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PubMed1991

Sympathetic stimulation-evoked overflow of norepinephrine and neuropeptide Y from the heart.

Neuropeptide Y (NPY) and norepinephrine are released together on sympathetic activation. To compare the time courses of NPY and norepinephrine washout from cardiac tissues, we measured the overflow of NPY-like immunoreactivity (NPY-LI) and norepinephrine in coronary sinus blood before, during, and after 3-minute trains of ansae subclaviae stimulation in 13 anesthetized dogs. We also measured vagally induced cardiac cycle length responses before and after ansae stimulation. Ansae stimulation increased NPY-LI and norepinephrine overflow from the heart in a frequency-dependent manner (p less than 0.02). After stimulation of the ansae at 5 and 10 Hz, the peak norepinephrine overflows decayed by 90% within 2 minutes, but the NPY-LI overflows required 17 +/- 11 and 35 +/- 21 minutes, respectively, to decay by 90%. Cardiac vagal effects were inhibited after 5- and 10-Hz ansae stimulations, and the peak inhibitions decayed by 90% after 19 +/- 7 and 39 +/- 16 minutes, respectively. The 90% decay times of the NPY-LI overflows were longer (p less than 0.003) than those of the norepinephrine overflows but did not differ significantly (p greater than 0.4) from the 90% decay times of the inhibition of vagal effects. We characterized NPY-LI in coronary sinus and arterial plasma by reversed-phase high-performance liquid chromatography. Before ansae stimulation, the main peak of NPY-LI in the plasma had a retention time similar to that of the oxidized human NPY-(1-36) standard. During ansae stimulation, however, there was a substantial increase in the peak of NPY-LI that eluted in a position similar to that of the monoxidized human NPY-(1-36) standard. These data support the hypothesis that neurally released NPY mediates the sympathetically evoked inhibition of vagal effects and indicate that the time course of removal of NPY from the heart differs substantially from that of norepinephrine. Moreover, under basal conditions, most NPY in the circulation is present in the oxidized form or as a fragment of the 36-amino-acid peptide. In contrast, cardiac sympathetic stimulation evokes the overflow of monoxidized NPY-(1-36) into the coronary sinus plasma.

Animals↗

PubMed1999

Effects of norepinephrine on the renal vasculature in normal and endotoxemic dogs.

Septic shock is often complicated by systemic hypotension despite normal or increased cardiac output. Restoration of arterial pressure usually requires the administration of systemic vasopressor agents, such as norepinephrine. However, because norepinephrine induces vasoconstriction in other vascular beds, it may decrease visceral blood flow, impairing visceral organ function. Because sepsis is often associated with impaired peripheral vascular responsiveness, we hypothesized that, unlike in normal circulatory conditions, norepinephrine would improve visceral organ blood flow in sepsis by selectively increasing organ perfusion pressure. Thus, in nine pentobarbital-anesthetized, mechanically ventilated dogs, we measured the effect of norepinephrine infusion (0.3 microgram/kg/min) on renal, hepatic, and portal steady-state pressure-flow relations (P/Q) and the dynamic vascular P/Q, created by transient inferior vena caval occlusion, under basal and endotoxic conditions. Norepinephrine increased organ perfusion pressures during both control and endotoxemic conditions. However, even after controlling for the pressure effect using a general linear model, NE was associated with an increase in renal blood flow both before and after endotoxin administration. We conclude that, unlike the effects of administering norepinephrine under baseline conditions, norepinephrine infusion during endotoxic shock actually increases renal blood flow and that this effect is not the result of an increase in perfusion pressure alone.

Animals↗

PubMed1967

Comparison of effects of deoxycorticosterone and dexamethasone on cardiovascular responses to norepinephrine.

