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PubMed1999

Role of diacylglycerol (DAG) in hormonal induction of S phase in hepatocytes: the DAG-dependent protein kinase C pathway is not activated by epidermal growth factor (EGF), but is involved in mediating the enhancement of responsiveness to EGF by vasopressin, angiotensin II, and norepinephrine.

The role of diacylglycerol (DAG) in hormonal induction of S phase was investigated in primary cultures of rat hepatocytes. In this model, several agonists that bind to G protein-coupled receptors act as comitogens when added to the cells soon after plating (i.e., in Go/early Gl phase), while the cells are most responsive to the mitogenic effect of epidermal growth factor (EGF) at 24-48 h of culturing (i.e., mid/late Gl). It was found that the cellular concentration of DAG rose markedly and progressively during the first 24 h of culturing. Exposure of the hepatocytes at 3 h to alpha1-adrenergic stimulation (norepinephrine with timolol), vasopressin, or angiotensin II further increased this rise, producing a sustained increase in the DAG level. Norepinephrine, which was the most efficient comitogen, produced the most prolonged DAG elevation. In contrast, no significant increase of DAG was found in response to EGF, neither at 3 nor at 24 h, using concentrations that markedly stimulated the ERK subgroup of the mitogen-activated protein kinases (MAPK) and DNA synthesis. Addition of Bacillus cereus phosphatidylcholine-specific phospholipase C (PC-PLC) strongly elevated DAG, while Streptomyces phospholipase D (PLD) increased phosphatidic acid (PA) but not DAG. B. cereus PC-PLC and the protein kinase C (PKC) activator tetradecanoyl phorbol-acetate (TPA), like norepinephrine, vasopressin, and angiotensin II, stimulated MAPK and enhanced the stimulatory effect of EGF on DNA synthesis. The PKC inhibitor GF109203X did not diminish the effect of EGF on MAPK or DNA synthesis, but strongly inhibited the effects of norepinephrine, vasopressin, angiotensin II, TPA and B. cereus PC-PLC on MAPK and almost abolished the enhancement by these agents of EGF-stimulated DNA synthesis. These results suggest that although generation of DAG is not a direct downstream response mediating the effects of the EGF receptor in hepatocytes, a sustained elevation of DAG with activation of PKC markedly increases the responsiveness to EGF. Mechanisms involving DAG and PKC seem to play a role in the comitogenic effects of various agents that bind to G protein-coupled receptors and activate the cells early in Gl, such as norepinephrine, angiotensin II, and vasopressin.

Angiotensin II↗

PubMed1989

Effects of chronic infusion of norepinephrine on cardiac structure, function, and biochemistry: physiologic versus pathologic hypertrophy.

Ventricular hypertrophy should be divided into at least physiologic and patholgic states in order to clarify structural and functional clinical alterations. The elucidation of the structural, functional, and biochemical mechanisms of ventricular hypertrophy is vital to designing effective preventive and therapeutic measures for the hypertensive patient. Tissue markers may help differentiate pathologic from physiologic hypertrophy. Studies have established the concept that norepinephrine may be a myocardial cellular hypertrophying hormone. The studies ranged from the direct application of norepinephrine to isolated myocardial cells to the chronic subhypertensive infusion of norepinephrine into the conscious, free-roaming dog. Norepinephrine infusion can produce physiologic ventricular hypertrophy or a pathologic state of hypertrophic cardiomyopathy, the former by a three- to four-month infusion and the latter by an infusion of more than six months. The biochemical effect of subhypertensive infusion of norepinephrine was studied prior to the production of ventricular hypertrophy, thereby permitting the elucidation of the mechanism of the hypertrophic process. The biochemical stimulus for the production of myocardial cellular hypertrophy is postulated to be a diminution of cyclic AMP and a stimulation of alpha-1 receptors. Because the ventricular septum has the highest content of adenylate cyclase, which does not increase with cyclic AMP, these changes are postulated to be the biochemical basis for septal hypertrophy in the disease entity hypertrophic cardiomyopathy. A unique conscious-canine model for the production of a myocardial infarction capable of creating a controlled localized occlusion of the coronary artery is presented.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Plasma norepinephrine and mortality.

