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PubMed1984

Vasoactive agents and production of thrombosis during intravascular coagulation 1--comparative effects of norepinephrine in thrombin and adenosine diphosphate (ADP) treated rabbits.

Pathogenesis of the microthrombi produced during intravascular coagulation was investigated in rabbits given intravenous infusions of thrombin or adenosine diphosphate (ADP). Thrombin, at a dosage producing a fibrinogen consumption of 70% within 4 h (1 unit/kg/min), failed to produce extrapulmonary microthrombi unless fibrinolysis inhibition (epsilon-aminocaproic acid-EACA) or alpha-adrenergic stimulation (norepinephrine) were provided simultaneously. The mechanism whereby norepinephrine initiated glomerular capillary thrombosis was not related to interference with fibrinolysis nor to potentiation of platelet aggregation and blood coagulation, as indicated by similar consumption of plasminogen and platelets in animals given thrombin alone or combined with norepinephrine, and by the lack of correlation between fibrinogen consumption and the incidence and severity of glomerular thrombosis produced with various dosages (1 to 3 mu/kg/min) of norepinephrine. With norepinephrine, microthrombi were also observed in the adrenals, the spleen and the gastric mucosa. Aspirin prevented the phenomena in the latter two organs, but was inactive or aggravating on thrombogenesis elsewhere. ADP associated with thrombin failed to trigger formation of microthrombi but initiated platelet-rich thrombi in the pulmonary vasculature when associated with norepinephrine. We conclude that unlike thrombin, ADP cannot be held responsible for the microthrombi elicited during experimental intravascular coagulation. Furthermore, the ability of norepinephrine to elicit glomerular thrombosis in thrombin injected rabbits may provide an explanation for requirement of alpha-adrenergic stimulation in the endotoxin-induced generalized Shwartzman reaction.

Adenosine Diphosphate↗

PubMed1993

Effects of epinephrine and norepinephrine on hemodynamic parameters and arrhythmias during a continuous infusion of amitriptyline in rats.

Epinephrine and norepinephrine were evaluated in treatment of hemodynamic compromise in amitriptyline intoxication. One hundred and one male Wistar rats were monitored hemodynamically during amitriptyline intoxication and given one of three infusion rates (0.1, 0.5 or 5.0 mg/kg/min) of either epinephrine or norepinephrine. Sixteen rats served as controls and received only glucose after intoxication. Amitriptyline intoxication lowered mean arterial pressure, heart rate, left ventricular max dP/dt, and increased left ventricular end-diastolic pressure. All doses of norepinephrine and the two higher doses of epinephrine increased mean arterial blood pressure and left ventricular max dP/dt. Heart rate increased with both drugs, more with epinephrine, but not beyond pre-intoxicated levels at any dose. Left ventricular end-diastolic pressure was unaltered by both drugs. Malignant arrhythmias appeared in 7% of all animals, whereas a progressive decline of cardiac contractility caused cardiac arrest in 36% of all animals. This suggests that myocardial depression is the aspect most likely to cause death. At intermediate doses epinephrine resulted in significantly fewer arrhythmias and lower mortality compared to norepinephrine. We conclude that epinephrine and norepinephrine each appeared effective in reversing amitriptyline-induced hemodynamic alterations. Epinephrine had fewer arrhythmogenic properties than norepinephrine and may be preferable to norepinephrine.

Amitriptyline↗

PubMed1988

Pulmonary vascular efflux of norepinephrine in Dahl rats susceptible or resistant to salt-induced hypertension.

The purpose of these studies was to determine whether the accumulation of norepinephrine by the pulmonary circulation is altered in the Dahl model of genetic hypertension. Pulmonary norepinephrine accumulation was evaluated by performing a compartmental analysis of the efflux of L-[3H]norepinephrine from perfused lungs after inhibition of the norepinephrine-metabolizing enzymes. The lungs were isolated from Dahl salt-hypertension-susceptible (S) and salt-hypertension-resistant (R) rats that had been on a high sodium diet for 3 weeks. In both S and R rats, norepinephrine was accumulated into a single compartment with an efflux half-time of approximately 23 min, in addition to its distribution in the extracellular space. The size of the extracellular space was significantly increased in the S rats, but there was no difference in the size of the compartment of L-[3H]norepinephrine efflux between S (6.4 +/- 1.2 ml/g) and R (3.7 +/- 0.7 ml/g) rats. These data indicate that impaired accumulation and efflux of norepinephrine by the lungs does not contribute to the pathogenesis of hypertension in Dahl S rats.

