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PubMed1981

Effects of norepinephrine on transmembrane calcium transport in rat mast cells.

The effect of norepinephrine on transmembrane passage of calcium in rat peritoneal mast cells, was studied in an in vitro system. It was found the histamine release from mast cells induced by the ionophore A 23 187 in normal calcium medium and compound 48/80 in a calcium-free medium was suppressed by 10(-3) M norepinephrine but not at concentrations in the range 10(-5)-10(-4) M. When the secretory process is totally dependent on the presence of calcium in the incubation medium, i.e. calcium-depleted cells, 10(-5) M norepinephrine suppresses the histamine release induced by low concentrations of compound 48/80. The effect of norepinephrine (10(-5) M) on strontium-induced "spontaneous' histamine release was also studied. It was found that norepinephrine (10(-5) M) totally inhibits the progressive histamine release induced by strontium. It is possible to evoke secretion in a calcium-free medium, and subsequent introduction of Ca2+ will result in optimal histamine release. This demonstrates a secretory process in which we can distinguish between utilization of endogenous versus exogenous calcium. The release that is dependent on extracellular calcium is inhibited by norepinephrine (10(-5) M). These data indicate that the suppressive effect of norepinephrine (concentrations less than 10(-3) M) on histamine release from rat mast cells is due to an interference in transmembrane passage of calcium.

Animals↗

PubMed1984

Interference of calcium entry blockade in vivo with pressor responses to alpha-adrenergic stimulation: effects of two unrelated blockers on responses to both exogenous and endogenously released norepinephrine.

To the extent that calcium availability is the final common mediator of vasoconstrictor responses, calcium entry blockade might interfere with physiologic responses to adrenergic stimulation. To test this hypothesis, we studied the effects of calcium entry blockade on pressor responses to norepinephrine in pithed, normal Sprague-Dawley rats in two different ways: (1) by evaluating the effects on pressor responsiveness to exogenous norepinephrine during differential blockade of alpha 1-(prazosin, 0.3 mg/kg) and of alpha 2-receptors (yohimbine, 0.3 mg/kg) and (2) by comparing the effects of calcium entry blockade with those of prazosin and those of rauwolscine (a specific alpha 2-antagonist) on pressor responses to infusions of both endogenously released norepinephrine (electrical stimulation of the pithing rod) and exogenous norepinephrine. In the presence of alpha 1-blockade, both nitrendipine (0.01 mg/kg) and verapamil (0.6 mg/kg) shifted the norepinephrine pressor dose-response curve to the right but were ineffective in alpha 2-blocked animals. Furthermore, nitrendipine (range 0.01 to 0.3 mg/kg) proved to be more effective (p less than .001) against exogenous norepinephrine than against electrical stimulation of the spinal cord, a behavior opposite that of selective alpha 1-blockade (prazosin) and directionally comparable to that of selective alpha 2-antagonism (rauwolscine). These data indicate that calcium entry blockade in vivo preferentially antagonizes the alpha 2-pressor component of exogenous norepinephrine. In addition, both calcium entry blockers were consistently more active (p less than .01) than rauwolscine (0.01 to 1 mg/kg) in antagonizing the pressor response to neural stimulation, suggesting that mechanisms different from "classical" alpha 2-antagonism may also contribute to the overall effect of calcium entry blockade on the adrenergic control of peripheral vascular tone.

Adrenergic alpha-Agonists↗

PubMed1988

Norepinephrine spillover to plasma during steady-state supine bicycle exercise. Comparison of patients with congestive heart failure and normal subjects.

This study was performed to determine the relative contributions of plasma norepinephrine clearance and norepinephrine release to the increase in plasma norepinephrine concentration that occurs during exercise and to determine whether the high rates of cardiac norepinephrine release from the heart and kidney in patients with heart failure are associated with diminished reserve for regional sympathetic nervous stimulation. During supine steady-state bicycle exercise at 50% of maximum voluntary exercise capacity, the plasma norepinephrine concentration of six patients with congestive heart failure rose from 385 +/- 88 to 2,200 +/- 497 pg/ml, whereas that of nine normal subjects rose from 208 +/- 21 to 882 +/- 257 pg/ml. The change in plasma concentration in both groups was due to an increase in norepinephrine spillover to plasma without a change in plasma norepinephrine clearance. In patients with heart failure, cardiac spillover increased from 80 +/- 26 to 528 +/- 265 ng/min during exercise, and renal spillover rose from 146 +/- 71 to 418 +/- 69 ng/min. In the normal subjects, cardiac spillover rose from 5 +/- 2 to 73 +/- 23 ng/min, and renal spillover increased from 76 +/- 27 to 275 +/- 106 ng/min. There is no evidence of a reduced reserve for overall or regional sympathetic stimulation in patients with heart failure. Reduced reflex responses in these patients are more likely due to end-organ refractoriness than to inadequate stimulation.