Plasma norepinephrine levels, which reflect sympathetic nervous system activity, are almost universally elevated in patients with left ventricular dysfunction. This elevation occurs in patients with overt, symptomatic heart failure (HF) and in patients with asymptomatic left ventricular dysfunction. Evidence suggests that the elevation in plasma norepinephrine levels can be at least partly attributed to an increase in sympathetic nervous system activity. It has become evident that elevated plasma norepinephrine levels are directly related to prognosis; patients with levels > 900 pg/ml have a poor prognosis and shortened life expectancy. However, plasma norepinephrine levels bear little relationship to physiologic and clinical variables observed in HF, including ejection fraction and exercise capacity. Data from the V-HeFT II show that at 2-year follow-up, a progressive rise of plasma norepinephrine was observed in both treatment arms, suggesting that disease progresses despite treatment with either an angiotensin-converting enzyme inhibitor, enalapril, or vasodilator therapy with hydralazine/isosorbide dinitrate. It is possible that interventions aimed at the progressive neurohormonal activation that occurs in HF may improve the course of illness. Further study is needed to test this hypothesis.

Enalapril↗

PubMedDate not supplied

Regulation of cardiac transient outward potassium current by norepinephrine in normal and diabetic rats.

BACKGROUND: Alpha-adrenergic stimulation regulates cardiac contractility by reducing repolarising K+ currents. Despite this, no published work exists on the effects of norepinephrine on isolated cardiac transient outward current, responsible for action potential duration in the rat and human. Besides, diabetes alters cardiac inotropic responses to sympathetic innervation, and this can result from altered responsiveness of the transient outward current to norepinephrine. METHODS: Transient outward K+ current was measured using the whole-cell configuration of the patch-clamp technique. Myocytes were isolated from the right ventricle of healthy and streptozotocin-induced diabetic rats. RESULTS: Norepinephrine, through alpha(1)-adrenoceptors, reduces current amplitude in a concentration-dependent way, with no effects on current kinetics or voltage dependence of inactivation. Diabetes reduces current amplitude and accelerates its inactivation process. Norepinephrine also reduces current amplitude in diabetic cells; however diabetes shifts to the right the concentration-response curve and reduces the maximum effect of the neurotransmitter. CONCLUSIONS: Norepinephrine reduces the amplitude of isolated ventricular transient outward K+ current with no effects on current properties in myocytes isolated from either healthy or diabetic hearts. Diabetes shifts the concentration-response curve; thus diabetic myocytes are more resistant to sympathetic regulation than are healthy cells.

Adrenergic alpha-Agonists↗

PubMed1992

Renal effects in cirrhotic patients with avid sodium retention of atrial natriuretic factor injection during norepinephrine infusion.

The administration of atrial natriuretic factor to patients with cirrhosis, and avid sodium retention causes marked hypotension and blunted kidney responses. To evaluate whether the unresponsiveness of the kidney is caused by a fall in mean blood pressure below a critical value for the renal blood perfusion pressure (80 mm Hg), we studied nine such patients and compared the effects of synthetic atrial natriuretic factor alone (1 micrograms/kg as a bolus) with those of an atrial natriuretic factor combination with infused norepinephrine titrated to raise baseline blood pressure by 15 to 20 mm Hg (182 to 625 ng/kg/min). The administration of atrial natriuretic factor during norepinephrine infusion caused a fall in mean blood pressure to values not less than 80 mm Hg in eight of nine patients, with a slight natriuresis (greater than 5 mumol/min) in five patients but no changes in the other four. The mean urinary sodium output was markedly lower than that previously observed after atrial natriuretic factor injection into normal subjects and into cirrhotic patients without avid sodium retention. Unlike sodium excretion, urine flow rate and free water clearance (which were not affected by atrial natriuretic factor alone) were markedly improved by the coadministration of norepinephrine and atrial natriuretic factor. In four additional patients we studied the urinary electrolyte excretion during a low-dose infusion of atrial natriuretic factor (20 ng/kg/min) to which an infusion of norepinephrine titrated to maintain blood pressure over 80 mm Hg was added. In only one of these four patients urinary sodium output consistently increased during atrial natriuretic factor infusion, and the output increased even more when norepinephrine was added.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1997

Nitric oxide formation lowers norepinephrine-induced intrahepatic resistance without major effects on the metabolism in the perfused rat liver.