Animals↗

PubMed1976

[Effects of K+ or norepinephrine on oxygen uptake in brown adipose tissue (author's transl)].

This investigation was undertaken to clarify the mechanism of the stimulated--respiration caused by K+ or norepinephrine in brown adipose tissue. 1. The addition of 30 approximately 100 mM K+ stimulated remarkably oxygen uptake in brown adipose tissue, and similarly norepinephrine (0.1 or 1.0 mug/ml) caused a marked stimulation. 2. Even if Na+ in normal Ringer solution was replaced by Choline or Li+, oxygen uptake caused by K+ (30 mM) or norepinephrine (1.0 mug/ml) was unaffected. 3. K+ -induced oxygen uptake was not observed when a Ca2+ -deficient tissue was incubated in Ca2+ -free Ringer, while norepinephrine-induced oxygen uptake clearly observed. And the oxygen uptake of Ca2+ -deficient tissue due to K+ was recovered by the addition of 5 mM Ca2+. 4. Mn2+ (6 mM) or La3+ (10 mM) inhibited significantly oxygen uptake due to K+, but not oxygen uptake due to norepinephrine. 5. K+ -induced oxygen uptake was unaffected by 10(-4) or 10(-3)M ouabain, but norepinephrine-induced oxygen uptake was inhibited considerably by 10(-4)M ouabain. 6. The oxygen uptake due to K+ was unaffected by propranolol (33 muM), whereas that due to norepinephrine was significantly inhibited in the presence of propranolol. 7. In the tissue from reserpine-treated animal, the oxygen uptake caused by K+ was observed. According, from these positive results we are justified to suggest that K+ -induced oxygen uptake is dependent on the presence of Ca2+, and not always caused by catecholamines released secondarily from nerve terminal.

Adipose Tissue, Brown↗

PubMed2002

Comparison of norepinephrine-dobutamine to dopamine alone for splanchnic perfusion in sheep with septic shock.

AIM: To compare the effect of norepinephrine-dobutamine with dopamine alone on splanchnic perfusion in sheep with septic shock. METHODS: Twenty sheep with septic shock induced by lipopolysaccharides were divided into two groups. When systolic pressure decreased by 5.3 kPa, basic values of hemodynamic parameters and intestinal intramucosal pH (pHi) were recorded. Each group was randomized to receive an intravenous infusion of norepinephrine-dobutamine or dopamine, and titrated to obtain mean arterial pressure (MAP) > 12 kPa with an optimal cardiac preload. Hemodynamic parameters and mucosal pHi were repeated at 1, 2, 3, and 4 h after basic measurement. RESULTS: After norepinephrine-dobutamine or dopamine infusion, MAP, cardiac output, and oxygen delivery increased in all animals compared with basic values in both groups (P < 0.05). Compared with baseline values, lactate concentrations decreased at 3 h and 4 h [from (4 +/- 2) mmol/L to (2 +/- 1) mmol/L] in the norepinephrine-dobutamine group (P < 0.05 ). Arterial lactate concentrations had no change in dopamine group, but arterial pH decreased from 7.40 +/- 0.05 to 7.26 +/- 0.06 at 1 h (P < 0.05 ). No difference in pHi was found in dopamine group, but in the norepinephrine-dobutamine group, compared with baseline, pHi increased from 7.19 +/- 0.04 to 7.36 +/- 0.07 at 3 h (P < 0.05). CONCLUSION: Both norepinephrine-dobutamine and dopamine alone could improve systemic hemodynamics in sheep with septic shock, but norepinephrine-dobutamine was better than dopamine on splanchnic perfusion.

Adrenergic alpha-Agonists↗

PubMed1992

Arterial norepinephrine changes in patients with septic shock.

