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The clearance of norepinephrine from plasma and the spillover rate of norepinephrine into plasma were determined in conscious unrestrained spontaneously hypertensive rats by measuring the concentrations of 3H-norepinephrine and norepinephrine in arterial plasma after 90 min of i.v. infusion with 3H-norepinephrine. In 50 conscious spontaneously hypertensive rats treated with saline (control animals), the following basal values were obtained: plasma norepinephrine concentration = 149 +/- 5 pg/ml; plasma epinephrine concentration = 61 +/- 4 pg/ml; norepinephrine clearance = 188 +/- 4 ml min-1 kg-1; and norepinephrine spillover rate = 27.5 +/- 0.8 ng min-1 kg-1. A significant portion of infused 3H-norepinephrine appeared to be cleared from the plasma by the uptake1 process, since desipramine decreased norepinephrine clearance by 32%. The vasodilating agents hydralazine and minoxidil produced dose-related increases in norepinephrine spillover rate and plasma norepinephrine concentration, but the percent increases in norepinephrine spillover rate exceeded the percent increases in plasma norepinephrine concentration because of concomitant increases in norepinephrine clearance, particularly after treatment with minoxidil. The increase in norepinephrine clearance caused by hydralazine and minoxidil probably resulted from the increase in cardiac output and resultant increase in hepatic and/or pulmonary blood flow. Adrenal secretion of norepinephrine did not appear to contribute to the elevation in norepinephrine spillover rate elicited by hydralazine and minoxidil. Chlorisondamine suppressed norepinephrine spillover rate by 77%, in association with a 70% decline in plasma epinephrine concentration, whereas bretylium lowered norepinephrine spillover rate by only 41%, with no change in plasma epinephrine concentration. The decrements in norepinephrine clearance caused by chlorisondamine (-23%) and bretylium (-15%) were more or less proportional to the magnitude of the vasodepression caused by these drugs. Both norepinephrine spillover rate and clearance fell in a dose-related fashion after treatment with clonidine. After treatment with the sympathoinhibitory agents chlorisondamine, bretylium and clonidine, the percent decreases in norepinephrine spillover rate always exceeded the percent decreases in plasma norepinephrine concentration. Based on these observations, we conclude that norepinephrine spillover rate provides a more accurate measurement of the activity of the peripheral sympathetic nervous system than does plasma norepinephrine concentration in conscious spontaneously hypertensive rats.
The aim of the present study was to investigate the potential of human platelets for sulfoconjugation of plasma norepinephrine. For this purpose the uptake and the efflux of norepinephrine and norepinephrine sulfate were studied in vitro in intact human platelets. Incubation of platelets with 0.5 mumol/l norepinephrine led to a rapid uptake of norepinephrine within 1 min (22.76 +/- 4.14 pmol/2.5 x 10(9) platelets/min), whereby 63.7% was transformed to norepinephrine sulfate. The substrate kinetics showed a different slope of norepinephrine uptake with increasing norepinephrine concentrations in the incubation medium (0.1-0.5 mumol/l). At 0.1 mumol/l norepinephrine the uptake was more efficient than at higher norepinephrine concentrations. Incubation with norepinephrine sulfate slightly decreased intraplatelet norepinephrine sulfate (p < or = 0.01). Incubation of human platelets in a catecholamine free medium led to an efflux of norepinephrine and norepinephrine sulfate (21.8%, 11.2% of total intraplatelet content, respectively). The present findings indicate a net uptake of norepinephrine into the platelets. At physiological norepinephrine concentrations the uptake seems to be achieved predominantly by an active transport mechanism. Moreover, data indicate a net efflux of norepinephrine sulfate. Therefore it is concluded that human platelets might contribute to the formation of plasma norepinephrine sulfate by norepinephrine uptake, intraplatelet sulfoconjugation and release of norepinephrine sulfate.
