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PubMed1985

Uptake and metabolism of norepinephrine by endothelium of dog pulmonary artery.

The contribution of endothelium of dog pulmonary artery to the extraneuronal metabolism of norepinephrine was determined. Pulmonary artery was cut into helical strips; the endothelium was removed from half of the strips by gently stroking them with a wooden applicator stick. All strips were immersed in l-[3H]norepinephrine (2 X 10(-7) M) and mounted for superfusion. Superfusate was collected continuously before, during, and after electrical stimulation (10 V, 2 ms, 2 Hz). Column chromatography was used to separate [3H]norepinephrine and its radiolabeled metabolites in superfusate. Quantitation was by liquid scintillation spectrometry. Previous studies have established that 3,4-dihydroxyphenylglycol is of neuronal origin and that O-methylated metabolites are of extraneuronal origin. Since cocaine prevented neuronal uptake of norepinephrine, the reduction in metabolites of norepinephrine of extraneuronal origin in arteries with endothelium removed represented the contribution of endothelium to extraneuronal metabolism. O-Methylated metabolites were decreased from 3.50 to 2.17 X 10(3) dpm/2 ml of superfusate during basal conditions preceding electrical stimulation and from 11.16 to 6.94 X 10(3) dpm/2 ml of superfusate during electrical stimulation when endothelium had been removed. Decreases in extraneuronal metabolite production continued throughout the basal periods following stimulation. These studies suggest that in small pulmonary artery a substantial amount of the total norepinephrine that is released at the neuroeffector junction may be metabolized following uptake into endothelium.

Animals↗

PubMed1988

Increased response of brachial artery diameter to norepinephrine in hypertensive patients.

The hyperresponsiveness of small arteries to norepinephrine is well documented in essential hypertensive patients. Our objective was to investigate in situ the reactivity to norepinephrine of the diameter of large arteries, which are involved in the arterial disease of hypertension as well as small arteries. Brachial artery diameter, blood flow velocity, local volumic blood flow, and local vascular resistances were determined noninvasively with a pulsed Doppler system in 19 patients with essential hypertension and 9 normotensive subjects, before and after the administration of placebo (glucose) or increasing doses of norepinephrine (10, 20, and 40 ng.kg-1.min-1 iv) given in a single-blind fashion. In hypertensive patients, norepinephrine (40 ng.kg-1.min-1) induced 1) a significant decrease in brachial artery diameter, local blood velocity, volumic flow, and conductance and 2) a small increase in mean arterial pressure. These hemodynamic changes did not occur in the placebo group and were significantly greater in hypertensive patients than in normotensive subjects, although plasma norepinephrine increased to the same extent in both groups. We conclude that in hypertensive patients the increase in vascular reactivity to norepinephrine involves not only the resistive vessels but also the large arteries thus decreasing their conducting and buffering function.

Adult↗

PubMed1992

Chronic elevation of norepinephrine in conscious dogs produces hypertrophy with no loss of LV reserve.

Elevated plasma catecholamine levels may cause both myocardial hypertrophy and tissue damage. To determine whether the left ventricle from dogs with chronic norepinephrine infusion can sustain additional functional loads, we altered ventricular preload or afterload and determined both global and left ventricular (LV) wall function. Dogs were instrumented to measure LV wall function, LV internal base diameter, and LV pressures and were allowed to fully recover. Preload was altered by volume loading and afterload by injection of phenylephrine. Osmotic infusion pumps were implanted to continuously release norepinephrine at 0.5 micrograms.kg-1.min-1 for 28 days, and the volume loading and phenylephrine were repeated on days 14 and 28. Heart rate decreased, whereas there were no differences in mean arterial pressure, maximum first derivative of LV pressure (dP/dt), LV dP/dt/developed pressure of 40 mmHg, LV dP/dt/end-diastolic circumference, slope of the pressure-diameter relation, peak systolic wall stress, LV/end-diastolic diameter, or LV/end-systolic diameter during norepinephrine infusion. Diastolic and systolic wall thickness and chamber weights were increased (P less than 0.05). Indexes of diastolic function, including end-diastolic pressure, end-diastolic pressure-end-diastolic diameter relationship, maximum negative dP/dt, and the time constant (tau) were unchanged after chronic norepinephrine infusion, although maximum end-diastolic pressure during volume loading was increased from 17.7 +/- 2.0 to 21.7 +/- 1.0 mmHg. Chronic norepinephrine infusion did not alter tau, and tau increased equivalently with phenylephrine injection in both normal (36 +/- 1 to 62 +/- 5 ms) dogs and in those chronically infused with norepinephrine (36 +/- 1 to 56 +/- 5 ms).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Norepinephrine levels in paraventricular nucleus of spontaneously hypertensive rats: role of neuropeptide Y.

