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.