Cardiovascular responses to graded iv infusions of norepinephrine were observed in 24 dogs that had been treated for 1 week with either placebo, dexamethasone, or deoxycorticosterone. Eight dogs served as control and received daily iv injections of placebo; eight dogs received the mineralocorticoid, deoxycorticosterone; and eight received the glucocorticoid, dexamethasone. The three groups did not differ with respect to base-line hemodynamic variables either before administration of norepinephrine or after autonomic reflexes had been inhibited by ganglionic blockade. Comparisons of the three groups' hemodynamic responses to norepinephrine were made both before and after ganglionic blockade with the parallel line bioassay as a statistical test. Dogs given deoxycorticosterone had much greater increases in mean arterial pressure and peripheral resistance with norepinephrine than did dogs given dexamethasone or placebo. Dogs given dexamethasone had slightly greater increases in mean arterial pressure than did dogs given placebo; changes in peripheral resistance were similar in the two groups. The augmented response of mean arterial pressure was apparent only after ganglionic blockade in the dexamethasone group. The vascular effects of norepinephrine, therefore, were markedly augmented by treatment with doxycorticosterone and only slightly augmented by treatment with dexamethasone. The effect of norepinephrine on mean right atrial pressure was augmented in both groups treated with steroid before hexamethonium but only in the group treated with dexamethasone after hexamethonium. The results indicate that deoxycorticosterone and dexamethasone have different qualitative and quantitative effects on circulatory responses to norepinephrine.

Animals↗

PubMed1972

Studies of isolated fetal mouse hearts in organ culture. Evidence for a direct effect of triiodothyronine in enhancing cardiac responsiveness to norepinephrine.

Definitive confirmation or denial of the hypothesis that thyrotoxic hearts are supersensitive to catecholamines has been difficult to obtain, largely because secondary alterations in neural and humoral factors that occur after thyroid administration in vivo may obscure the primary changes induced by the hormone on the myocardium itself. To study the direct action of thyroid hormone apart from secondary factors, thyrotoxicosis should be induced in isolated hearts in vitro, but the slow onset of thyroid action plus the rapid deterioration of conventional in vitro preparations have precluded such experiments.Recen'ly a method was developed for maintaining intact, spontaneously-beating hearts from late-fetal mice in organ culture for several weeks. When 5 x 10(-7) to 5 x 10(-6)m l-triiodothyronine is added to the culture medium arrhythmias and or tachycardia gradually appear, just as in thyrotoxicosis in vivo. Accordingly, these "thyrotoxic" hearts were used in the present experiments to test for altered responsiveness to norepinephrine. Dose-response curves to norepinephrine were identical for hearts maintained for 3 hr in triiodothyro-nine-treated or control medium. After 2 days, however, the curve was shifted to the left in triiodothyronine-treated hearts. Thus, 10(-8)m norepinephrine increased the atrial rate by 20+/-6.1 (sem) beats/min in hearts exposed to 5 x 10(-6)m triiodothyronine and by 1+/-3.0 in control hearts (P < 0.02); 10(-7)m norepinephrine raised the rate by 79+/-22.3 in treated hearts vs. 17+/-9.8 in controls (P < 0.05). At maximal doses (10(-6)m norepinephrine), increases were identical. In addition, norepinephrine (10(-8)-10(-6)m) induced arrhythmias in 56% of treated hearts vs. 14% of controls (P < 0.01). Thus, in a precisely controlled environment free of differences in neural and humoral factors, triiodothyronine can act directly on the fetal mouse heart to enhance sensitivity to norepinephrine.

Animals↗

PubMed1973

Mechanism of effect of alpha adrenergic stimulation with norepinephrine on renal water excretion.

The present study was undertaken to investigate the mechanism whereby alpha adrenergic stimulation with intravenous norepinephrine results in a water diuresis. Renal perfusion pressure was kept constant in all experiments by adjustment of a suprarenal aortic clamp. In hydropenic anesthetized dogs the intravenous infusion of norepinephrine (0.5 mug/kg per min) was associated with a mean decrease in urinary osmolality from 616 to 126 mosmol/kg (P < 0.001) which increased to 532 mosmol/kg (P < 0.001) after the infusion was discontinued. During the same period of time the mean free water clearance increased from -0.437 to 1.59 (P < 0.001) and then returned to -0.314 ml/min (P < 0.001) after cessation of the infusion. This diuretic effect occurred in both innervated and denervated kidneys and was not associated with an increase in glomerular filtration rate or solute excretion. Systemic arterial pressure increased from 121 to 142 mm Hg during the norepinephrine infusion. Studies were also performed in hypophysectomized animals receiving a constant infusion of either 80 mug/kg per min or 20-40 muU/kg per min of vasopressin. In these animals, intravenous norepinephrine was not associated with changes in either urinary osmolality or free water clearance. The intrarenal administration of norepinephrine, in doses comparable with those reaching the kidneys during the intravenous studies, also resulted in no significant change in either urinary osmolality or free water clearance in hypophysectomized animals receiving 20-30 muU/kg per min of vasopressin. These results thus indicate that the water diuresis associated with intravenous norepinephrine is mediated primarily by suppression of vasopressin release rather than by changes in renal hemodynamics, renal innervation, or an effect of norepinephrine on the water permeability of the tubular epithelium.