PURPOSE: Guinea pig seminal vesicle smooth muscle displays an initial androgen dependent, proliferative response during early puberty, followed by progression to an androgen resistant, amitotic state in adults. We determined the role of norepinephrine in androgen dependent pubertal proliferation and in the subsequent terminal differentiation of adult seminal vesicle smooth muscle. MATERIALS AND METHODS: Guinea pig seminal vesicle provided a suitable model since its unique anatomy allowed clean harvest of smooth muscle without epithelium. Norepinephrine release from postganglionic adrenergic nerve terminals in seminal vesicle smooth muscle was measured using several techniques. Prazosin sensitive electrical field stimulation of contractile responses qualitatively assessed norepinephrine release. Norepinephrine release was quantified directly in vitro from incubated seminal vesicle smooth muscle minces and indirectly ex vivo from intact tissue using the endogenous seminal vesicle smooth muscle concentration ratio of 3,4-dihydroxyphenylglycol-to-norepinephrine (Sigma Chemical Co., St. Louis, Missouri). Norepinephrine mediated seminal vesicle smooth muscle proliferation was assessed by the time course relationships of androgen induced norepinephrine release, protein kinase C activation-depletion and increases in total DNA, the impact of in vivo reserpine induced norepinephrine depletion on protein kinase C activation-depletion and the mitogenic response, and the alpha1-adrenoceptor mediated mitogenic response in cultured seminal vesicle smooth muscle cells. RESULTS: In prepubertal smooth muscle androgen induced norepinephrine release from postganglionic neurons. The effect was independent of preganglionic innervation. Increased norepinephrine release was concurrent with the onset of androgen induced protein kinase C activation-depletion and cellular proliferation. In vivo norepinephrine depletion to 1% or less of control values by chronic reserpine treatment selectively antagonized the androgen induced increases in smooth muscle DNA and protein kinase C down-regulation. Norepinephrine depletion by reserpine neither induced apoptosis nor altered cell number. Cell culture experiments demonstrated that alpha1-adrenoceptors mediated the proliferative response to norepinephrine. Together these findings indicate that increased norepinephrine release has an obligatory role in androgen dependent muscle cell proliferation during puberty. Terminally differentiated smooth muscle in adults was characterized by androgen resistance to elevated norepinephrine release and protein kinase C activation. CONCLUSIONS: Androgen induced norepinephrine release from postganglionic neurons in seminal vesicle smooth muscle mediated the proliferative response that occurs in early pubertal development. Normal uncoupling of elevated norepinephrine release and protein kinase C activation-depletion may represent a key event in the normal terminal differentiation of accessory sex organ smooth muscle in adults.
Norepinephrine stimulates the growth of a range of bacterial species in nutritionally poor SAPI minimal salts medium containing 30% serum. Addition of size-fractionated serum components to SAPI medium indicated that transferrin was required for norepinephrine stimulation of growth of Escherichia coli. Since bacteriostasis by serum is primarily due to the iron-withholding capacity of transferrin, we considered the possibility that norepinephrine can overcome this effect by supplying transferrin-bound iron for growth. Incubation with concentrations of norepinephrine that stimulated bacterial growth in serum-SAPI medium resulted in loss of bound iron from iron-saturated transferrin, as indicated by the appearance of monoferric and apo- isoforms upon electrophoresis in denaturing gels. Norepinephrine also caused the loss of iron from lactoferrin. The pharmacologically inactive metabolite norepinephrine 3-O-sulfate, by contrast, did not result in iron loss from transferrin or lactoferrin and did not stimulate bacterial growth in serum-SAPI medium. Norepinephrine formed stable complexes with transferrin, lactoferrin, and serum albumin. Norepinephrine-transferrin and norepinephrine-lactoferrin complexes, but not norepinephrine-apotransferrin or norepinephrine-albumin complexes, stimulated bacterial growth in serum-SAPI medium in the absence of additional norepinephrine. Norepinephrine-stimulated growth in medium containing (55)Fe complexed with transferrin or lactoferrin resulted in uptake of radioactivity by bacterial cells. Moreover, norepinephrine-stimulated growth in medium containing [(3)H]norepinephrine indicated concomitant uptake of norepinephrine. In each case, addition of excess iron did not affect growth but significantly reduced levels of radioactivity ((55)Fe or (3)H) associated with bacterial cells. A role for catecholamine-mediated iron supply in the pathophysiology of infectious diseases is proposed.