Bicycling↗

PubMed1993

Silent ischemia in unstable angina is related to an altered cardiac norepinephrine handling.

BACKGROUND: Inferential evidence suggests that silent ischemia might be related to sympathetic activity. Study of [3H]norepinephrine kinetics is a suitable tool to assess the regional sympathetic activity. This method was applied to investigate whether silent myocardial ischemia in unstable angina is related to and depends on cardiac sympathetic overactivity. METHODS AND RESULTS: Patients with active unstable angina were compared with patients with inactive unstable angina, stable effort angina, and controls. Silent myocardial ischemia was evaluated by three 24-hour Holter monitoring periods on alternate days, and [3H]norepinephrine kinetics was assessed under rest conditions and following the cold pressor test. Simultaneously, catecholamine concentrations were measured in the aortic, coronary sinus, and peripheral venous blood. Different than the other groups (p = 0.0013), in patients with active unstable angina, the majority of silent ischemic episodes occurred without increase in heart rate. These patients had a positive coronary sinus-aorta norepinephrine gradient, both at rest and following the cold pressor test. [3H]Norepinephrine kinetics demonstrated an increased selective cardiac spillover, both at rest and, even more, after the cold pressor test. Reduced cardiac [3H]norepinephrine extraction also was found. A significant relation was found between the number of ischemic episodes or the overall duration of silent ischemia and norepinephrine spillover, both at rest and following cold application. CONCLUSIONS: During the acute phase of unstable angina (but not in the quiescent phase or in stable effort angina), a disorder in cardiac norepinephrine handling occurs. This results in a reflex cardiac sympathetic overactivity that plays a major role in the occurrence of silent myocardial ischemia.

Angina, Unstable↗

PubMed1994

Isoform-specific regulation of myocardial Na,K-ATPase alpha-subunit in congestive heart failure. Role of norepinephrine.

BACKGROUND: Myocardial ouabain-binding sites and Na,K-ATPase activity are reduced in congestive heart failure (CHF), but the mechanisms by which CHF reduces the Na,K-ATPase remain unknown. We proposed to investigate whether the changes are accompanied by isoform-specific reductions of the Na,K-ATPase alpha-subunit proteins in CHF and whether similar changes could be produced by exogenous norepinephrine administration. METHODS AND RESULTS: CHF was induced in dogs by rapid ventricular pacing at a rate of 225 beats per minute for 8 weeks (protocol 1). A second group of dogs were paced at 100 beats per minute and served as controls. In protocol 2, norepinephrine was infused in normal dogs using a subcutaneous osmotic minipump for 8 weeks. The control dogs received normal saline through the pump. Animals were studied after 8 weeks of pacing or norepinephrine infusion. After the baseline hemodynamics and interstitial norepinephrine concentration had been obtained, the hearts were removed for measuring [3H]ouabain-binding sites and Na,K-ATPase alpha-subunit proteins using isoform-specific monoclonal antibodies. RESULTS: Myocardial [3H]ouabain-binding sites were reduced in dogs with CHF and chronic norepinephrine infusion. The Western blot analysis showed that adult canine hearts possess both alpha 1 and alpha 3 isoforms of the Na,K-ATPase alpha-subunit but not the alpha 2 isoform protein. CHF and NE infusion had no effect on the Na,K-ATPase alpha 1-subunit protein but did reduce the alpha 3 isoform protein significantly. In addition, there was a significant inverse correlation between the amount of myocardial alpha 3 isoform protein and interstitial norepinephrine content in the dogs. In contrast, the specific activity of the sarcolemmal marker 5'-nucleotidase did not differ among the groups of animals. CONCLUSIONS: The reduction of myocardial Na,K-ATPase in CHF is limited to the alpha 3 isoform. Furthermore, because similar changes in myocardial ouabain-binding sites and Na,K-ATPase alpha 3 isoform were produced by chronic norepinephrine infusion, the decrease in the Na,K-ATPase in CHF is most likely mediated via excess sympathetic stimulation.

