The sympathetic nervous system regulates cardiovascular function by activating adrenergic receptors in the heart, blood vessels and kidney. α₂-Adrenergic receptors are known to have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system^,,,; however, the individual roles of the three highly homologous α₂-adrenergic-receptor subtypes (α_2A, α_2B, α_2C) in this process are not known. We have now studied neurotransmitter release in mice in which the genes encoding the three α₂-adrenergic-receptor subtypes were disrupted. Here we show that both the α_2A- and α_2C-subtypes are required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. α_2A-Adrenergic receptors inhibit transmitter release at high stimulation frequencies, whereas the α_2C-subtype modulates neurotransmission at lower levels of nerve activity. Both low- and high-frequency regulation seem to be physiologically important, as mice lacking both α_2A- and α_2C-receptor subtypes have elevated plasma noradrenaline concentrations and develop cardiac hypertrophy with decreased left ventricular contractility by four months of age.