BACKGROUND: Measurement of cardiac norepinephrine spillover may indicate the amount of transmitter at neuroeffector sites but does not distinguish neuronal release or reuptake in determining this amount or provide information about other aspects of sympathetic function. This report examines how cardiac spillover of the norepinephrine metabolite dihydroxyphenylglycol (DHPG) provides additional distinct information about cardiac sympathetic function. METHODS AND RESULTS: Arterial and coronary venous blood samples were taken during cardiac catheterization and intravenous infusion of [3H]norepinephrine in 57 subjects. Subjects were given intravenous yohimbine or underwent mental stress, handgrip exercise, and cycling exercise to activate sympathetic nerves or were given intravenous desipramine to block norepinephrine reuptake. Cardiac DHPG spillover (601 +/- 41 pmol/min) was eightfold greater than norepinephrine spillover (78 +/- 10 pmol/min) at rest and increased during sympathetic activation by 65% of the increase of norepinephrine. This and the desipramine-sensitive cardiac production of [3H]-labeled DHPG from [3H]norepinephrine indicated that 10.5 times more endogenous norepinephrine is recaptured than escapes into plasma; that more than 90% of recaptured norepinephrine is sequestered into storage vesicles; and that under resting conditions, most cardiac spillover of DHPG and turnover of norepinephrine are from metabolism of transmitter leaking from vesicles; the latter process is independent of exocytotic transmitter release with a rate at rest over 100-fold that of norepinephrine spillover and over 10-fold that of norepinephrine reuptake. CONCLUSIONS: Cardiac spillover of DHPG provides information about processes close to or within sympathetic nerve endings that cannot be provided by measurements of norepinephrine spillover alone. This includes quantitative information about the role of neuronal uptake in terminating the actions of norepinephrine at neuroeffector sites and the importance of vesicular-axoplasmic exchange of norepinephrine as a dynamic process contributing to norepinephrine turnover.
The isolated perfused guinea-pig heart prelabeled with (-)-[7-3H]-norepinephrine was used to examine the effects of increasing concentrations of ouabain on the sympathetic nerve stimulation-evoked release of endogenous norepinephrine and [3H]norepinephrine in the presence and absence of physostigmine or atropine. The overflow of norepinephrine and [3H]norepinephrine from guinea-pig hearts was measured during postganglionic stimulation of the cardiac accelerator fibers (5 Hz for 60 sec, 2 msec duration, for 300 pulses). Perfusion with 10(-7) M ouabain for 20 min had no effect on the release of norepinephrine or [3H]norepinephrine after nerve stimulation. However, perfusion with either 10(-6) or 3 X 10(-6) M ouabain for 15 min resulted in a significant decrease in the nerve stimulation-evoked release of norepinephrine (44.6 +/- 2.24 and 44.0 +/- 2.17%, respectively) and [3H]norepinephrine (43.8 +/- 1.62 and 44.9 +/- 2.16%, respectively) compared with previous control outputs. Perfusion of hearts with physostigmine (10(-6) M), an acetylcholinesterase inhibitor, or atropine (3 X 10(-6) M), a muscarinic blocking agent, did not alter the release of norepinephrine or [3H]norepinephrine after nerve stimulation. Perfusion with physostigmine during perfusion with 10(-6) M ouabain resulted in a decrease in the release of norepinephrine and [3H]norepinephrine only slightly greater than 10(-6) M ouabain alone, which was not significant, but the release of norepinephrine during stimulations performed after a 45-min washout of 10(-6) M ouabain was decreased significantly when 10(-6) M physostigmine was present. Perfusion of hearts with atropine during perfusion with either 10(-6) or 3 X 10(-6) M ouabain reversed the inhibitory effect of ouabain on the release of norepinephrine and [3H]norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Congestive heart failure is a clinical syndrome characterized by neuroendocrine activation. Measurements of plasma norepinephrine and plasma renin activity were performed in the Vasodilator-Heart Failure Trial II (V-HeFT II) to characterize the effect of therapy on neuroendocrine activation and to examine the responses to therapy among patients with different degrees of activation. METHODS AND RESULTS: The baseline median plasma norepinephrine value (n = 743) was 490 pg/mL and the baseline median plasma renin activity (n = 737) was 6.9 ng.mL-1 x hr-1. Baseline plasma renin activity and plasma norepinephrine correlated poorly with each other (r = 0.12), implying that these two neuroendocrine systems are being activated by separate processes. By univariate analysis, the logarithms of the plasma norepinephrine (p < 0.0001) and the plasma renin activity (p = 0.01) were significantly related to all-cause mortality. In a multivariate analysis that included other significant univariate prognostic variables (i.e., baseline ejection fraction, peak oxygen consumption during exercise, and cardiothoracic ratio), log plasma norepinephrine but not plasma renin activity remained a significant (p = 0.02) predictor of mortality. Baseline plasma norepinephrine correlated poorly with baseline left ventricular ejection fraction (r = -0.18), peak oxygen consumption (r = -0.15), and cardiothoracic ratio (r = 0.11). Neither the plasma norepinephrine (r = 0.09) nor the plasma renin activity (r = 0.18) was closely associated with a quality of life assessment at baseline. The baseline plasma norepinephrine level in patients randomized to enalapril (mean, 593 +/- 388 [SD] pg/mL; n = 372) and