Animals↗

PubMed1994

Norepinephrine-induced human platelet activation in vivo is only partly counteracted by aspirin.

BACKGROUND: Epinephrine and mental stress may, via platelet stimulation, enhance the risk of thrombus formation. Norepinephrine is more likely than epinephrine to activate platelets in vivo because of higher levels in plasma but is less well studied in this respect. The antiplatelet drug of choice for patients with coronary artery disease, aspirin, may be less effective during sympathoadrenal activation. We therefore investigated platelet responses in vivo to exogenous norepinephrine with and without aspirin pretreatment. METHODS AND RESULTS: Platelet aggregability in vivo was assessed in 11 healthy male subjects, by filtragometry ex vivo (which reflects platelet aggregability in vivo) and by measurements of plasma beta-thromboglobulin (beta-TG, which reflects platelet secretion). Norepinephrine infusions elevated venous plasma norepinephrine from 1.5 to 4 and 15 nmol/L, respectively, and enhanced platelet aggregability (filtragometry) concentration dependently (P < .001). Platelet secretion (beta-TG levels) increased during high-dose infusion (P < .01). Aspirin pretreatment (500 mg orally 12 hours earlier) reduced the excretion of 11-dehydrothromboxane B2 by 62 +/- 5% (P < .001) and attenuated platelet aggregability at rest (P < .05) but not the effect of norepinephrine infusion on platelet aggregability. Conversely, resting plasma beta-TG levels and the urinary excretion of high-molecular-weight beta-TG were not altered by aspirin pretreatment, whereas the norepinephrine-induced increase in plasma beta-TG was abolished. CONCLUSIONS: Norepinephrine, at plasma levels easily attained during exercise, enhances platelet aggregability and platelet secretion in vivo in healthy humans. Aspirin may be less effective as an antithrombotic drug during sympathoadrenal activation in humans.

Adult↗

PubMed1994

Alpha-adrenoceptor stimulation with exogenous norepinephrine or release of endogenous catecholamines mimics ischemic preconditioning.

BACKGROUND: Brief episodes of ischemia induced by proximal coronary artery occlusion can precondition the myocardium. Whether other stressful stimuli have the potential to protect the myocardium from subsequent ischemia remains controversial. METHODS AND RESULTS: To study the hypothesis that transient alpha-adrenoceptor stimulation mimics preconditioning, for 5 minutes we administered 0.25 micrograms.kg-1.min-1 norepinephrine or saline 10 minutes before a 30-minute coronary occlusion and 4 hours of reperfusion in an in vivo rabbit model. The area of necrosis (AN) and area of risk (AR) were measured. We found that norepinephrine pretreatment caused a reduction in infarct size when compared with controls (AN/AR, 0.17 +/- 0.04 versus 0.31 +/- 0.04; P < .02). Ischemic preconditioning also reduced infarct size (AN/AR, 0.22 +/- 0.03). The protection observed with norepinephrine treatment was entirely eliminated by pretreatment with alpha-adrenergic blockade using prazosin (AN/AR, 0.42 +/- 0.06). Tyramine, an agent that causes release of endogenous catecholamines, was administered (1.5 mg/kg i.v.) 10 minutes before coronary occlusion in another group of rabbits. Tyramine pretreatment resulted in a smaller infarct size than in untreated controls (AN/AR, 0.16 +/- 0.04 versus 0.41 +/- 0.07; P < .01). Both norepinephrine and tyramine caused an increase in systemic arterial pressure during infusion; tyramine also increased heart rate. In rabbits pretreated with prazosin, heart rate and systemic pressure during the norepinephrine infusion were similar to baseline values. During coronary occlusion, the degree of ischemia was similar in all groups. CONCLUSIONS: Exposure of the heart to either transient exogenous norepinephrine or endogenous release of norepinephrine and/or other catecholamines by tyramine can mimic the effects of ischemic preconditioning in rabbits.

Animals↗

PubMedDate not supplied

Raised cerebrospinal fluid norepinephrine in some patients with primary hypertension.