Arterial, mixed venous (pulmonary arterial), and peripheral venous norepinephrine and epinephrine levels; hemodynamics; and blood lactate levels were measured in 28 patients with septic shock (16 men and 12 women). During hospital follow-up, 18 patients (64%) died of circulatory failure. There were no significant differences in hemodynamic parameters or initial blood lactate levels between survivors and nonsurvivors. Initial arterial, mixed venous, and peripheral venous norepinephrine levels were elevated above normal in both survivors and nonsurvivors. However, norepinephrine levels at all three sampling sites were significantly higher in nonsurvivors than in survivors. Arterial or mixed venous norepinephrine level was better than peripheral venous norepinephrine level in distinguishing survivors from nonsurvivors. In contrast, the differences in plasma epinephrine levels between survivors and nonsurvivors became significantly different only after 48 hr of follow-up. During 60 degrees head-up tilt, the increase in plasma norepinephrine level was significantly higher in survivors compared to non-survivors, suggesting a differential response in the sympathetic nervous system in the two groups of patients. These data suggest that measurement of arterial or mixed venous plasma norepinephrine levels may be a useful guide for assessing the clinical course of patients in septic shock. Moreover, the differences in the sympathetic nervous system response to a 60 degree tilt may predict a poor outcome in these patients.

Acidosis, Lactic↗

PubMed1992

Effect of the dopamine D2 receptor agonist quinpirole on renal sympathetic nerve activity and renal norepinephrine spillover in anesthetized rabbits.

Cardiovascular and sympathetic nervous system effects of the dopamine D2 receptor-selective agonist quinpirole were studied in anesthetized rabbits. Sodium nitroprusside was administered for comparison. The animals received a tracer infusion of [3H] norepinephrine i.v. Arterial and renal venous concentrations of endogenous norepinephrine and epinephrine and [3H]norepinephrine, the firing rate of the renal sympathetic nerves and renal blood flow were determined. Quinpirole (100 micrograms kg-1 + 5 micrograms kg-1 min-1 i.v.) lowered blood pressure and renal vascular resistance. The firing rate of the renal sympathetic nerves was increased, but there was no reflex tachycardia. Despite the increase in renal sympathetic firing, the renal spillover of norepinephrine into blood was decreased. The increase in total body norepinephrine spillover during quinpirole-induced hypotension was less than expected from baroreflex activation. Effects of quinpirole were antagonized by domperidone (1000 micrograms kg-1 + 200 micrograms kg-1 h-1). The distinguishing feature of this study is the simultaneous measurement of sympathetic firing and norepinephrine spillover in the same organ, the kidney, under conditions of intact sympathetic impulse traffic. Quinpirole activated presynaptic D2 receptors and thus reduced the released norepinephrine per action potential. Consequences of the presynaptic inhibition were reductions of blood pressure and renal vascular resistance and absence of reflex tachycardia.

Animals↗

PubMed2003

[Comparison of effect of norepinephrine-dobutamine and that of dopamine alone on splanchnic perfusion in sheep with septic shock].

OBJECTIVE: To compare the effect of norepinephrine-dobutamine and that of dopamine alone on splanchnic perfusion in sheep with septic shock. METHODS: Twenty sheep with septic shock induced by lipopolysaccharides were divided into two groups. When systolic pressure was decreased to 39.75 mm Hg(1 mm Hg=0.133 kPa), basic values of hemodynamic parameters and intestinal intramucosal pH (pHi) were monitored. The animals were randomized to either receive an intravenous infusion of norepinephrine-dobutamine in combination or dopamine alone, and the dosage was titrated to obtain a mean arterial pressure (MAP)> 90.00 mm Hg with an optimal cardiac preload. Hemodynamic parameters and mucosal pHi were repeatedly measured at 1-, 2-, 3-, 4-hour after basic measurement. RESULTS: After norepinephrine-dobutamine or dopamine infusion, MAP, cardiac output, and oxygen delivery were increased in all animals compared to basic values in both groups (P<0.05). Compared to baseline values (4.0+/-1.8)mmol/L, lactate concentrations were decreased at 3-hour (2.3+/-1.1) mmol/L and 4-hour (2.1+/-1.1)mmol/L in the norepinephrine-dobutamine group (P<0.05). There were no differences in arterial lactate concentrations in the dopamine group, but arterial pH was decreased from 7.40+/-0.05 to 7.26+/-0.06 at 2-hour (P<0.05 ). No Change in pHi was found in the dopamine group, but in the norepinephrine-dobutamine group, compared to baseline, pHi was increased from 7.19+/-0.04 to 7.36+/-0.07 at 3-hour (P<0.05). CONCLUSION: Both norepinephrine-dobutamine and dopamine could improve systemic hemodynamics in sheep with septic shock, but the effect of norepinephrine-dobutamine in combination was better than dopamine on splanchnic perfusion.