to hydralazine and isosorbide dinitrate (mean, 544 +/- 297 pg/mL; n = 371) were similar. Thirteen weeks after randomization, plasma norepinephrine did not change (-5 +/- 393 pg/mL) in 312 patients randomized to enalapril but increased significantly by 74 +/- 311 pg/mL (p < 0.0001) in 300 patients assigned to hydralazine-isosorbide dinitrate. The plasma norepinephrine increased significantly more in patients assigned to hydralazine-isosorbide dinitrate than those on enalapril at both 13 weeks (p = 0.01) and at 1 year (p = 0.04) (90 +/- 302 pg/mL [n = 240] versus 14 +/- 376 pg/mL [n = 265]). Based on previous reports and examination of survival among several plasma norepinephrine strata, the baseline plasma norepinephrine data were grouped into three relatively homogeneous strata for further analysis. The cumulative mortality was significantly different between the three strata (p < 0.0001). The patients with plasma norepinephrine > 900 pg/mL had a higher mortality than those with corresponding values from 601 to 900 pg/mL or < 600 pg/mL. The survival benefit of enalapril compared with hydralazine-isosorbide dinitrate was most evident in those patients with a plasma norepinephrine value > 900 pg/mL. Although the plasma renin activity was not strongly associated with survival, patients in the upper quartile (> 16 ng.mL-1 x hr-1) had the worst prognosis. Among this group, the patients on enalapril demonstrated significantly better survival than those on hydralazine-isosorbide dinitrate (p = 0.02). CONCLUSIONS: This study confirms that plasma norepinephrine is an independent predictor of prognosis in patients with congestive heart failure. Hydralazine-isosorbide dinitrate treatment, unlike enalapril treatment, was associated with increased plasma norepinephrine concentration during the first year of follow-up. The enalapril group had a significantly lower mortality, and this survival benefit of enalapril as compared with hydralazine-isosorbide dinitrate was most evident among patients with the most marked neuroendocrine activation. Neuroendocrine activation is an important prognostic factor for patients with congestive heart failure and is an important determinant of the differential response to vasodilators.
This study determined the fractional extraction of epinephrine and norepinephrine by the in situ dog pancreas. Plasma samples for epinephrine measurements were taken simultaneously from the femoral artery and the superior pancreaticoduodenal vein. Pancreatic extraction of epinephrine was 73 +/- 5% when basal arterial epinephrine levels were 380 +/- 93 pg/mL, 76 +/- 4% when arterial levels were 896 +/- 123 pg/mL (epinephrine infused intravenously at 20 ng/kg/min), and 84 +/- 1% when arterial levels were 2,956 +/- 414 pg/mL (epinephrine infused intravenously at 80 ng/kg/min) suggesting that the process of epinephrine extraction by the pancreas is not saturable over this range. During a similar sampling protocol, norepinephrine was infused intravenously at 4 micrograms/kg/min; pancreatic extraction of norepinephrine was then 65 +/- 7% when arterial norepinephrine levels were 107,000 +/- 28,000 pg/mL. In separate experiments, lower rates of norepinephrine (12 to 1,200 ng/min) were infused directly into the pancreatic artery and pancreatic norepinephrine extraction was calculated; it ranged between 66% and 75%. Because the pancreas produces as well as extracts norepinephrine, a third technique was required to determine pancreatic norepinephrine extraction at the lower endogenous levels of norepinephrine; 3H-norepinephrine was infused intravenously and the arteriovenous difference of 3H-norepinephrine was measured. Fractional extraction of 3H-norepinephrine was 74 +/- 4% both in the basal state (arterial norepinephrine level = 202 +/- 44 pg/mL) and during systemic, glucopenic, stress induced by 2-deoxy-glucose (arterial norepinephrine level = 636 +/- 70 pg/mL). These data suggest that also the norepinephrine extraction process by the pancreas is not saturable.(ABSTRACT TRUNCATED AT 250 WORDS)
The release of [3H]norepinephrine from isolated mouse vas deferens has been measured. 1-Phenylephrine and 1-norepinephrine significantly enhanced the spontaneous release of radioactivity. As shown by a combination of HPLC and scintillation spectrometry, the release of total radioactivity in response to 1-phenylephrine or 1-norepinephrine consisted mainly of [3H]norepinephrine. Evidence has been obtained that the release of endogenous norepinephrine by exogenous norepinephrine and 1-phenylephrine is independent of the external Ca2+ concentration. The released endogenous norepinephrine in turn inhibits the release of norepinephrine in response to electrical field stimulation. In the presence of yohimbine, the enhancement of spontaneous release due to 1-phenylephrine (or to 1-norepinephrine) was not affected, whereas there was a significant superimposed release of [3H]norepinephrine in response to field stimulation, indicating that the inhibition of stimulation-induced norepinephrine release is an alpha 2-adrenoceptor-mediated process. An important consequence of these findings is to question previous interpretations that the effects of administration of 1-norepinephrine or 1-phenylephrine are due exclusively to their direct effects on the effector cells. The Ca-independent release of endogenous norepinephrine might partly initiate their pharmacological responses. It is concluded that this Ca-independent release is of functional importance, since norepinephrine may accumulate in a concentration sufficient to modulate the release of norepinephrine from varicosities in response to electrical stimulation.