To test whether central neurogenic factors participate in blood pressure elevation in primary hypertension, we studied the concentrations of: norepinephrine, epinephrine and dopamine-beta-hydroxylase (DBH) in cerebrospinal fluid (CSF); and norepinephrine, epinephrine, DBH and plasma renin activity (PRA) in plasma of 22 subjects (seven with primary hypertension, 11 normotensive patients with non-systemic neurological disorders, and four with secondary hypertension). Plasma and CSF norepinephrine (NE) were increased in primary hypertensives compared to normotensives. Cerebrospinal fluid norepinephrine was related to diastolic blood pressure, and systolic blood pressure when normotensive and primary hypertensives were taken together. The CSF norepinephrine of primary hypertensive patients was correlated with natural log PRA. The CSF norepinephrine was correlated inversely with age in primary hypertensive patients but not in the normotensive subjects. The low CSF norepinephrine and epinephrine, despite markedly increased plasma NE and epinephrine, in two patients with pheochromocytoma, indicate a blood-brain barrier for these neurohormones. The observations support the view that the central sympathetic nervous system is involved in the pathogenesis of primary hypertension, particularly in younger patients.

Adult↗

PubMed1991

Plasma norepinephrine and dihydroxyphenylglycol in essential hypertension.

The aim of the present study was to examine whether essential hypertension is associated with altered plasma concentrations of dihydroxyphenylglycol, the principal presynaptic metabolite of norepinephrine. Forearm venous plasma dihydroxyphenylglycol and norepinephrine were determined at rest and during graded orthostasis in 47 normotensive control subjects and 58 outpatients with essential hypertension. There was no group difference in age. At supine rest as well as during sitting and standing, hypertensive subjects had plasma norepinephrine concentrations similar to those in normotensive control subjects, but plasma dihydroxyphenylglycol concentrations were higher than those in normotensive control subjects. Both groups showed a linear relation between plasma dihydroxyphenylglycol (ordinate) and plasma norepinephrine (abscissa). The resulting regression line was steeper (p less than 0.02) and its ordinate intercept higher (p less than 0.01) in hypertensive than in control subjects. Eleven normotensive and 14 hypertensive subjects were also tested 3 hours after desipramine (1.5 mg/kg orally) was administered to inhibit neuronal norepinephrine reuptake. The drug did not alter plasma norepinephrine, but did reduce plasma dihydroxyphenylglycol and did abolish plasma dihydroxyphenylglycol responses to upright posture in both groups of subjects. The mean plasma dihydroxyphenylglycol concentration observed in the presence of desipramine again was higher in the hypertensive than in the control group (p less than 0.01) and closely agreed, in both groups, with the dihydroxyphenylglycol concentration given by the ordinate intercept of the dihydroxyphenylglycol versus norepinephrine regression line in the absence of desipramine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Norepinephrine overflow and renin pattern of the individual kidney in patients with unilateral renal artery stenosis.

This study was performed to determine divided renal efferent sympathetic nerve activity from kidneys in seven patients with renin-positive, unilateral renal artery stenosis before and 30 minutes after an acute intravenous dose of 1.25 mg enalaprilat. Renal norepinephrine release was calculated from split renal plasma flow, venoarterial plasma concentration gradients across the kidney, and the fractional extraction of tritiated norepinephrine. All patients had unilateral renin secretion, the affected kidney increasing its plasma renin activity gradient 1.7-fold, whereas no statistically significant change was noted on the contralateral side in response to enalaprilat. Total norepinephrine release to plasma and norepinephrine plasma clearance (assessed by isotope dilution) were similar before and after administration of enalaprilat (approximately 400 ng/min and 1.0 l/min), despite a 26% fall in mean arterial pressure (from 125 mm Hg, p less than 0.01). Heart rate remained unchanged. After enalaprilat, norepinephrine venoarterial difference increased in the renin-secreting kidney (from 264 to 396, SED = 57 pg/ml, p less than 0.05), whereas it increased only slightly in the contralateral kidney (from 149 to 256, SED = 72 pg/ml, NS). Tritiated norepinephrine extraction fell approximately 25% (p less than 0.01) in both kidneys. Thus, renal norepinephrine spillover increased from 49 to 62, SED = 9 ng/min (NS) and from 81 to 129, SED = 17 ng/min (p less than 0.05) from the affected and the contralateral kidney, respectively. Hence, in this relatively small study in patients with renovascular hypertension, no evidence for increased renal nerve activity could be observed in the affected kidney, despite its marked renin production.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1993

Influence of endogenous angiotensin on the renovascular response to norepinephrine.