Animals↗

PubMed1977

Specific enhancement of norepinephrine-induced contraction in rat veins after beta adrenergic antagonists.

Propranolol markedly increased the norepinephrine-induced maximal force in circular smooth muscle of the rat portal, mesenteric, renal and, to a lesser extent, femoral veins without affecting aortic or mesenteric artery responses to norepinephrine. Furthermore, two other beta receptor antagonists, practolol and N-isopropylmethoxamine, specifically enhanced maximal venous responses to norepinephrine. Contractions to norepinephrine, but not to serotonin, were increased by propranolol only in veins, even after the vasodilator, papaverine. The ability of propranolol to enhance norepinephrine-induced contraction in these rat veins paralleled the effectiveness of isoproterenol to relax such tissues. In addition, beta receptor antagonists enhanced the response of veins to the field stimulated release of norepinephrine from sympathetic nerves. These data support the conclusion that beta adrenergic stimulation modulates norepinephrine-induced constriction in certain rat veins but not in the aorta or mesenteric artery.

Adrenergic beta-Antagonists↗

PubMed1991

Increased plasma dihydroxyphenylalanine during sympathetic activation in humans is related to increased norepinephrine turnover.

Plasma concentrations of dihydroxyphenylalanine (DOPA) were measured before and during isometric handgrip exercise or mental stress and after coffee drinking or intravenous infusion of desipramine to examine the influence of sympathetic nervous activity on DOPA formation. Sympathetic activity was assessed by the spillover of norepinephrine into plasma. Turnover of norepinephrine was assessed by the plasma concentration of its intraneuronal metabolite, dihydroxyphenylglycol (DHPG). In normal subjects the resting plasma concentration of DOPA was 6.05 +/- 0.16 nmol/L (n = 42). Plasma DOPA level was increased by stimulation of the sympathetic nervous system; handgrip exercise caused a 0.49 +/- 0.07 nmol/L increase (n = 15), mental stress a 0.25 +/- 0.10 nmol/L increase (n = 34), and coffee drinking a 0.85 +/- 0.19 nmol/L increase (n = 9). Desipramine decreased plasma DOPA level by 0.25 +/- 0.06 nmol/L (n = 23). The small but consistent changes in plasma DOPA level during manipulations of sympathetic activity were positively correlated with changes in norepinephrine spillover (r = 0.55, n = 81) and plasma DHPG level (r = 0.66, n = 81). Percentage increases in plasma DOPA level during sympathetic activation were similar to those in plasma DHPG but were a sixth of the percentage increases in norepinephrine spillover. The similar increases in plasma DOPA and DHPG levels indicated that production of DOPA was related to the turnover of norepinephrine in sympathetic nerves. The smaller percentage increases in plasma DOPA (smaller than those in norepinephrine spillover) were consistent with the partial contribution of exocytotic neurotransmitter release to the turnover of norepinephrine in sympathetic nerves.

Adult↗

PubMed1990

Mechanism of death in patients with congestive cardiac failure: the change in plasma norepinephrine and its relation to sudden death.

