Vasken Dilsizian - Atlas of Cardiac Innervation

Sympathetic neuronal synapse in the heart. The sympathetic neuronal transmitter norepinephrine ( NE ) is synthesized from tyrosine. First, it is converted to dopamine by cytoplasmic enzymes. Dopamine then is transported to intraneuronal vesicles, where NE is synthesized and stored. Upon neuronal stimulation, the vesicles fuse with the presynaptic membrane and release the NE into the cleft. The released NE then binds to the postsynaptic - and -adrenergic receptors, which are G-proteincoupled receptors, to transduce signals to improve excitationcontraction coupling of the myocardium and to increase heart rate and force. Cleft NE also activates the presynaptic 2-adrenergic receptors to inhibit further NE release. The effect of the NE is terminated by two mechanisms: approximately 80 % of the NE is taken up to the presynaptic area by an ATP-dependent active process via a transporter called human norepinephrine transporter 1 (hNET1; uptake-1 system), whereas the reminder spills over into the nonneuronal tissue and bloodstream (uptake-2 system). Thus, several molecules in this pathway may serve as targets for the functional imaging of sympathetic tone in the heart. For example, to target the neurotransmitter NE, 123I -m IBG and 11C-HED were developed. Both radiotracers mimic the neuronal transport and storage process of NE and represent cardiac sympathetic activity. hNET1 also may be an ideal target to represent the uptake-1 system activity in the heart. AC adenyl cyclase, AMP adenosine monophosphate, cAMP cyclic adenosine monophosphate, COMT catechol- O -methyltransferase, DA dopamine, DHPG dihydroxyphenylglycol, DOPA dihydroxyphenylalanine, MAO monoamine oxidase, NMN normetanephrine (Data from Haider et al. []).

Down-regulation of the presynaptic hNET1 in heart failure. In patients with heart failure (ischemic or nonischemic), initially there is increased sympathetic activity with increased release of NE from the presynaptic vesicles as a compensatory reaction to contribute to increased cardiac contractility. ( a , b ) There is corresponding down-regulation of the hNET1 transporter (decreased uptake-1 system) in idiopathic dilated cardiomyopathy (IDCM) and ischemic cardiomyopathy (ISCM) []).