The purpose of this study was to elucidate the role of endogenous angiotensin II in mediating the renovascular effects of renal adrenergic stimulation. Six conscious dogs instrumented for monitoring of renal blood flow were subjected to step increases every 10 minutes in the rate of norepinephrine infusion into the renal artery. Under control conditions, infusion of norepinephrine (10-40 ng/min per milliliter per minute of control renal blood flow) increased plasma renin activity and decreased renal blood flow progressively by approximately 10-75%. When increments in angiotensin II during norepinephrine infusion were abolished by fixing plasma levels of angiotensin II at either normal or high concentrations by chronic infusion of captopril plus angiotensin II, renal blood flow responses to adrenergic stimulation were greatly attenuated at rates of norepinephrine infusion that decreased renal blood flow up to approximately 40% under control conditions. Thus, acutely generated angiotensin II appeared to contribute to the renovascular effects of norepinephrine. However, when endogenous levels of angiotensin II were suppressed to low levels by chronic infusion of captopril alone, norepinephrine induced severe renal ischemia at much lower rates of infusion than occurred when the renin-angiotensin system was intact. Since this enhanced sensitivity to norepinephrine did not occur during chronic captopril infusion when angiotensin II was given simultaneously at rates that restored mean arterial pressure to normotensive levels or higher, low arterial pressure during chronic captopril administration may predispose the kidneys to excessive renal vasoconstriction during renal adrenergic stimulation.

Angiotensin II↗

PubMed1993

Potentiation of norepinephrine-induced contractions by endothelin-1 in the rabbit aorta.

Subthreshold concentrations of endothelin-1 potentiated the norepinephrine-induced contraction in isometrically mounted rings of the rabbit aorta. Pretreatment with endothelin-1 (0.1 nM) for 10 minutes increased the sensitivity of the aortic rings to norepinephrine without affecting the maximal contraction. This amplification was unaffected by removal of the endothelium but was prevented by the protein kinase C inhibitors staurosporine (0.01 microM) and calphostin C (0.1 microM). Pretreatment of the aortic rings for 24 hours with phorbol 12-myristate 13-acetate (0.1 microM) also abolished the potentiation. Norepinephrine-induced contraction was potentiated by pretreating with phorbol 12-myristate 13-acetate (10 nM) and by increasing the concentration of K+ in the bath solution from 4.6 to 8.6 mM. The potentiation of the norepinephrine-induced contraction by endothelin-1 (0.1 nM) or by phorbol 12-myristate 13-acetate (10 nM) was not associated with an increase in norepinephrine-induced 45Ca2+ uptake or influx, whereas the potentiation due to an increase in the concentration of K+ in the bath solution from 4.6 to 8.6 mM was associated with an increase in norepinephrine-induced 45Ca2+ uptake. We conclude that endothelin-1 potentiation of the norepinephrine-induced contraction occurs in the absence of changes in stimulated Ca2+ entry and is endothelium independent. It is probable that endothelin-1 increases the sensitivity of the contractile apparatus to Ca2+ by activating protein kinase C-dependent mechanisms.

Alkaloids↗

PubMed1993

Angiotensin II increases norepinephrine release from atria by acting on angiotensin subtype 1 receptors.

Norepinephrine stores in electrically driven guinea pig isolated atria were loaded with [3H]norepinephrine, and norepinephrine release was deduced from the radioactivity efflux. Electrical field stimulation of sympathetic nerve endings was applied during the refractory period of atrial contractions. The stimulation-induced release of norepinephrine was increased by angiotensin II (Ang II) (10(-8) to 10(-6) mol/L) in a concentration-dependent manner. The maximum observed effect was a 55% augmentation. The effects of 10(-7) and 10(-6) mol/L Ang II were abolished by 10(-6) and 10(-5) mol/L of the subtype 1 Ang II receptor antagonist losartan, respectively. Losartan by itself (10(-6) mol/L) caused a 14% reduction of norepinephrine release. The subtype 2 Ang II receptor ligand PD 123319 (1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)- 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate) in a concentration of 10(-4) mol/L had no detectable influence on transmitter release and did not antagonize the effect of Ang II. Angiotensin I (10(-6) and 10(-5) mol/L) increased norepinephrine release maximally by 23%. This effect was antagonized by 10(-5) mol/L losartan and did not appear in the presence of 10(-6) mol/L of the converting enzyme inhibitor ramiprilat. These results suggest that Ang II increases norepinephrine release by an activation of subtype 1 receptors, whereas angiotensin I is converted to Ang II to become effective.