Recent evidence supports the view that the sympathetic system actively participates in the development of hypertension. Because norepinephrine, contained within central neurons involved in cardiovascular sympathetic regulation, is known to coexist with neuropeptide Y, it is possible that a functional interaction between neuropeptide Y and norepinephrine exists within the brain. In an effort to clarify whether or not central catecholamine systems are modulated by neuropeptide Y in hypertensive situations, the paraventricular nucleus of spontaneously hypertensive rats was exposed to neuropeptide Y (10(-9) M), and levels of norepinephrine were sampled by microdialysis. Norepinephrine levels in spontaneously hypertensive rats were significantly increased and did not change after exposure to neuropeptide Y, in sharp contrast to the decreases seen in Wistar-Kyoto controls. To ascertain whether these alterations in norepinephrine control were specific to the model used, a similar series of experiments was carried out in the paraventricular nucleus of aortic-banded rats. These studies supported the previous findings. Norepinephrine levels in aortic-banded rats were markedly elevated when compared with sham-operated controls and demonstrated no change after exposure to neuropeptide Y, whereas decreases of > 50% were seen in sham-operated controls. These results support the view that mechanisms normally involving neuropeptide Y as a neuromodulator in the paraventricular nucleus are altered in hypertensive situations. It is suggested that hypertension may precipitate changes in mechanisms involving brain neuropeptide Y and increased sympathetic activity.

Animals↗

PubMed1976

Cerebral circulation and norepinephrine: relevance of the blood-brain barrier.

The systemic administration of norepinephrine has minimal effects on the cerebral circulation, perhaps due to blood-brain barrier mechanisms. To test hypothesis, the cerebrovascular effects of norepinephrine beyond the blood-brain barrier were studied in anesthetized baboons, Intraventricular norepinephrine (40 mug/kg) resulted in significant increases in cerebral blood flow (40%), cerebral oxygen consumption (21%), and cerebral glucose uptake (153%). Intracarotid hypertonic urea opens the blood-brain barrier by osmotic disruption; Consequent to hypertonic urea, the intracarotid infusion of norepinephrine, 50 ng/kg-min, significantly increase cerebral blood flow (49%), cerebral oxygen consumption (21%), and cerebral glucose uptake (76%), It appears probable that the cerebrovascular responses to norepinephrine are dependent on the integrity of the blood-brain barrier; It is likely that the increase in cerebral blood flow, associated with norepinephrine when it bypasses the barrier, is secondary to an increase in cerebral metabolism.

Animals↗

PubMed1983

Neural control of insulin secretion: interaction of norepinephrine and acetylcholine.

We have quantitatively characterized the interaction of several concentrations of norepinephrine and acetylcholine applied simultaneously on insulin secretion in response to an intermediate glucose concentration (10 mM) from statically incubated pancreatic islets isolated from normal rats. When either norepinephrine or acetylcholine were applied alone, insulin secretion was respectively inhibited or enhanced in a dose-dependent manner. When combinations of norepinephrine and acetylcholine were applied simultaneously to the islet, insulin secretion was enhanced, inhibited, or not affected. The net effects of the interaction of norepinephrine and acetylcholine on insulin secretion were not only a function of the concentration of each neurotransmitter but also the relative concentrations of both neurotransmitters. Analysis of these interaction data suggests that 1) insulin secretion is the result of a complex interaction between sympathetic and parasympathetic neural and metabolic inputs; 2) norepinephrine and acetylcholine modulate insulin secretion primarily by direct action on the beta-cell membrane; 3) insulin secretion is more sensitive to perturbations in norepinephrine concentration than acetylcholine concentrations under these experimental conditions; and 4) the autonomic nervous system has the potential to play a major role in the control of insulin secretion in response to glucose.

Acetylcholine↗

PubMed1986

Norepinephrine turnover in brown adipose tissue is stimulated by a single meal.