Animals↗

PubMed1983

Lateral hypothalamic lesions and norepinephrine turnover in rats.

Animals with lateral hypothalamic lesions lost significantly more weight in the 18 h following this lesion than did sham-operated animals or rats with cerebral cortical lesions deprived of food for the same time period. In the acutely fasted sham-operated animals the turnover of norepinephrine in interscapular brown adipose tissue, heart, and pancreas was slowed but in fasted rats with lateral hypothalamic lesions norepinephrine turnover rates were three- to ninefold faster in all three organs. Exposure to the cold (4 degrees C) significantly increased norepinephrine turnover in the interscapular brown adipose tissue, heart, and pancreas of fasted sham-operated rats, but did not further increase the rate of turnover in lateral hypothalamic-lesioned rats. Rats with lesions in the cerebral cortex responded in a fashion similar to that of the sham-operated animals. Gastric erosions and microhemorrhagic gastric mucosa were observed in five of six acutely fasted rats with lateral hypothalamic lesions whereas all sham-operated rats had a normal appearance of the stomach lining. Animals with lateral hypothalamic lesions made 3 wk earlier also showed an increased rate of norepinephrine turnover in the interscapular brown adipose tissue, heart, and pancreas following an 18 h fast. Rats with bilateral lesions in the paraventricular region of the hypothalamus, however, responded similarly to sham-operated animals with a reduction in the turnover in norepinephrine with fasting and an increase in norepinephrine turnover rate after cold exposure even with fasting. These data suggest that lateral hypothalamic lesions produce an acute increase in turnover of norepinephrine, and that this increased turnover persists for up to 3 wk.

Adipose Tissue, Brown↗

PubMed1981

The effect of pimozide on CSF norepinephrine in schizophrenia.

The authors measured CSF norepinephrine concentrations in drug-free schizophrenic patients with and without probenecid administration and in drug-free normal control subjects. Schizophrenic patients had significantly higher baseline norepinephrine values. The dopamine metabolite homovanillic acid correlated significantly with norepinephrine. During chronic treatment with the neuroleptic pimozide, patients' norepinephrine levels were significantly decreased. The pimozide-induced decrease in norepinephrine, as well as the percent decrease, correlated significantly with the patients' decrease in global psychosis. These data are consistent with recent reports of elevated concentrations of norepinephrine in specific brain areas of schizophrenic patients, and they support a role for norepinephrine metabolism in the pharmacological effects of antipsychotic drugs.

Adolescent↗

PubMed2002

Inhibition by venlafaxine of the increase in norepinephrine output in rat prefrontal cortex elicited by acute stress or by the anxiogenic drug FG 7142.

Venlafaxine is an antidepressant drug that inhibits the reuptake of serotonin and norepinephrine with different efficacies. The effects of repeated administration of this drug on the increase in the extracellular concentration of norepinephrine in the prefrontal cortex, induced by stress or by the anxiogenic drug FG 7142, were studied in freely moving rats. Exposure to foot-shock stress induced a marked increase (+120%) in the extracellular norepinephrine concentration in the prefrontal cortex of control rats. Long-term administration of venlafaxine (10 mg/kg i.p., once a day for 21 days) reduced the effect of stress on norepinephrine output by 75%. This effect of venlafaxine persisted for at least 5 days after discontinuation of drug treatment. Acute administration of FG 7142 (20 mg/kg i.p.), a benzodiazepine receptor inverse agonist, increased norepinephrine output (+90%) in control rats. Chronic treatment with venlafaxine prevented the effect of FG 7142. In contrast, the acute administration of this antidepressant had no effect on the stress- or FG 7142-induced increase in norepinephrine output. These plastic changes in the sensitivity of norepinephrine neurones to foot-shock stress and to an anxiogenic drug may reveal an important neuronal mechanism for the physiological regulation of emotional state. Furthermore, this mechanism might be relevant to the anxiolytic and antidepressant effects of venlafaxine.