Nitric oxide (NO) and norepinephrine are potent vasoactive agents that are involved in the control of portal blood flow. We have studied NO and norepinephrine in a non-recirculated rat liver perfusion to analyze their influence on portal flow and hepatic metabolism. Animals were either pretreated with endotoxin (4 hours; 10 mg/kg intraperitoneally) to activate the inducible NO synthase (NOS2), or used without pretreatment for the constitutive NO synthase (NOS3). In both groups, portal flow, bile flow, bile secretion, and the sinusoidal bile acid uptake were reduced by norepinephrine with a simultaneous increase of glucose and lactate output. The addition of the substrate for NO synthesis, L-arginine (0.5 mmol/L), to the perfusate markedly inhibited the effect of 0.1 micromol/L norepinephrine on portal flow from -2.6 +/- 0.32 to 0.3 +/- 0.1 mL/g/10 min in endotoxin-treated animals, and from -2.9 +/- 0.45 to 0.77 +/- 0.29 mL/g/10 min in the untreated ones. In contrast, neither NO formation after L-arginine supplementation nor inhibition of NO synthesis via the structural analogue (N(G)-monomethyl-L-arginine [L-NMMA]) changed cholestatic and glycogenolytic effects caused by norepinephrine. Only the sinusoidal bile acid uptake was reduced following increased NO formation. Thus, we conclude that endogenous NO formation prevents alpha-catecholaminergic-increased intrahepatic resistance without a major influence on the metabolic effects.

Animals↗

PubMed1992

Norepinephrine stimulates the direct breakdown of phosphatidyl inositol in rat tail artery.

When segments of rat tail artery were labeled with [3H]inositol and then stimulated with norepinephrine (NE), the inositol phosphates produced were primarily IP and IP2, together with a small but significant amount of Ins(1,4,5)P3 and a very small amount of Ins(1,3,4,5)P4. It has been unclear in many studies whether or not the relatively large levels of IP and IP2 produced in [3H]inositol-labeled tissue represent indirect products of phosphatidyl inositol(4,5)bis phosphate breakdown (through Ins(1,4,5)P3) or direct products of phosphatidyl inositol 4 monophosphate and phosphatidyl inositol breakdown. In order to answer this question tail artery segments were prelabeled with [3H]inositol and then permeabilized with beta escin and stimulated with norepinephrine and GTP gamma S, so that increases in IP, IP2, and Ins(1,4,5)P3 were still observed. If these permeable segments were stimulated with agonist in the presence of compounds known to inhibit Ins(1,4,5)P3 5-phosphatase, such as glucose 6P, (2,3)diphosphoglycerate, or Ins(1,4,5)P3, the levels of labeled Ins(1,4,5)P3 and labeled IP2 were increased, while the level of stimulated labeled IP was unchanged. This indicated that some of the IP2 and IP formed in these cells was produced from PIP2 but that some of these compounds might be formed from PIP or PI. When the isomers of inositol monophosphate, Ins 1P and Ins 4P, were separated by HPLC, it was shown that after prelabeled tail artery was stimulated by norepinephrine for periods of 1-2 min, the predominant isomer formed was Ins 4P, indicating either PIP2 or PIP as the source. However, after 5-20 min stimulation, both Ins 1P and Ins 4P were formed in equal amounts, suggesting that during sustained stimulation of smooth muscle PI itself was broken down directly. Therefore it appears that within 1-2 min of norepinephrine addition to vascular smooth muscle the bulk of the IP and IP2 produced are derived from PIP2 via IP3, while after 20 min of norepinephrine treatment much of the IP comes directly from PI. This suggests that the regulation of PLC in this tissue is more complicated than has been previously believed.

Animals↗

PubMedDate not supplied

Pulmonary vascular extraction of circulating norepinephrine in infants with bronchopulmonary dysplasia.

Although the pulmonary circulation in infants with advanced bronchopulmonary dysplasia (BPD) is characterized by abnormal structure and vasoreactivity, metabolic lung functions have not been studied in these infants. To test the hypothesis that patients with severe BPD may have abnormal metabolic lung function, we assessed the pulmonary vascular extraction of circulating norepinephrine in six children with BPD during cardiac catheterization. Plasma norepinephrine levels were measured from simultaneously drawn mixed venous (main pulmonary artery) and left atrium or femoral artery samples. In comparison with four infants with mild heart disease without pulmonary hypertension, we found that infants with BPD extract proportionately less norepinephrine than non-BPD infants [-7 +/- 50% (BPD) versus +27 +/- 6% (non-BPD); P less than 0.001, t test]. Three infants with BPD had higher arterial than mixed venous concentrations of plasma norepinephrine, suggesting net production across the lung. Plasma catecholamine levels and percent extraction correlated poorly with cardiac index and systemic and pulmonary vascular resistance indices. However, this study group was characterized by a high incidence of pulmonary (6/6) and systemic (4/6) hypertension, left ventricular hypertrophy (4/6), and subsequent death (3/6). We conclude that infants with severe BPD and pulmonary hypertension have decreased pulmonary vascular clearance or net production of circulating norepinephrine, but links between altered pulmonary catecholamine metabolism and pulmonary hypertension, or other cardiovascular abnormalities associated with BPD, remain speculative.