A single meal stimulates brown adipose tissue (BAT) thermogenesis in rats. In the present study the role of norepinephrine in this thermogenic response was assessed from the rate of its turnover in BAT after a single test meal. For comparison, norepinephrine turnover was determined in the heart and spleen. A total of 48 male Wistar rats (200 g) were trained to eat during two feeding sessions per day. On the experimental day, one group (n = 24) was meal deprived and the other (n = 24) was given a low-protein high-carbohydrate test meal for 2 h. The synthesis inhibition method with alpha-methyl-p-tyrosine was employed to determine norepinephrine turnover from its concentration at four hourly time points after the meal. Tissue concentrations of norepinephrine were determined by radioimmunoassay. Norepinephrine concentration and turnover rate were increased more than threefold in BAT of the meal-fed compared with the meal-deprived rats (P less than 0.001 and P less than 0.005 for concentration and turnover, respectively). Neither were significantly altered by the meal in the heart or spleen. Other measures of turnover kinetics, turnover time and rate constant, were not significantly affected in any of the tissues examined. Our data suggest that norepinephrine mediates a portion of the thermic effect of meals that originate in BAT.

Adipose Tissue, Brown↗

PubMed1988

Effects of food and light on norepinephrine turnover.

To study diurnal differences in norepinephrine turnover, groups of rats were housed in rooms with alternating 12 h light and 12 h dark where half the animals were in a normal light cycle and half were in a reversed light cycle. Norepinephrine turnover was measured in all groups beginning at 1000 by inhibition of tyrosine hydroxylase. When rats are fed ad libitum, the turnover of norepinephrine in interscapular brown adipose tissue and heart was significantly higher in the normal cycle than in the reversed cycle. In addition, there was an interaction between the turnover of norepinephrine and the feeding and lighting schedules. When animals were adapted to eating from 0700 to 1900, the turnover of norepinephrine was somewhat faster when the animals ate in the reversed cycle than when they ate in the normal cycle. Conversely, when the feeding schedule was reversed and animals ate between 1900 and 0700, the turnover of norepinephrine in the absence of food was slightly slower in the animals eating in the reversed cycle than in those eating in the light cycle. This interaction between lighting and food intake observed in both male and female rats was abolished by ventromedial hypothalamic lesions. These data suggest that food intake and lighting conditions interact as controllers of the sympathetic nervous system and that these interactions are modulated by the ventromedial hypothalamus.

Adipose Tissue, Brown↗

PubMed1982

Renal handling of dopa, dopamine, norepinephrine, and epinephrine in the dog.

The uptake and excretion of endogenous dopa, dopamine, norepinephrine, and epinephrine by the kidney were studied. Blood samples were taken from the aorta at the origin of the renal artery and from the renal vein during a timed urine collection in each of six anesthetised greyhound dogs. Arterial plasma dopa (1,043 +/- 129 pg/ml) and epinephrine (218 +/- 96 pg/ml) were consistently higher than venous levels of dopa (591 +/- 80) and epinephrine (54 +/- 16 pg/ml), showing extraction of these by the kidney, whereas arterial plasma norepinephrine (329 +/- 89 pg/ml) and dopamine (64 +/- 9 pg/ml) were lower than the venous levels of norepinephrine (695 +/- 161 pg/ml) and dopamine (239 +/- 45 pg/ml), indicating secretion of these catecholamines into the circulation. The dopa extracted did not appear in the urine. Norepinephrine (7.2 +/- 1.7 ng/min), epinephrine (4.5 +/- 1.7 ng/min), and dopamine (3.2 +/- 0.7 ng/min) were excreted in the urine. These rates of urinary excretion could be accounted for by glomerular filtration and tubular secretion of the three catecholamines. The kidney extracts circulating dopa. It extracts and excretes epinephrine, norepinephrine, and dopamine, and, in addition, secretes both dopamine and norepinephrine into the circulation. These observations emphasize the important relationship between renal function and the peripheral sympathetic nervous system.

Animals↗

PubMed1987

Norepinephrine increases Na+-K+-ATPase and solute transport in rabbit proximal tubules.

We studied the effects of norepinephrine on solute transport and oxidative metabolism in proximal tubules. Norepinephrine (10(-6) M) in the bath stimulated fluid absorption (Jv) by proximal convoluted tubules from 0.76 +/- 0.10 to 1.01 +/- 0.11 nl X mm-1 X min-1 (P less than 0.001). Bicarbonate, chloride, and phosphate transport also increased in proportion to the increases in Jv. Norepinephrine increased ouabain-sensitive oxygen consumption (QO2) in suspensions of cortical tubules by 1.3 nmol X mg protein-1 X min-1 and had no effect on ouabain-insensitive QO2 or mitochondrial respiration. Na+-K+-ATPase activity in basolateral membranes prepared from cortical homogenates incubated with norepinephrine increased from 277.1 +/- 34.9 to 411.1 +/- 38.6 nmol Pi X mg protein-1 X min-1 (P less than 0.005). Norepinephrine also increased Na+-K+-ATPase activity of cortical homogenates by 72% but had no effect on Na+-K+-ATPase if added directly to purified basolateral membranes. These studies show that norepinephrine stimulates solute transport in the proximal tubule by increasing Na+-K+-ATPase activity indirectly through some component or components of the adrenergic receptor system.

