AT1 and AT2-receptor antagonists inhibit Ang II-mediated facilitation of noradrenaline release in human atria.
It is generally accepted that regulation of blood pressure and sympathetic neurotransmission by angiotensin (Ang) II is brought about through activation of AT1-receptors. Since recent studies demonstrated a high proportion of AT2-receptors in the human heart, the aim of our study was to investigate whether Ang II modulates noradrenaline release also through activation of AT2-receptors in this tissue. Human atrial appendages were prelabeled with [3H]-noradrenaline and electrically field-stimulated. Stimulation-induced outflow of radioactivity was taken as an index of endogenous noradrenaline release. Ang I and II enhanced noradrenaline release in a dose-dependent manner up to 55 and 72%, respectively. These effects were blocked by the selective AT1-receptor antagonists EXP3174 and irbesartan (10 nmol/L). Moreover, the selective AT2-receptor antagonists PD123319 and CGP42112A (0.1 and 1 micromol/L) also inhibited Ang II-induced facilitation of noradrenaline release. Captopril (5 micromol/L) shifted the dose response curve for Ang I less potent to the right than EXP3174 (10 nmol/L). Ang I and II enhanced the stimulation-induced noradrenaline release significantly more potent in tissues of patients pretreated with ACE inhibitors than without. In conclusion, both AT1- and AT2-receptors seem to play a role in Ang II-mediated facilitation of noradrenaline release in the human heart. Chronic treatment with ACE inhibitors appears to affect cardiac sympathetic neurotransmission possibly by upregulation of presynaptic Ang II receptors.
El Muayed
Malek
M
Department of Internal Medicine I, The University of Texas, Houston, Texas, USA.
Stegbauer
Johannes
J
Oberhauser
Vitus
V
Vonend
Oliver
O
Rump
Lars Christian
LC
D000328:Adult; D000368:Aged; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D009638:Norepinephrine