It has previously been observed that patients with congestive cardiac failure who die with progressive pump dysfunction tend to have higher levels of plasma norepinephrine than do patients who die suddenly and unexpectedly. However, it may be difficult to distinguish death with pump failure from sudden death. We have analyzed retrospectively 10 patients with congestive cardiac failure who clearly died suddenly and unexpectedly, and have compared them with 10 patients who clearly died of progressive pump dysfunction. Each patient had at least two sequential measurements of plasma norepinephrine before death. Patients dying of progressive pump failure tended to have a progressive rise in plasma norepinephrine from 475 to 1119 pg/ml (P less than 0.004) over an average period of 39 months. Patients dying suddenly and unexpectedly, on the other hand, had a non-significant decrease in plasma norepinephrine from 485 to 407 pg/ml over an average period of 26 months. The data suggest that an increase in plasma norepinephrine may be a marker for death from progressive pump dysfunction. This hypothesis may now be tested in two large multicenter trials where plasma norepinephrine is being monitored over time. The concept that changes in plasma norepinephrine can predict the type of death in patients with congestive cardiac failure may, if valid, be useful in clinical practice.

Death, Sudden↗

PubMed1990

Effect of age on prejunctional modulation of norepinephrine release.

The effect of age on prejunctional modulation of norepinephrine release was studied in tail arteries isolated from Fischer-344 rats, age 6 to 27 months. Tail arteries were perfused in vitro, and norepinephrine released during adrenergic nerve stimulation was collected and analyzed by high-pressure liquid chromatography with electrochemical detection. There was no progressive change with age in norepinephrine content in the tail artery, although content at 6 months was significantly less than 12 months. The most significant finding was a decline with age in the effect of the alpha-2 adrenergic antagonist yohimbine to increase norepinephrine release, suggesting an age- related fall in the effectiveness of prejunctional alpha-2 adrenoceptor activation. In the absence of drugs there was an age-related increase in fractional norepinephrine release, and an age-related increase in the effect of deoxycorticosterone and cocaine was also seen. The increased effect of deoxycorticosterone and cocaine appears to be related to increased norepinephrine levels in the junctional cleft as opposed to an age-related increase in the activity of catecholamine metabolism and uptake. These results suggest that the age-related increase in fractional norepinephrine release may be due, in part, to a decline in negative feedback mediated by prejunctional alpha-2 adrenergic receptors.

Age Factors↗

PubMed1990

Prazosin-sensitive component of the inotropic response to norepinephrine in rabbit heart.

Earlier experiments have usually failed to demonstrate a competitively displaceable alpha adrenoceptor blocker-sensitive component in the dose-dependent inotropic response to norepinephrine in mammalian hearts. We reinvestigated if it was possible to reveal this phenomenon by carefully choosing a concentration of the alpha adrenoceptor blocker prazosin that would give a significant displacement while it still was possible to completely surmount the blockade by reasonable concentrations of norepinephrine. Both inotropic and lusitropic dose-dependent responses to norepinephrine in rabbit heart papillary muscles were recorded. In the presence of 3 X 10(-9) M prazosin there was a significant rightward shift of a component corresponding to about 20% of the total inotropic response to norepinephrine. The prazosin-sensitive component was shifted significantly more to the left by 3 X 10(-5) M cocaine than the nonsensitive component. The maximal inotropic response to norepinephrine was increased at lower prazosin-concentrations (3 X 10(-9) M), whereas at 10(-7) M prazosin the maximal response was unchanged compared to the absence of prazosin. The maximal lusitropic response to norepinephrine was increased monophasically and dose-dependently by prazosin. Thus, by carefully considering the relative potencies of the agonist and the antagonist it was possible to demonstrate an alpha adrenoceptor blocker sensitive component in the inotropic response to norepinephrine in rabbit heart. The effect of cocaine upon the prazosin-sensitive component would indicate that the alpha adrenoceptor population in rabbit myocardium is located more closely to the sympathetic nerve endings than the beta adrenoceptor population.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Vascular responsiveness to norepinephrine in sympathicotonic orthostatic intolerance.