Animals↗

PubMed1981

Effects of epinephrine and norepinephrine infusion on lung fluid balance in sheep.

The effect of an intravenous infusion of epinephrine or norepinephrine (45 microgram.kg-1.min-1) on the transcapillary exchange of fluid and protein were studied in anesthetized sheep prepared with lung lymph fistulas. After infusion of epinephrine, pulmonary lymph flow (Qlym) and the ratio of lymph to plasma protein concentration (L/P) did not change significantly from base line despite an increase in mean pulmonary arterial pressure (Ppa) from 17.3 +/- 0.8 to 22.6 +/- 0.09 Torr, In contrast, Qlym increased (p less than 0.05) from 9.24 +/- 1.53 to 11.46 +/- 1.97 ml/h and L/P decreased (p less than 0.05) from 0.78 +/- 0.03 to 0.74 +/- 0.04 after infusion of norepinephrine; these changes were associated with an increase in Ppa from 16.5 +/- 1.5 to 21.6 +/- 1.8 Torr. Pulmonary vascular resistance (PVR) increased from 5.90 +/- 0.83 to 12.12 +/- 1.23 Torr. 1-1 min (p less than 0-.01) after epinephrine and from 6.52 +/- 0.82 to 9.26 +/- 1.74 Torr.1-1 min (p less than 0.05) after norepinephrine. Left atrial hypertension, induced in four sheep infused with norepinephrine and in five sheep infused with epinephrine by inflating a left atrial balloon, increased Qlym and decreased L/P in all animals. Thus the infusions of epinephrine or norepinephrine did not increase lung vascular permeability to proteins. Epinephrine infusion also did not increase fluid filtration despite increases in Ppa and PVR, suggesting that pulmonary microvascular pressure did not increase significantly due to greater constriction of precapillary than postcapillary vessels. However, norepinephrine infusion increased filtration, suggesting that microvascular pressure was increased due to a greater constriction of postcapillary than precapillary vessels.

Animals↗

PubMedDate not supplied

Presynaptic modulation by melatonin of the nicotine-induced calcium-dependent release of norepinephrine from rat vas deferens.

This study demonstrates that melatonin potentiates the nicotine-induced calcium-dependent release of [3H]-norepinephrine from the rat vas deferens. Slices of the prostatic portion of the rat vas deferens were labelled in vitro with [3H]-norepinephrine and superfused with physiological solution. Nicotine (1 mM, 4 min) induced a calcium-dependent release of norepinephrine during the first (N1 = 1.43 +/- 0.16%) and the second (N2 = 1.11 +/- 0.2%, n = 22) nicotine stimulations. The ratio N2/N1 between two consecutive periods of nicotine stimulations was: 0.84 +/- 0.09 (n = 22). Melatonin (10-300 nM) did not modify the spontaneous release of [3H]-norepinephrine but potentiated in a concentration-dependent manner the calcium-dependent release. The competitive melatonin receptor antagonist luzindole did not modify the calcium-dependent release of [3H]-norepinephrine when added alone but completely antagonized the potentiation of release elicited by melatonin, suggesting interaction at the level of a melatonin receptor. We conclude that melatonin potentiates the nicotine-evoked release of [3H]-norepinephrine in the rat vas deferens through activation of melatonin presynaptic heteroreceptors on noradrenergic nerves involved in a positive feedback mechanism. This mechanism may mediate the increase in sympathetic neurotransmission observed with melatonin in the vas deferens. We cannot exclude, however, an effect of melatonin on cellular proteins and enzymes associated with the exocytotic process, which directly or indirectly may lead to the facilitation of release.

Animals↗

PubMed1976

Reduction of 14C-norepinephrine metabolism in rabbit aorta by vasodilators.

