We examined cardiac norepinephrine kinetics in 11 patients with hypertrophic cardiomyopathy (HCM) and in 10 controls. Neuronal uptake of norepinephrine was assessed by comparing 1) the extraction of labelled norepinephrine and isoproterenol, which is not a substrate for neuronal uptake; and 2) the relation between dihydroxyphenylglycol (DHPG) production an intraneuronal metabolite of norepinephrine, and spillover of norepinephrine. Cardiac norepinephrine extraction was less in HCM patients than in C (59 plus or minus 17 vs 79 plus or minus 13%, p less than 0.05), whereas extraction of isoproterenol was similar (13 plus or minus 23 vs 13 plus or minus 14%). The arteriovenous difference in norepinephrine was larger in the HCM patients (73 plus or minus 77 vs 13 plus or minus 50 pg/ml, p less than 0.05) as was the arteriovenous difference times blood flow (7.3 plus or minus 7.3 vs 0.8 plus or minus 3.0 ng/min p less than 0.05). The slope of the line relating cardiac DHPG production to cardiac norepinephrine spillover was less in the HCM patients than in controls (p less than .005), indicating that the increased norepinephrine arteriovenous difference in HCM is not due to increased norepinephrine release (which would result in increased DHPG production), but due to decreased norepinephrine neuronal uptake. These results indicate that cardiac norepinephrine neuronal uptake is defective in HCM. This defect may increase norepinephrine levels at myocardial adrenoceptors and thereby play a role in the pathophysiology of HCM.