Sympathicotonic orthostatic intolerance (hypotension, tachycardia, or both) is associated with normal or excessive orthostatic increases in plasma norepinephrine concentration and is reversible by the inflation of a military anti-shock trouser suit enveloping the lower limbs and abdomen. These facts suggest that one possible mechanism of the disorder might be a defect in alpha-adrenergic receptor or postreceptor responsiveness of the veins or arterioles. We have investigated in 11 patients and 15 healthy controls the blood pressure and heart rate responses to increasing rates of intravenous norepinephrine infusion (1 to 16 micrograms/min), the dorsal hand vein contractile responses to increasing rates of norepinephrine infusion (1 to 256 ng/min) with a linear variable differential transformer, and the platelet alpha 2-adrenergic receptor densities and dissociation constants. No statistically significant difference in any of these parameters was found between the normal subjects and nine of the 11 patients with orthostatic intolerance. The venous contractile response to norepinephrine was excessive in one patient and was virtually absent in another. Because supersensitivity of the hand veins to norepinephrine suggests up-regulation of alpha 2-receptors resulting from postganglionic autonomic insufficiency, this finding in one patient with sympathicotonic orthostatic hypotension might have been caused by venous denervation. The venous unresponsiveness to norepinephrine in the other patient presumably resulted from a defect in the venous receptors or smooth muscle function. It is evident that norepinephrine responsiveness and the innervation of the arterioles and hand veins was normal in the other nine patients, in whom the defect must have been mediated by some other mechanism.

Adolescent↗

PubMed1990

Mechanism of norepinephrine stimulation of glucose transport in isolated rat brown adipocytes.

Cold exposure reverses the diabetogenic effects of high-fat feeding and markedly stimulates glucose uptake in rat brown adipose tissue (BAT). Considering that cold exposure increases the plasma levels of norepinephrine and lipolytic hormones, but decreases the levels of insulin, we have examined the effects of these agents on glucose transport in isolated rat brown adipocytes using D-[U-14C]glucose as a tracer. It was found that norepinephrine (0.1 microM), glucagon (0.1 nM) and ACTH (100 nM) all increased brown adipocyte respiration (2-10 times) and glucose transport (2-5 times). Studies with adrenergic agonists and antagonists revealed that norepinephrine increases glucose uptake via beta-adrenergic pathways. On the other hand, insulin also increased glucose transport (6 times) but inhibited (40-60 percent) the calorigenic effects of the lipolytic hormones. Both norepinephrine and glucagon potentiated the submaximal insulin responses for glucose transport, demonstrating the existence of metabolic interactions between norepinephrine-, glucagon-, and insulin-mediated glucose uptake. Remarkably, the stimulatory effects of these lipolytic agents were reproduced by dibutyryl cAMP (1 mM), isobutylmethylxanthine (0.1 mM) and palmitic acid (0.5 mM), suggesting that cAMP increases glucose transport via activation of lipolysis and thermogenesis. Considering that the stimulatory effects of norepinephrine (0.1 microM) on respiration and glucose transport were totally blocked by 2-tetradecylglycidic acid (50 microM), a specific inhibitor of mitochondrial carnitine acyl transferase, it is concluded that norepinephrine increases BAT glucose transport via fatty acid-activation of mitochondrial thermogenesis.

Adipose Tissue, Brown↗

PubMed1990

Characteristics of the histamine-sensitive calcium store in vascular smooth muscle. Comparison with norepinephrine- or caffeine-sensitive stores.

Using the microfluorometry of an intracellularly trapped calcium indicator dye, quin2, characteristics of intracellular Ca2+ store sites sensitive to histamine, norepinephrine, or caffeine were investigated using rat vascular smooth muscle cells in primary culture at 25 degrees C. With similar time courses, both histamine- and the norepinephrine-sensitive Ca2+ store sites were readily depleted in Ca2(+)-free medium and almost completely replenished by loading the cells with 1.0 mM Ca2+ solution for 3 min, while the caffeine-sensitive Ca2+ store site was little affected. In the absence of extracellular Ca2+, transient elevations of cytosolic Ca2+ repeatedly appeared in response to repetitive applications of histamine, norepinephrine, or caffeine, with progressive reductions in peak levels. Histamine released Ca2+ from the norepinephrine-sensitive store site and norepinephrine released Ca2+ from the histamine-sensitive one. On the other hand, caffeine had little effect on the histamine- and/or the norepinephrine-sensitive Ca2+ store site in Ca2(+)-free medium, and vice versa. We propose that the location and mechanisms of release of Ca2+ of the histamine-sensitive Ca2+ store site are identical with events at the norepinephrine-sensitive site, and differ from the caffeine-sensitive one, in vascular smooth muscle cells in primary culture.