In the present study, both of the major enzymes, monoamine oxidase and catechol-o-methyltransferase, involved in the degradation of norepinephrine were examined indirectly in segments of rabbit aorta by exposure of tissues to 14C-norepinephrine and subsequent isolation of metabolites from homogenates by chromatographic techniques. Segments of aorta were preincubated with vasodilators to examine their influence on accumulation and metabolism of 14C-norepinephrine. The accumulation of labeled norepinephrine by aortae was enhanced after preincubation with hydrochlorothiazide or diazoxide, and reduced after preincubation with sodium nitroprusside or nitroglycerin. However, the fraction of accumulated 14C-norepinephrine which was degraded was significantly reduced after exposure to all four vasodilators. These results suggest that a decrease in degradation of norepinephrine in vascular smooth muscle can be observed (1) in vitro and (2) fairly rapidly after exposure to vasodilators.

Animals↗

PubMed2002

Effects of sustained-release moxonidine, an imidazoline agonist, on plasma norepinephrine in patients with chronic heart failure.

BACKGROUND: In chronic heart failure, sympathetic activation is increased. Moxonidine acts on central nervous system receptors to decrease sympathetic activation. We investigated the dose-response relationship of a new sustained-release (SR) preparation of moxonidine and the plasma concentration of norepinephrine in patients with chronic heart failure. METHODS AND RESULTS: A total of 268 patients with chronic heart failure in NYHA functional class II to IV on optimal standard therapy were randomized to placebo or 1 of 5 doses of moxonidine SR: 0.3, 0.6, 0.9, 1.2, or 1.5 mg BID. After a dose-titration phase (7 weeks), patients were followed up for another 12 weeks at their maximally tolerated dose. Blood samples for plasma norepinephrine were collected at baseline and weekly during the initial 7 weeks, at week 19, and at the end of the study. At baseline and 7 and 19 weeks, sampling was also done 4 hours after the dose. After the active phases of the study, plasma norepinephrine was evaluated for an additional 3 days. A marked, statistically significant dose-related decrease in plasma norepinephrine was observed for predose levels as well as 4 hours after the dose at week 19. At the highest dose (1.5 mg BID), the trough reduction in norepinephrine was 52%. These reductions were accompanied by a modest decrease in heart rate, a modest increase in left ventricular ejection fraction, and a dose-related increase in adverse events. CONCLUSIONS: Plasma norepinephrine was markedly reduced in a dose-related manner by moxonidine SR. This reduction was accompanied by evidence of reverse remodeling, but also by an increase in adverse events.

Blood Pressure↗

PubMed1994

Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure.

BACKGROUND: Although heart rate variability (HRV) at 0.1 Hz has been proposed as a noninvasive clinical measure of cardiac sympathetic nerve firing, this premise has not been sufficiently validated by comparison with techniques such as microneurography and the measurement of norepinephrine spillover from the heart that more directly reflect presynaptic sympathetic activity. METHODS AND RESULTS: We compared the three techniques under conditions of effective cardiac sympathetic denervation, pure autonomic failure (n = 4), dopamine beta-hydroxylase deficiency (n = 1), and after cardiac transplantation (n = 9) as well as in the context of sympathetic nervous activation in cardiac failure (n = 15) and with aging (n = 10). Age-matched comparisons were made in each case with healthy individuals drawn from a pool of 52 volunteers. In pure autonomic failure and early after transplantation, cardiac norepinephrine spillover was negligible, and HRV was low. Late after transplantation, however, cardiac norepinephrine spillover returned to normal levels, and HRV remained low. In comparison to younger subjects (18 to 35 years old), older individuals (60 to 75 years old) had higher muscle sympathetic nerve activity (young, 22.9 +/- 1.9; old, 31.3 +/- 5.8 bursts per minute; P < .05) and cardiac norepinephrine spillover (young, 14.3 +/- 2.5; old, 20.1 +/- 3.0 ng/min; P < .05). In contrast, total HRV was reduced by 89%, and at 0.1 Hz it was reduced by 93% (P < .05). Cardiac failure was also characterized by elevated cardiac norepinephrine spillover (cardiac failure patients, 59 +/- 4; healthy volunteers, 18 +/- 3 ng/min; P < .01) but reduced 0.1 Hz HRV (cardiac failure patients, 49 +/- 17; healthy volunteers, 243 +/- 4 ms2; P < .05). CONCLUSIONS: HRV at 0.1 Hz depends on factors in addition to cardiac sympathetic nerve firing rates, including multiple neural reflexes, cardiac adrenergic receptor sensitivity, postsynaptic signal transduction, and electrochemical coupling, and is not directly related to cardiac norepinephrine spillover, which is a more direct measure of the sympathetic nerve firing rate.