Animals↗

PubMed2005

Human skeletal muscle lipolysis is more responsive to epinephrine than to norepinephrine stimulation in vivo.

CONTEXT: Triglyceride (TG) deposits in skeletal muscle (SM) are an important energy reservoir, and increased im TG content is associated with muscle insulin resistance. OBJECTIVE: The objective of the study was to investigate the effect of endogenous catecholamines on TG lipolysis in human SM in vivo. Adipose tissue (AT) was studied for comparison. DESIGN AND MAIN OUTCOME MEASURES: Glycerol levels (index of lipolysis) were measured using microdialysis in the gastrocnemius muscle and abdominal sc adipose tissue during a hyperinsulinemic, hypoglycemic clamp (n = 13) and in response to in situ perfusion of epinephrine and norepinephrine (10(-10) to 10(-5) m) (n = 12). Local tissue blood flow was monitored with the ethanol perfusion technique. SETTING: This was an experimental study. PARTICIPANTS: The study population consisted of healthy subjects. RESULTS: Plasma epinephrine increased 10-fold and plasma norepinephrine 2-fold in response to insulin-induced hypoglycemia. In parallel, the fractional glycerol release (difference between tissue and arterial glycerol) increased 2-fold in both tissues (P < 0.0001). No changes in AT and SM blood flow were registered. When the catecholamines were perfused in situ, tissue glycerol increased significantly at 10(-7) m of either epinephrine and norepinephrine (P < 0.0001) in AT. The maximum stimulation was seen at 10(-6) m norepinephrine (2-fold increase) and 10(-5) m epinephrine (3-fold increase). In SM, tissue glycerol increased at 10(-7) m epinephrine and 10(-6) m norepinephrine, respectively (P < 0.0001); the maximum increase of glycerol values (at 10(-6) m) was 2.5 times for epinephrine and 1.6 times for norepinephrine, respectively (P < 0.01). CONCLUSIONS: The lipolytic activity of SM is increased by endogenous catecholamines in vivo and appears to be more responsive to epinephrine than norepinephrine stimulation.

Adipose Tissue↗

PubMed1979

Increased ratio between changes in blood pressure and plasma norepinephrine in essential hypertension.

The pathogenic role of the sympathetic system in essential hypertension was evaluated by combined analysis of plasma catecholamine levels and the pressor sensitivity to endogenous norepinephrine. The latter was estimated indirectly by the ratio between changes in blood pressure and those in plasma norepinephrine after adrenergic neuronal blockage with debrisoquine (given orally for 6 weeks). Normal subjects and patients with borderline or established essential hypertension had comparable pretreatment levels of plasma norepinephrine and epinephrine. Debrisoquine lowered plasma norepinephrine by a similar degree (almost 50%) in these three groups; in contrast, blood pressure decreased only slightly in normal or borderline hypertensive subjects [-3.4 +/- 3.2% and -5.4 +/- 1.6% (SE), respectively] but fell significantly more (P less than 0.005) in patients with established essential hypertension (-20.7 +/- 3.9%). The ratio between percentile changes in blood pressure and those in endogenous norepinephrine levels was comparable in normal and borderline hypertensive subjects (0.03 +/- 0.08 and 0.17 +/- 0.04, respectively), but increased (P less than 0.001) in established essential hypertension (0.62 +/- 0.11). This suggests that essential hypertension may be maintained, at least partly, by the inappropriate association of normal plasma norepinephrine levels with increased norepinephrine pressor sensitivity.

Blood Pressure↗

PubMed1984

Effect of overeating on plasma and urinary concentrations of norepinephrine.

