Determinants of cardiac tyrosine hydroxylase activity during exercise-induced sympathetic activation in humans.
This study assessed whether the mechanisms regulating cardiac norepinephrine (NE) synthesis with changes in NE release are influenced by functions of sympathetic nerves affecting transmitter turnover independently of transmitter release. Differences in arterial and coronary venous plasma concentrations of NE and its metabolites and of dihydroxyphenylalanine (DOPA), the immediate product of tyrosine hydroxylase (TH), were examined before and during cycling exercise. Relative increases during exercise in cardiac tyrosine hydroxylation (as reflected by the %increase in cardiac DOPA spillover) matched closely corresponding increases in NE turnover, but were much lower than increases in NE release. The much larger relative increases in release than turnover of NE were largely attributable to the extensive contribution to transmitter turnover from intraneuronal metabolism of NE leaking from storage vesicles. This contribution remains unchanged during sympathetic activation so that the relative increase in NE turnover is much smaller than that in exocytotic release of NE. To replenish the NE lost from stores during sympathetic activation, TH activity need increase only in proportion to the smaller increase in turnover rather than the larger relative increase in release. The ability to "gear down" increases in tyrosine hydroxylation relative to increases in NE release provides sympathetic nerves the capacity for a more extended range of sustainable release rates than otherwise possible.
Eisenhofer
G
G
Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Rundqvist
B
B
Friberg
P
P
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000328:Adult; D002396:Catechols / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004837:Epinephrine / Q000378:metabolism; D006321:Heart / Q000294:innervation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology*; D009638:Norepinephrine / Q000378:metabolism*; D009647:Normetanephrine / Q000378:metabolism; D010507:Periodicity; D005082:Physical Exertion / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D002396:Catechols; D009647:Normetanephrine; D015102:3,4-Dihydroxyphenylacetic Acid; D004295:Dihydroxyphenylalanine; D014446:Tyrosine 3-Monooxygenase; D003891:Desipramine; D009638:Norepinephrine; D004837:Epinephrine