Analysis of Variance↗

PubMedDate not supplied

Decreased release of norepinephrine in the isolated kidney of the adult spontaneously hypertensive rat.

Renal resistance vessels of the mature spontaneously hypertensive rat (SHR) exhibit an increased reactivity to exogenous norepinephrine, but a normal response to renal nerve stimulation. This difference could be due either to depression of the exocytotic process or to accelerated disposition of the released transmitter. We compared the overflow of norepinephrine in isolated perfused kidneys from adult SHR and normotensive rats. After previous incubation with 3H-norepinephrine, renal nerve stimulation caused smaller increases in the overflow of intact tritiated transmitter and its metabolites in kidneys form SHR than in those from normotensive controls. A similar difference was found when the amounts of endogenous norepinephrine were measured radioenzymatically. The tissue content of norepinephrine was comparable in kidneys from both hypertensive and normotensive animals. The uptake of 3H-norepinephrine was comparable in kidneys from SHR and normotensive controls; cocaine caused a comparable depression of the 3H-uptake in which then explains the normal vasoconstrictor response to renal nerve stimulation despite the increased responsiveness of the vascular smooth muscle cells to norepinephrine.

Adrenergic Fibers↗

PubMed1975

Dissociation constant of the norepinephrine-receptor complex in normotensive and hypertensive rats.

Previous reports have suggested that smooth muscle obtained from the thoracic aorta of spontaneously hypertensive rats is less responsive to vasoconstrictive agents than that obtained from normotensive rats. The present study was undertaken to determine whether the responsiveness of aortic muscles from normotensive and spontaneously hypertensive rats correlates with a difference in the affinity of the adrenergic receptors for norepinephrine and whether antihypertensive therapy alters the affinity of the adrenergic receptors for norepinephrine. The affinity of the adrenergic receptors for norepinephrine was determined by computing the dissociation constant of the norepinephrine-receptor complex (KDR). The values computed for KDR in aortic muscles from normotensive and spontaneously hypertensive rats that had received no antihypertensive therapy were 1.07 X 10(-7)M and 1.17 X 10(-7)M, respectively. The values computed for KDR in aortic muscles from normotensive and spontaneously hypertensive rats that had received antihypertensive therapy were 1.38 X 10(-7)M and 1.29 X 10(-7)M, respectively. The differences in these values for KDR are not significant. These results indicate that the difference in the contractility of aortic muscles from normotensive and spontaneously hypertensive rats is not related to an alteration in the affinity of the adrenergic receptors for norepinephrine and that the affinity of the adrenergic receptors for norepinephrine is not altered by antihypertensive therapy. Thus, it appears that the etiology of hypertension cannot be directly correlated with a difference in the affinity of the adrenergic receptors for norepinephrine.

Animals↗

PubMed1981

Role of the prostaglandin in norepinephrine release during augmented renal sympathetic nerve activity in the dog.