This study examined the effect of overeating on plasma norepinephrine concentrations and urinary norepinephrine excretion in man, since overeating sucrose or fat increases norepinephrine turnover in rodents. Five normal subjects were overfed by 50% for 20 days, without substantially changing the proportions of protein, fat, and carbohydrate in the diet, after a control period of normal feeding. Sodium intake remained constant throughout the study. There was no effect of overfeeding on plasma norepinephrine concentrations when subjects were resting supine either before or after a meal. However, plasma norepinephrine concentrations after 10 min of orthostasis were 40% lower (P less than 0.05) at the end of overfeeding. Plasma norepinephrine concentrations during slow walking also tended to be lower during overfeeding, but this effect was not statistically significant. Mean 24-h norepinephrine and epinephrine excretion were not altered. These data do not support the hypothesis that overeating increases sympathetic nervous system activity in man.

Adult↗

PubMed2003

CaM kinase IIalpha mediates norepinephrine-induced translocation of cytosolic phospholipase A2 to the nuclear envelope.

Several growth factors, hormones and neurotransmitters, including norepinephrine, increase cellular calcium levels, promoting the translocation of cytosolic phospholipase A(2) to the nuclear envelope. This study was conducted to investigate the contributions of the calcium-binding protein calmodulin and of calcium-calmodulin-dependent protein kinase II to cytosolic phospholipase A(2) translocation to the nuclear envelope elicited by norepinephrine in rabbit aortic smooth-muscle cells. Norepinephrine caused cytosolic phospholipase A(2) accumulation around the nuclear envelope as determined from its immunofluorescence; cytosolic phospholipase A(2) translocation was blocked by inhibitors of calmodulin and calcium-calmodulin-dependent protein kinase II or calcium-calmodulin-dependent protein kinase IIalpha antisense oligonucleotide. Calmodulin and calcium-calmodulin-dependent protein kinase II inhibitors did not prevent cytosolic calcium increase but attenuated cytosolic phospholipase A(2) phosphorylation caused by norepinephrine or ionomycin. In vascular smooth-muscle cells reversibly permeabilized with beta-escin and treated with alkaline phosphatase, norepinephrine failed to cause cytosolic phospholipase A(2) phosphorylation and translocation to the nuclear envelope; these effects of norepinephrine were minimized by the phosphatase inhibitor okadaic acid. Recombinant cytosolic phospholipase A(2) phosphorylated by purified calcium-calmodulin-dependent protein kinase II, but not unphosphorylated or dephosphorylated cytosolic phospholipase A(2), introduced into permeabilized vascular smooth-muscle cells in the absence of calcium accumulated around the nuclear envelope. These data suggest that norepinephrine-induced translocation of cytosolic phospholipase A(2) to the nuclear envelope is mediated by its phosphorylation by calcium-calmodulin-dependent protein kinase II and that calcium alone is insufficient for cytosolic phospholipase A(2) translocation to the nuclear envelope in rabbit vascular smooth-muscle cells.

Active Transport, Cell Nucleus↗

PubMed1987

Presynaptic alpha 2-adrenoceptor mediated regulation of norepinephrine release in perfused mesenteric vasculatures in young and adult spontaneously hypertensive rats.

The present study was designed to evaluate the role of the presynaptic alpha 2-adrenoceptor in the pathogenesis of hypertension. Norepinephrine overflow during sympathetic nerve stimulation and its changes by presynaptic alpha 2-adrenoceptor inhibition were examined in the perfused mesenteric vasculatures of young and adult spontaneously hypertensive rats (SHR) compared with age-matched Wistar Kyoto rats (WKY). Electrical sympathetic nerve stimulation caused significantly greater overflow of endogenous norepinephrine from the adrenergic nerve terminals in young SHR than in age-matched WKY. Yohimbine, an alpha 2-adrenoceptor blocking agent, facilitated norepinephrine overflow from the adrenergic nerve terminals. The effects of yohimbine on norepinephrine overflow and pressor responses to electrical nerve stimulation were less in young SHR than in age-matched WKY. Norepinephrine overflow in adult SHR was similar to that in adult WKY, and differences in the effect of yohimbine on norepinephrine overflow between SHR and WKY were not marked at this chronic stage. These results suggest that enhanced norepinephrine overflow in the mesenteric vasculatures can be observed only in young SHR; this may be due in part to an impaired negative feed-back mechanism on the nerve terminals by presynaptic alpha 2-adrenoceptors.

