concluded that ACEI increases neuronal uptake of catecholamines in SHR in a blood pressure-independent manner. This effect occurs acutely and is independent of central sympathetic activity. Therefore, we hypothesize that ACEI modulate the activity of the cardiac noradrenaline transporter by direct activation. The improved uptake of noradrenaline may contribute to the antihypertensive and cardioprotective effects of ACEI.
Raasch
W
W
Institute of Experimental and Clinical Pharmacology and Toxicology, Medical University of Luebeck, Germany. raasch@medinf.mu-luebeck.de
Betge
S
S
Dendorfer
A
A
Bartels
T
T
Dominiak
P
P
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D017328:Fosinopril / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006329:Heart Conduction System / Q000378:metabolism*; D006352:Heart Ventricles; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009638:Norepinephrine / Q000493:pharmacokinetics*; D051381:Rats; D011918:Rats, Inbred SHR / Q000378:metabolism*; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D017328:Fosinopril; C046965:fosinoprilat; D009638:Norepinephrine