Adolescent↗

PubMed1991

Effects of bufalin on norepinephrine turnover in canine saphenous vein.

Abundant experimental data suggest that an endogenous digitalislike factor is responsible for some essential hypertension. Some forms of hypertension have also been associated with increased levels of catecholamines. We therefore designed experiments to investigate the role of digitalislike factors in the regulation of norepinephrine turnover in the neurovascular junction. We chose bufalin, an amphibian-derived compound that shares many of the physiological properties postulated as characteristic of digitalislike compounds, as a model of the mammalian compound. In vitro experiments in canine saphenous veins showed that, in addition to inhibiting norepinephrine uptake, bufalin increased norepinephrine overflow by an amount larger than could be explained solely by uptake inhibition. The effect of bufalin on norepinephrine overflow is inhibited by tetrodotoxin, which suggests a dependence of this response on Na+ influx through the neuronal membranes. We propose that Na+,K(+)-ATPase inhibition resulting in neuronal depolarization is responsible for the augmented norepinephrine turnover caused by bufalin and that these indirect effects of norepinephrine on the cardiovascular system may play a role in the etiology of hypertension.

Animals↗

PubMed1993

Pressor reactivity to norepinephrine and angiotensin in salt-sensitive hypertensive patients.

The mechanisms responsible for increased blood pressure in response to a high dietary sodium intake in salt-sensitive patients with essential hypertension are only partially understood. The possibility that increased reactivity to pressor hormones might contribute to hypertension in these patients has not been adequately investigated. We studied 11 salt-sensitive and 15 salt-resistant patients with essential hypertension while they were ingesting a diet with 20 meq/day sodium for 9 days or one with 200 meq/day sodium for 14 days. During the last 4 days of each dietary regimen, they received 30 mg/day of slow-release nifedipine. Blood pressure response to increasing doses of norepinephrine and angiotensin II (Ang II) was studied at the end of each of four phases of the study. Salt-sensitive patients exhibited a greater blood pressure response to norepinephrine than salt-resistant patients, irrespective of the dietary sodium intake and whether we took into account the dose infused or the actual plasma levels of norepinephrine achieved during the infusion. The blood pressure response to Ang II, on the other hand, was greater in salt-sensitive than salt-resistant patients during low but not during high sodium intake. The blood levels of norepinephrine achieved during the infusion of this hormone were lower in salt-sensitive than in salt-resistant patients. These studies indicate that an increased reactivity to the pressor action of norepinephrine might contribute to the maintenance of hypertension in salt-sensitive patients. The increased reactivity appears to be specific for norepinephrine. In fact, we observed increased reactivity to Ang II during low but not during high sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Insulin attenuates norepinephrine-induced venoconstriction. An ultrasonographic study.

To directly assess insulin-related venomotor changes objectively and quantitatively, we used a modified ultrasonographic technique to measure venous diameter. Ten healthy men and women were studied by use of an Acuson 128 XP ultrasonograph with a linear 7.5-MHz ultrasonographic transducer (sensitivity, +/- 0.1 mm). Venous diameter was measured with the arm kept at 30 degrees elevation and with a pneumatic cuff above the elbow inflated at 40 mm Hg for the last 2 minutes of each 5-minute observation period. Norepinephrine was infused at incremental concentrations of 12.5, 25, 50, and 100 ng/min (75, 150, 300, and 600 pmol/min, respectively) for 5 minutes each. Maximal venoconstriction was achieved by the dose of 100 ng/min norepinephrine, which was then combined with insulin doses of 8, 16, 24, and 32 microU/min (60, 120, 180, and 230 fmol/min, respectively) for 5 minutes each. In six different subjects, methylene blue, an inhibitor of guanylate cyclase, was infused simultaneously with 32 microU/min insulin and 100 ng/min norepinephrine. Mean resting diameter of the vein (1.8 +/- 0.6 mm [mean +/- SD]) increased (to 3.0 +/- 1.0 mm) after cuff inflation. Incremental doses of norepinephrine caused highly reproducible dose-dependent decrease in venous diameter (to 1.8 +/- 0.6 mm, P < .001). Incremental doses of insulin, when combined with the maximum dose of norepinephrine, caused highly reproducible dose-dependent increases in mean venous diameter (P < .001) compared with norepinephrine alone. Methylene blue, which had no independent effect on venous diameter, inhibited the venodilator effect of insulin (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