Age Factors↗

PubMed1977

The effect of ovarian steroids on hypothalamic norepinephrine neuronal activity.

The concentration of norepinephrine and the apparent turnover of norepinephrine in the hypothalamus was studied in castrated rats and after the injection of ovarian steroids. Both parameters were found to vary not only with the hormone treatment, but also with the time of the day. Norepinephrine concentration in the anterior hypothalamus of castrated male and female rats was significantly higher in the afternoon than in the morning, but no statistical difference was observed in the concentration of norepinephrine in the posterior hypothalamus. Three days after the injection of a single dose of 20 microgram oestradiol benzoate, norepinephrine concentration and apparent turnover were found with decreased significant values in the anterior hypothalamus of castrated females, killed in the afternoon. Progesterone 2 mg injected three days after the priming dose of oestradiol benzoate, produced 4 h later in the afternoon a significant rise in norepinephrine concentration and apparent turnover. These results suggest that the apparent turnover of hypothalamic norepinephrine in the afternoon is reduced by oestrogen and increased by oestrogen plus progesterone.

Animals↗

PubMed2005

Effect of hypoxia on norepinephrine of various tissues in rats.

OBJECTIVE: To determine the effects of hypoxia and hypoxic exercise (HE) on the norepinephrine levels of various tissues in rats. METHODS: Male Wistar rats were randomly assigned to 3 groups: an HE group (n = 6), a hypoxic-sedentary (HS) group (n = 6), and a normoxic-sedentary (NS) group (n = 6). The HE rats had access, ad lib, to an exercise wheel for 8 weeks. HE and HS rats were maintained in a normobaric hypoxic chamber with an FIO2 of 16%. Norepinephrine levels were measured and compared in liver, heart, diaphragm, soleus, and gastrocnemius tissues from the 3 groups. RESULTS: Liver norepinephrine levels in the HE and HS groups were significantly lower than the levels in the NS group (P < .05). No significant difference was found in liver norepinephrine levels between the HE and the HS groups. The heart norepinephrine levels in the NS group were significantly lower than the levels in the HE (P < .01) and HS groups (P < .01). In contrast, no significant differences were found in the norepinephrine levels for the diaphragm and soleus muscle among the 3 groups. The norepinephrine levels in the gastrocnemius white muscles were significantly higher in the HS group than in the HE (P < .05) and NS groups (P < .01). P < .01 represents a significant difference at the level of 1%. CONCLUSIONS: This study demonstrated that hypoxia and HE both elicit a decreased sympathetic response in the liver tissue of male Wistar rats but cause an increased response in heart tissue. These results suggest that the sympathetic responses to long-term hypoxia and HE training are different in various rat tissues.

Animals↗

PubMed1992

Role of norepinephrine in the lack of reflex tachycardia after angiotensin converting enzyme inhibitor treatment.

Angiotensin converting enzyme inhibitors decrease blood pressure without causing reflex tachycardia in hypertensives, but do not always do so in normotensives. To investigate this phenomenon, hemodynamic changes in normotensive rabbits receiving a subpressor dose of norepinephrine were studied following captopril or diltiazem treatment. We also investigated the effect of captopril on baroreceptor reflex in relation to norepinephrine infusion; the baroreflex sensitivity was determined by the relationship between mean arterial pressure and pulse interval receiving graded doses of phenylephrine. Captopril infusion decreased mean arterial pressure and pulse interval from 84 +/- 4 to 74 +/- 5 mmHg and 244 +/- 7.4 to 216 +/- 7.6 msec, respectively. In contrast, in rabbits receiving a norepinephrine infusion captopril lowered mean arterial pressure to the same extent (92 +/- 5 to 76 +/- 3 mmHg, p less than 0.05) without producing reflex tachycardia. When diltiazem was administered, reflex tachycardia occurred in rabbits both with and without a norepinephrine infusion. There was no difference in the baroreflex sensitivity between rabbits receiving norepinephrine with and without captopril treatment. However, the baroreflex curve showed a slight shift to lower pressures after norepinephrine infusion in the rabbits receiving captopril. These results suggest that elevating circulating norepinephrine might be involved in preventing reflex tachycardia after captopril.