To determine the role of the prostaglandins on renal norepinephrine release, the effect of inhibition of prostaglandin synthesis was examined in anesthetized dogs during reflex activation of the renal adrenergic nerves. Hypotension increased the renal vein plasma concentrations of norepinephrine from 380 +/- 59 to 608 +/- 106 pg/ml (mean +/- SEM; P less than 0.01) and of PGE2 from 55 +/- 7 to 81 +/- 41 pg/ml (P less than 0.05). Subsequent administration of indomethacin or meclofenamate lowered the renal venous concentration of PGE2 to 26 +/- 3 pg/ml (P less than 0.01), had no significant effect on the norepinephrine concentration (620 +/- 89 pg/ml). Administration of indomethacin or meclofenamate to dogs with sodium depletion lowered renal venin plasma concentration of PGE2 from 108 +/- 40 to 20 +/- 3 pg/ml (0.05 less than P less than 0.1) but had no effect on the renal venous norepinephrine concentration (475 +/- 50 vs. 397 +/- 46 pg/ml). In dogs fed a normal salt diet, inflation of a balloon placed in the thoracic inferior vena cava lowered cardiac output and increased the renal venous concentrations of norepinephrine from 212 +/- 60 to 496 +/- 112 pg/ml (P less than 0.01) and of PGE2 from 28 +/- 5 to 96 +/- 18 pg/ml (P less than 0.01). Subsequent administration of indomethacin lowered the renal venous concentration of PGE2 to 16 +/- 5 pg/ml (P less than 0.01), but had no significant effect on the concentration of norepinephrine (548 +/- 91 pg/ml). During the three experimental conditions examined, renal blood flow was lowered by inhibition of prostaglandin synthesis. These results in the dog suggest that the attenuating effect that prostaglandins exert on the renal vascular action of the adrenergic nerves is not due to inhibition of norepinephrine release.

Animals↗

PubMed1982

Norepinephrine sensitivity and desensitization of cultured single vascular muscle cells.

Isolated single vascular muscle cells were used for studies of the inherent norepinephrine sensitivity and the conditions important for detecting highest norepinephrine sensitivity. Rat vascular muscle cell contractions were quantitated from spontaneous contractions during pulse applications of the drugs, with a time course designed to simulate norepinephrine release in situ. Isolated vascular muscle cells showed a sensitivity to norepinephrine two orders of magnitude greater than those found from isolated intact blood vessels. Associated with the high sensitivity, there was a marked reduction in the response to a second application of norepinephrine or phenylephrine. The reduced second response appears to result from desensitization that is more pronounced in cells that have been exposed to only trace concentrations of catecholamines. These data appear to suggest that there might be continuous suppression of transmitter sensitivity that occurs as a result of transmitter exposure, and possibly cell-to-cell associations. Desensitization would at first severely limit the response to norepinephrine by reducing or eliminating the response to prolonged exposure or a second dose. Thereafter, a lessening of the desensitization process on continuous exposure to catecholamines would be the result, in part, of lowered sensitivity and, in part, of a smaller desensitization response. This process would continuously modulate norepinephrine sensitivity, based on the frequency and extent of stimulation, and we have called it the theory of physiological desensitization.

Animals↗

PubMed1986

Effect of norepinephrine and cyclic AMP on intracellular sodium ion activity and contractile force in canine cardiac Purkinje fibers.

The effect of norepinephrine on the Na+-K+ pump was investigated by simultaneously measuring intracellular sodium ion activity (aiNa) and contractile force of canine cardiac Purkinje fibers driven at 1.0 Hz in K+-free solution, high K+ solution, and in the presence of tetrodotoxin. In Tyrode solution containing 5.4mM [K+]o, 10(-6) M norepinephrine decreased aiNa, whereas in K+-free solution 10(-6) M norepinephrine did not lower aiNa. 16.2 mM [K+]o decreased aiNa from 8.8 +/- 0.9 mM to 6.5 +/- 0.5 mM (mean +/- SD, n = 5). Exposure to 10(-6) M norepinephrine in the presence of high [K+]o further decreased aiNa by 0.7 +/- 0.4 mM. This further decrease was prevented by exposure to 2.5 X 10(-6) M strophanthidin (n = 4). Blockade of the fast sodium channel with 5 X 10(-6) M tetrodotoxin lowered aiNa from 8.5 +/- 1.3 mM to 7.4 +/- 1.1 mM (n = 4). Exposure to 10(-6) M norepinephrine in the presence of tetrodotoxin further lowered aiNa by 0.9 +/- 0.2 mM. We also studied the effects of the analogues of adenosine 3':5'-cyclic monophosphate, N6, 2'-0-dibutyryladenosine 3':5'-cyclic monophosphate, and 8-(4-chlorophenylthiol)-adenosine 3':5'-cyclic monophosphate on aiNa and twitch tension. Both analogues lowered to aiNa and increased twitch tension mimicking the effects of norepinephrine. Our results support the hypothesis that norepinephrine lowers aiNa by stimulating the Na+-K+ pump in this tissue. This stimulation appears to be mediated by adenosine 3':5'-cyclic monophosphate and does not appear to be due to intercellular K+ accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