Bronchopulmonary Dysplasia↗

PubMed1994

PET studies of cocaine inhibition of myocardial norepinephrine uptake.

Positron emission tomography (PET), [11C]cocaine, and (-)-6-[18F]fluoronorepinephrine [(-)-6-[18F]NE] were used to determine the extent to which the binding of labeled cocaine in the baboon heart represents binding to the norepinephrine transporter and to characterize the functional consequences of cocaine administration on the norepinephrine transporter. Peak heart binding of [11C]cocaine was high (0.038-0.055%/g) and clearance was rapid (t1/2 from peak: 2.5-9 min) for both tracer doses and a pharmacological dose. The binding of a tracer dose of labeled cocaine could not be inhibited by desipramine, tomoxetine, cocaine, nomifensine, or benztropine. The behavior of a pharmacological dose of [11C]cocaine could not be distinguished from a tracer dose and also could not be inhibited by tomoxetine. However, pretreatment with cocaine profoundly inhibited norepinephrine uptake as assessed by (-)-6-[18F]NE. Recovery was slow with only 48% of the baseline (-)-6-[18F]NE uptake being recovered by 78 minutes after cocaine administration. [11C]Benzoylecgonine, a vasoactive metabolite of cocaine, showed negligible retention in heart. The results of this study (i.e., the rapid clearance of cocaine from the heart, the inability to inhibit cocaine binding with desipramine and tomoxetine, and its relatively long-lasting effects on norepinephrine uptake) reinforce the need to understand the link between cocaine pharmacokinetics and norepinephrine transporter function and its relationship to cardiotoxicity.

Animals↗

PubMed1998

Altered sarcoplasmic reticulum Ca2+ ATPase gene expression in congestive heart failure: effect of chronic norepinephrine infusion.

We have examined the ryanodine receptor, Ca(2+)-ATPase, calsequestrin and phospholamban mRNA levels in the left ventricles of pacing-induced heart failure and norepinephrine infusion dogs. The heart failure dogs showed a decrease in the levels of ryanodine receptor and Ca(2+)-ATPase mRNAs. Norepinephrine infusion caused a reduction of Ca(2+)-ATPase mRNA but no change in ryanodine receptor mRNA. There was a corresponding reduction of the immunoreactive Ca(2+)-ATPase protein levels in both heart failure and norepinephrine infusion animals compared to controls. In contrast, the mRNAs of calsequestrin and phospholamban were unchanged in dogs with either congestive heart failure or norepinephrine infusion. Thus, since norepinephrine infusion and congestive heart failure produced similar reductions of Ca(2+)-ATPase mRNA and protein, we postulate that the down-regulation of Ca(2+)-ATPase in congestive heart failure may be caused, at least in part, by sympathetic stimulation that occurs in heart failure.

Animals↗

PubMed1997

Norepinephrine induced growth and expression of virulence associated factors in enterotoxigenic and enterohemorrhagic strains of Escherichia coli.

The small intestine is richly innervated by the sympathetic nervous system. High concentrations of monoamines, most notably norepinephrine, are found throughout the various intestinal layers. In order to determine whether norepinephrine is capable of influencing bacterial pathogenesis, the growth and production of virulence factors in ETEC and EHEC were examined in a physiologically relevant medium utilizing very low initial bacterial inoculums to more closely mimie in vivo conditions. The growth of ETEC strain B44 and the production of the K99 pilus adhesin on a protein equivalent basis was greatly increased in the presence of norepinephrine. Growth of EHEC O157:H7 was also increased in norepinephrine containing medium as well as production of SLT-I and SLT-II. The ability of norepinephrine to increase both bacterial growth and expression of virulence factors was shown to be non-nutritional in nature. Given the abundant adrenergic innervation in the small intestine, these in vitro results suggest that the neurohumoral environment of the host may play a role in bacterial growth and expression of virulence factors.

Antigens, Surface↗

PubMed1987

Accumulation of adenosine 3',5'-monophosphate in slices of rat cerebral cortex induced by alpha-adrenergic agonists. I. Responses to methoxamine and norepinephrine in adult and neonatal tissue.