Animals↗

PubMed2006

Femoral artery constriction by norepinephrine is enhanced by methylprednisolone in a rat model.

BACKGROUND: Corticosteroids are associated with femoral head osteonecrosis and arterial hypertension. The patho-mechanism of femoral head osteonecrosis is often attributed to ischemia. The aim of this study was to investigate if corticosteroids directly constrict the femoral artery or if they have a permissive effect on norepinephrine and endothelin-1-induced vasoconstriction. METHODS: Femoral artery segments were harvested from twenty Wistar rats and mounted as ring preparations on a small-vessel myograph for the purpose of making isometric force measurements. For the norepinephrine study, twenty femoral artery segments from ten rats were stimulated cumulatively with norepinephrine before and after incubation with methylprednisolone (5 mug/mL). For the endothelin-1 study, forty femoral artery segments from ten rats were used. The four artery segments from each animal were randomized by pairs to either a corticosteroid treatment group (5 mug/mL methylprednisolone incubation, n = 20) or a control group (placebo incubation, n = 18, as two of the twenty control-group vessels did not meet protocol requirements). Isometric wall tension was plotted and quantified by the EC(50) (the plasma concentration of endothelin-1 required for obtaining 50% of maximal constriction in vivo). RESULTS: In the norepinephrine-stimulated group, incubation with methylprednisolone did not directly induce any vasoconstriction but did enhance norepinephrine-elicited vasoconstriction. The norepinephrine dose-response curve displayed a shift to the left after incubation with methylprednisolone. This shift was reflected by a significantly lower mean EC50 of 9.5 x 10(-7) M +/- 5.1 x 10(-7) M after methylprednisolone incubation compared with a mean of 2.5 x 10(-6) M +/- 1.1 x 10(-6) M before incubation (p < 0.005). In the endothelin-1-stimulated group, the endothelin-1 dose-response curve displayed a tendency toward stronger contraction in the vessels that were incubated with methylprednisolone, but this tendency did not reach significance. CONCLUSIONS: Incubation with methylprednisolone enhances norepinephrine-mediated contraction of the femoral artery in a rat model. CLINICAL RELEVANCE: Vasoconstriction of the vascular bed supplying the femoral head can diminish femoral head blood flow, and this may be a factor in the early pathogenesis of corticosteroid-associated femoral head osteonecrosis.

Animals↗

PubMed1994

Enhanced pressor responsiveness to norepinephrine in type II diabetes. Effect of ACE inhibition.

OBJECTIVE: To evaluate the effect of angiotensin-converting enzyme (ACE) inhibition on the pressor responsiveness to norepinephrine in type II diabetes. RESEARCH DESIGN AND METHODS: Eight normotensive subjects, eight mild-to-moderate hypertensive type II diabetic patients, and eight nondiabetic patients with essential hypertension were studied before and after 4 weeks of being administered enalapril. The pressor response to norepinephrine was assessed by infusing the hormone in an antecubital vein at incremental doses of 30 ng.kg-1.min-1 for periods of 5 min until reaching an increase of 20 +/- 2 mmHg in mean arterial pressure (MAP) measured by an automatic device at 1-min intervals. An effective dosage of norepinephrine that increased MAP by 20 mmHg (EDNE 20) was thereafter calculated. Before and during the last minute of norepinephrine infusion at maximum dosage, a venous blood sample was drawn to determine plasma renin activity (PRA), aldosterone, and norepinephrine levels. RESULTS: In the three groups of patients, blood pressure and aldosterone were reduced while PRA was raised following ACE inhibition. Basal and maximum postinfusion levels of norepinephrine were not modified by enalapril. The EDNE 20 was basally lower in diabetic patients and remained unchanged after ACE inhibition, contrary to that observed in nondiabetic patients with essential hypertension. CONCLUSIONS: Both normotensive and hypertensive type II diabetic patients have an increased pressor responsiveness to norepinephrine that is not modified by therapeutic doses of enalapril, contrary to what is observed in nondiabetic patients with essential hypertension.

Adult↗