Aminoquinolines↗

PubMed1989

Ascorbic acid within chromaffin granules. In situ kinetics of norepinephrine biosynthesis.

Ascorbic acid requirements for norepinephrine biosynthesis were investigated in intact bovine chromaffin granules using the physiologic substrate dopamine and a novel coulometric electrochemical detection high pressure liquid chromatography system for ascorbic acid. 10 mM external dopamine, 1 mM Mg-ATP, and 1 mM ascorbic acid produced maximal norepinephrine biosynthesis without granule lysis. When external ascorbic acid was omitted, intragranular ascorbic acid was consumed in a 1:1 ratio with respect to norepinephrine biosynthesis. The initial concentration of intragranular ascorbic acid was 10.5 mM, which was depleted in stepwise fashion to 15 lower concentrations over the range of 9.2-0.2 mM. Chromaffin granules containing these varying concentrations of intragranular ascorbic acid were then incubated with 1 mM exogenous ascorbic acid, and norepinephrine biosynthesis from dopamine was determined. The apparent Km of norepinephrine biosynthesis for intragranular ascorbic acid was 0.57 mM by Eadie-Hofstee analysis and 0.68 mM by Lineweaver-Burk analysis. These data indicate that intragranular ascorbic acid is available and required for norepinephrine biosynthesis, that ascorbic acid is a true co-substrate for dopamine beta-monooxygenase, and that intragranular ascorbic acid is maintained by extragranular ascorbic acid. Continued norepinephrine biosynthesis in granules is dependent on both intragranular and extragranular concentrations of the vitamin. Furthermore, in situ kinetics of dopamine beta-monooxygenase for ascorbic acid may be most accurately determined using intact granules and the true physiologic substrate.

Adrenal Medulla↗

PubMed1989

Dietary Ca2+ prevents NaCl-induced exacerbation of hypertension and increases hypothalamic norepinephrine turnover in spontaneously hypertensive rats.

Dietary calcium (Ca2+) supplementation lowers blood pressure in many forms of genetically mediated and experimentally induced hypertension. The present study tested the hypothesis that neuronal mechanisms underlie the blood pressure-lowering effect of dietary Ca2+ in NaCl-sensitive spontaneously hypertensive rats (SHR-S). SHR-S were fed one of the following diets: control (0.75% NaCl/0.68% Ca2+); high NaCl (8.00% NaCl/0.68% Ca2+); high Ca2+ (0.75% NaCl/2.00% Ca2+), and high NaCl/high Ca2+ (8.00% NaCl/2.00% Ca2+). SHR-S on the 8% NaCl diet for 2 weeks displayed significantly elevated blood pressure (161 +/- 4 mmHg) compared with those on the control diet (139 +/- 3 mmHg). Ca2+ supplementation prevented a rise in blood pressure in rats on the high-NaCl diet but did not alter blood pressure in rats consuming 0.75% NaCl. Plasma norepinephrine stores and turnover in the hypothalamus (anterior and posterior regions), brainstem (pons and medulla) and thoracic spinal cord were assessed using the dopamine-beta-hydroxylase inhibitor 1-cyclohexyl-2-mercapto-imidazole. The 8% NaCl diets reduced anterior hypothalamic region norepinephrine stores and turnover. Concomitant Ca2+ supplementation restored norepinephrine turnover to normal, but did not alter norepinephrine stores in the anterior hypothalamic region. In other regions, no significant differences in norepinephrine content or turnover were observed among groups. In SHR that are resistant to high-NaCl diets (SHR-R), the diets did not alter blood pressure, and neither dietary NaCl nor Ca2+ supplementation affected norepinephrine turnover in any brain region studied. These data indicate that in SHR-S on a diet high in NaCl, Ca2+ supplementation may prevent the NaCl-induced exacerbation of hypertension by increasing norepinephrine turnover in the hypothalamus.

Administration, Oral↗