In vivo measurement of neuronal uptake of norepinephrine in the human heart.

Abstract

Neuronal uptake (Uptake-i) of the sympathetic neurotransmitter norepinephrine from the circulation in the human heart was assessed in vivo with three techniques. 1) Cardiac removal of intravenously infused tracer-labeled norepinephrine was measured before and after Uptake-i blockade with desipramine; 2) the difference between the fractional extraction of radioactive norepinephrine and of radioactive isoproterenol, which is not a substrate for neuronal uptake, was used to estimate the removal of norepinephrine by Uptake-i in the heart compared with other vascular beds (arm, leg, brain, and lungs); and 3) regional arteriovenous differences in radioactive and endogenous dihydroxyphenylglycol (DHPG), an exclusively intraneuronal metabolite of norepinephrine, were compared in these beds. In untreated patients, cardiac removal of radioactive norepinephrine averaged 79%, whereas in desipramine-treated patients, cardiac removal of radioactive norepinephrine averaged 19%, a value similar to that of isoproterenol in untreated patients (14%), confirming that in the heart the non-neuronal removals of isoproterenol and norepinephrine were similar. In the heart, 69% of delivered norepinephrine was estimated to be removed by Uptake-i, a much higher percentage than that in the arm (14%), leg (7%), brain (10%), and lungs (4%). The cardiac arteriovenous increment in endogenous DHPG (137%) far exceeded that of the other beds (49%, 26%, 39%, and -19%, respectively), and radioactive DHPG in the great cardiac vein exceeded arterial levels by 113%, whereas in the other beds, arterial radioactive DHPG exceeded venous levels. The results indicate that the human heart is exceptionally dependent on neuronal uptake for in vivo removal of circulating norepinephrine. (Circulation 1988;78:41-48) S everal pathophysiological and therapeutic concepts in cardiology have been based on sympathetic neuroeffector mechanisms in the heart. A limitation in evaluating these concepts has been the inability to measure cardiac sympathetic function in vivo, especially the activity of the neuronal uptake process (Uptake-1), which is the predominant means for terminating the actions of the sympathetic neurotransmitter norepinephrine (NE). The present study introduces three clinical techniques to examine cardiac neuronal uptake of NE.In the first technique, cardiac removal of tracerlabeled NE was measured before and after Uptake-1 blockade with desipramine, a procedure previously used in laboratory animals. 1-3From the Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute (D.S.G., R.S), Cardiology Branch, National Heart, Lung, and Blood Institute (J.E.

Influences of Norepinephrine Transporter Function on the Distribution of Sympathetic Activity in Humans

“…Indeed, a larger proportion of the released norepinephrine is taken up through NET in the heart compared with other organs. 19 Another possible explanation for the discordant effect of NET inhibi- tion on the heart, vasculature, and kidney is an organ-specific alteration in baroreflex regulation. In an earlier study, NET inhibition with reboxetine was associated with a shift in the baroreflex heart rate curves such that at a given blood pressure heart rate was increased.…”

“…Indeed, a larger proportion of the released norepinephrine is taken up through NET in the heart compared with other organs. 19 Another possible explanation for the discordant effect of NET inhibi- …”

Norepinephrine Transporter–Deficient Mice Exhibit Excessive Tachycardia and Elevated Blood Pressure With Wakefulness and Activity

“…2,3 Peripherally, NET is perhaps most important in the heart. 4,5 In humans, approximately 92% of cardiac NE removal occurs via NET, with the remainder eliminated by extraneuronal carriers and circulatory dissipation. 6 Pharmacological blockade of NET increases extraneuronal concentrations of its substrate(s), 7 a mechanism employed in the treatment of depression and anxiety, 8,9 although autonomic side effects are common.…”

AN ASSESSMENT OF ECHOCARDIOGRAPHY AS A DIAGNOSTIC TOOL FOR DILATED CARDIOMYOPATHY IN TURKEY (<i>MELEAGRIS GALLOPAVO</i>)

“…The toxic levels of Fz added to the diets of poults may have resulted to a combination of myocyte injury and necrosis associated with myocardial fibrosis, which led to impaired mechanical function leading to ventricular dilation (Goldstein et al, 1998). Also addition of Fz may have led to direct toxicity or mechanical insults such as; chronic volume overload in mitral valvular regurgitation with myocyte failure and cytoskeletal uncoupling of the chambers leading to dilation (Goldstein et al, 1998). The differences observed between LVIDd and LVISd for poults fed Fz-containing diets and those in the control group are similar to that of Wu et al (2004), which reported increased left ventricular dimension for poults fed Fz-containing diets.…”