Aging is associated with elevations in plasma norepinephrine concentrations. The purpose of this investigation was to examine total body and regional norepinephrine spillover as an indicator of sympathetic nerve activity. Eight young (26 +/- 3 yr) and seven old (69 +/- 5 yr) male subjects were studied at rest and during 20 min of submaximal cycling exercise at 50% of peak work capacity. Norepinephrine spillover was determined by continuous intravenous infusion of [3H]norepinephrine. Arterial norepinephrine concentrations were significantly greater at rest for old vs. young subjects (280 +/- 36 vs. 196 +/- 27 ng/ml, respectively). Whereas total norepinephrine spillover did not differ between groups at rest, hepatomesenteric norepinephrine spillover was 50% greater in old subjects compared with their young counterparts (51 +/- 7 vs. 34 +/- 5 ng/min, respectively). Additionally, norepinephrine clearance rates at rest were significantly lower for the old subjects (-23%). During exercise, plasma norepinephrine concentrations increased compared with rest, with old subjects again demonstrating greater values than the young group. Hepatomesenteric norepinephrine spillover was significantly greater (+36%) during exercise for old subjects compared with young; however, no difference was found for whole body spillover rates between age groups. Norepinephrine clearance rates remained depressed (-80%) in the old subjects during exercise. Clearance of epinephrine mirrored that for norepinephrine both at rest and during exercise across age groups. It was concluded that in old subjects, a reduction in norepinephrine clearance and an increase in regional norepinephrine spillover can account for the higher plasma norepinephrine concentrations observed at rest. This relationship is not exacerbated by the stress imposed during an acute bout of exercise.
BACKGROUND: Reuptake of norepinephrine by cardiac sympathetic nerves before and during two levels of electrical stimulation of the left ansa subclavia was estimated in anesthetized dogs from the cardiac production of dihydroxyphenylglycol (DHPG), the intraneuronal metabolite of norepinephrine. METHODS AND RESULTS: The method depended on the effects of neuronal uptake blockade with desipramine on the cardiac production of [3H]DHPG from intravenously infused [3H]norepinephrine. The ratio of the desipramine-induced decrease in the cardiac extraction of [3H]norepinephrine to the production of [3H]DHPG was used to transform the cardiac production of DHPG from recaptured norepinephrine into a rate for norepinephrine reuptake. Cardiac spillover of norepinephrine into plasma increased from 49 +/- 12 to 205 +/- 40 and 451 +/- 118 pmol/min during sympathetic activation. Cardiac DHPG production increased from 108 +/- 18 to 166 +/- 34 and 240 +/- 47 pmol/min. Desipramine decreased resting cardiac DHPG production by 20% and completely blocked the stimulation-induced increase. Thus, most (80%) cardiac DHPG produced at rest was derived from norepinephrine leaking from storage vesicles. This amount remained constant, and that derived from recaptured norepinephrine increased during sympathetic activation. The cardiac extraction of [3H]norepinephrine (126,000 dpm/min) and production of [3H]DHPG (3,790 dpm/min) were decreased by 55-57% after desipramine. Thus, only 3% of the norepinephrine recaptured by cardiac sympathetic nerves appeared in plasma as DHPG. The remainder was sequestered into storage vesicles (more than 94%) or ultimately formed metabolites other than DHPG (less than 3%). Reuptake of norepinephrine by cardiac sympathetic nerves was 1,188 +/- 476 pmol/min and increased in parallel with cardiac norepinephrine spillover to 4,182 +/- 1,982 and 6,594 +/- 2,241 pmol/min during sympathetic stimulation. CONCLUSIONS: Of the norepinephrine released by cardiac sympathetic nerves, 16-fold more was recaptured than entered plasma. Combined estimation of norepinephrine reuptake and spillover offers an approach to assess the efficiency of neuronal reuptake in disorders of cardiac function.