The effects of adrenergic agonists and adenosine on the accumulation of adenosine 3',5'-monophosphate (cyclic AMP) were examined in cerebral cortical slices from adult and neonatal rats. Methoxamine (10 to 100 microM) produced up to a two-fold increase in tissue from adult animals only in the presence of optimal concentrations of adenosine (40 to 100 microM), but had no effect in neonatal tissue. Such responses were inhibited more readily by prazosin than by yohimbine, but the reverse was true for responses to norepinephrine; when tested without the addition of adenosine, however, responses to norepinephrine were somewhat more sensitive to prazosin. Under the latter conditions, norepinephrine induced about twice as much increase in cyclic AMP as did isoproterenol in adult tissue. While always prevented by alpha-adrenergic antagonists, the greater efficacy of norepinephrine was eliminated by methylxanthines only in some instances, but never in tissue from animals known to be less than 60 days of age. At 11 to 15 days of age, responses to norepinephrine were more than fourfold those to isoproterenol, even in the presence of methylxanthines, and were completely suppressed by propranolol. Responses to isoproterenol were enhanced when tested in the presence of adenosine, especially in neonatal tissue. The results suggest that both endogenous adenosine and age-related phenomena may account for some of the discrepancies among earlier studies. Moreover, they indicate that several populations of alpha-adrenergic receptors may be involved in responses to adrenergic agonists in rat cerebral cortical tissue.

Adenosine↗

PubMed1992

Effect of steroid hormones on serotonin, norepinephrine and epinephrine contents in the pineal-paraphyseal complex of the soft-shelled turtle (Lissemys punctata punctata).

Steroids (testosterone, oestrogen, progesterone, corticosterone, dexamethasone and deoxycorticosterone) were administered intramuscularly (0.1 mg.100 g bw-1) on seven consecutive days to juvenile male soft-shelled turtles. Serotonin, norepinephrine and epinephrine contents of the pineal-paraphyseal complex were measured spectrofluorometrically 24 h after the last injection. Testosterone and oestrogen decreased serotonin, norepinephrine and epinephrine levels. Progesterone treatment resulted in an increase of serotonin level and a fall in norepinephrine and epinephrine levels. Corticosterone treatment caused an increase of serotonin level and a decrease of norepinephrine and epinephrine levels. Dexamethasone failed to alter serotonin content, increased norepinephrine and decreased epinephrine levels. Deoxycorticosterone decreased serotonin and elevated epinephrine content.

Adrenal Cortex Hormones↗

PubMed1990

Intracellular free calcium concentration/force relationship in rabbit inferior vena cava activated by norepinephrine and high K+.

The changes in isometric force and the underlying fluctuations in intracellular free calcium concentration ([Ca2+]i) were monitored simultaneously in thin sheets of rabbit inferior vena cava loaded with the fluorescent Ca2+ indicator fura-2. In resting tissues bathed in physiological saline solution, the estimated [Ca2+]i was approximately 105 nM. The alpha-adrenergic agonist norepinephrine (10 microM) caused an initial rise in [Ca2+]i to 264 nM during force development, which dropped to 216 nM during force maintenance. The maintained norepinephrine-induced increase in force and [Ca2+]i was reversed in Ca2(+)-free (2 mM EGTA) solution. Membrane depolarization by high K+ (80 mM) significantly increased [Ca2+]i to 234 nM. Compared to norepinephrine, high K+ caused about the same steady-state increase in [Ca2+]i, but a smaller increase in force. [Ca2+]i/force curves were constructed at different concentrations of extracellular Ca2+, with either norepinephrine or high K+ as a stimulant. The curve generated with norepinephrine was located to the left of that generated with high K+.

Animals↗

PubMed1976

Changes in brain norepinephrine associated with sensitization to d-amphetamine.

Pretreatment of B6AF1/J mice with d-amphetamine HCl 10 mg/kg, twice daily for 5 days, produced a 4-fold increase in the running response to a test dose of 5 mg/kg amphetamine. Amphetamine pretreatment decreased whole-brain norepinephrine levels to 50% of control values and whole-brain dopamine to 85%. The test dose of 5 mg/kg amphetamine lowered whole brain norepinephrine levels of control mice from 0.50 mug/g to 0.28 mug/g in 2 h. In amphetamine-pretreated mice, this injection caused an increase in whole-brain norepinephrine levels from 0.22 mug/g to 0.55 mug/g at 30 min, followed by a decrease to 0.22 mug/g at 60 min. No change in whole brain dopamine levels was observed in either group. Amphetamine sensitization and norepinephrine depletion were still evident 25 days after pretreatment. No cross sensitization to morphine or cocaine was observed. Reserpine pretreatment resulted in a 3-fold increase in locomotor activity following injection of d-amphetamine, 5 mg/kg. No sensitization or changes in catecholamine levels were observed in amphetamine-treated A/J mice. These results suggest that the sensitization produced by amphetamine pretreatment may be related to the depletion of brain norepinephrine.

Animals↗

PubMed1980

The effects of tranylcypromine isomers on norepinephrine-H3 metabolism in rat brain.

The effects of d- and l-tranylcypromine on the disposition and metabolism of intracisternally administered l-norepinephrine-H3 were studied in rat brain. Both isomers inhibited the deamination of norepinephrine-H3. However, d-tranylcypromine was considerably more potent than the l-isomer in this respect. In addition, the l-isomer of tranylcypromine was found to enhance the disappearance of endogenous and tritiated norepinephrine from brain. Although this action appeared to result from an increase in catecholamine release, the possibility of uptake inhibition could not be eliminated. The l-isomer of tranylcypromine enhanced the disappearance of norepinephrine-H3 from brain when administered both 20 and 90 min following intracisternal injection of the label. Comparable doses of d-tranylcypromine did not exhibit this effect. Larger increases in brain levels of normetanephrine-H3 were produced by d,l-tranylcypromine than by either the d- or l-isomer alone, indicating that the racemic mixture may produce the greatest increase in the interaction of norepinephrine with its postsynaptic receptors.

Animals↗

PubMed1982

Response of blood pressure and plasma norepinephrine to propranolol, metoprolol and clonidine during isometric and dynamic exercise in hypertensive patients.

The effects of metropolol (beta 1-selective), propranolol (nonselective) and clonidine (central alpha-stimulant) on plasma norepinephrine, blood pressure and heart rate were assessed at rest, during isometric work and dynamic exercise in 15 patients with moderate hypertension. Metroprolol resulted in a lower diastolic blood pressure during isometric and dynamic exercise that propranolol, which was paralleled by a lower plasma norepinephrine level during dynamic work; both beta-adrenergic blocking compounds resulted in a lower heart rate in all test situations than that obtained with clonidine; clonidine produced similar control of diastolic blood pressure to that obtained with the beta-adrenergic blocking agents, but did not clearly attenuate the systolic blood pressure response to dynamic exercise. Plasma norepinephrine concentrations tended to be lowest following clonidine, especially during dynamic work. The findings support the hypothesis that the central action of clonidine inhibits peripheral release of norepinephrine, but is insufficient to attenuate cardiac stimulation by physical exercise. The fact that propranolol caused higher plasma norepinephrine concentrations than metoprolol during exercise may explain the difference in the blood pressure responses during exercise.

Adult↗

PubMed1982

Release of norepinephrine from brain vesicular preparations: effects of an adenylate cyclase activator, forskolin, and a phosphodiesterase inhibitor.

1. The calcium-dependent K+-evoked release of [3H]norepinephrine from guinea pig cerebral cortical vesicular preparations is inhibited by norepinephrine, clonidine, and epinephrine. Isoproterenol has no effect and phentolamine prevents the inhibition by norepinephrine. The results indicate that an alpha-adrenergic receptor mediates an inhibitory input to the calcium-dependent release process. The inhibition by norepinephrine is prevented by high concentrations (3.0 mM) of calcium ions. 2. A cyclic AMP phosphodiesterase inhibitor, ZK 62771, slightly elevates [3H]cyclic AMP levels in the guinea pig cerebral cortical preparation and potentiates the marked elevation of [3H]cyclic AMP elicited by the adenylate cyclase activator, forskolin. 3. Neither ZK 62771 nor forskolin alone has significant effects on K+-evoked release of [3H]norepinephrine from the cerebral cortical vesicular preparation; however, a combination of ZK 62771 and forskolin inhibits K+-evoked release by as much as 60%. The inhibition is reversed by high concentrations (2.0 mM) of calcium ions. The results suggest that a marked accumulation of cyclic AMP elicited via both activation of adenylate cyclase and inhibition of phosphodiesterase can be inhibitory to neurotransmitter release from central synaptic terminals.

Adenylyl Cyclases↗