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PubMed1979

The pattern of urinary catecholamines and their metabolites in Duchenne myopathy, in relation to disease evolution.

In this report we have tried to determine whether or not catecholamines are involved in the progressive muscular dystrophy. Catecholamines and their metabolites were studied in urines of children with Duchenne disease or other forms of myopathy (limb-girdle and facio-scapulo humeral myopathies). Catecholamine deaminated metabolites were normal in either form of myopathy; in contrast, Duchenne patients, contrarily to other children, eliminated excessive amounts of most amines (catecholamines and methoxylated amines) in relation to age and degree of disease evolution. Our results indicate that catecholamines are not the primary factors involved in the pathogenesis of Duchenne myopathy, but are rather secondary to some disease effects. It is suggested that the high excretion of catecholamines and their methoxylated amine metabolites observed in severely affected Duchenne boys might be related to thermoregulatory process or/and to alterations in some enzymatic systems.

Adolescent↗
PubMed1983

Glucuronide and sulfate catecholamine conjugates in rat and human plasma.

We have developed a method to selectively estimate free, glucuronidated and sulfated catecholamines (epinephrine [E], norepinephrine [NE], dopamine [DA]) in a single plasma sample. The method incorporates the first step of the catecholamine radioenzymatic assay and the selective enzymatic hydrolysis of conjugates by glucuronidase or sulfatase preparations. The method has been applied to rat and human plasma with a view to determine the relative importance of either conjugate (sulfate or glucuronide) toward free catecholamines. No previous reports were available for the concentration of either conjugate in rat plasma or the level of glucuronide conjugate in human plasma. Both sulfate and glucuronide conjugate of the three catecholamines were found in rat and human plasma, at different levels. Sulfate conjugates predominated in man and glucuronides in rat. In human, hand immersion in ice water for three minutes, which increased free catecholamine levels in the first minutes of the test, elicited too a delayed increase of glucuronide levels at the 30th minute (except for DA glucuronide which was already elevated at the third minute). As to the sulfates, only E sulfate was increased at the 10th minute. Our results suggest that glucuronidation may be an important pathway for catecholamine metabolism in man at rest or under sympathetic stimulation. In rat, our data point out the influence of blood sampling conditions (dietary, catheterization, decapitation) on the studied compounds and suggest that the nearest conditions from basal state may be fulfilled in sucrose-fed catheterized rats. The predominance of glucuronides in rat plasma agrees with previous metabolic reports.

Adult↗
PubMed1981

Effect of various stimulus parameters on electrically-induced catecholamine secretion by thin slices of bovine adrenal medulla.

We examined the role of various stimulus parameters in electrically-induced catecholamine secretion by thin slices of bovine adrenal medulla. The stimulus parameters examined were voltage, duration, pulse width, and frequency for square-wave monophasic pulses. As each was examined it was held constant at a selected value for the evaluation of subsequent stimulus characteristics. For 16 mm2 tissue slices, catecholamine secretion was approximately linearly related to stimulus voltage over the range 20--80 volts, with a threshold of 20 V. Increasing the voltage beyond 80 V did not enhance secretion. Similarly, catecholamine secretion was dependent upon the frequency of stimulation. For stimuli delivered at 50 V for a 10-sec interval there was a four-fold increase in secretion over the frequency range 10--100/sec. Increasing pulse width at a constant voltage (50 V) over the range 0.4--2.0 msec resulted in a four-fold increase in catecholamine secretion. For pulses of 50 V, 50/sec and 0.8 msec pulse width, secretion was dependent upon the duration of the stimulus. Enhanced secretion was evident for times as short as 2 sec; between 5 and 15 sec of stimulation catecholamine secretion was linearly related to stimulus duration. Over the range 2--15 sec there was a five-fold enhancement of secretion. Electrically-induced catecholamine secretion by slices was markedly dependent upon stimulus parameters. In general, it was enhanced by increasing voltage, stimulus duration, pulse width and frequency. For most experiments a good choice of stimulus parameters appears to be 50 V 10 sec duration, 0.8 msec pulse width delivered at a frequency of 50/sec. Maximizing all stimulus parameters resulted in a 17-fold enhancement of secretion.

Adrenal Medulla↗
PubMed1985

Comparison of 131I-metaiodobenzylguanidine scintigraphy with urinary and plasma catecholamine determinations in the diagnosis of pheochromocytoma.

In a retrospective study of 31 patients with suspected pheochromocytoma we examined the preoperative results of 131I-metaiodobenzylguanidine (131-I-MIBG) scintigraphy and a fluorimetric urine catecholamine determination test. An additional radioenzymatic plasma catecholamine determination test was performed in 25 patients. In 14 of the 31 patients the diagnosis of pheochromocytoma was later histologically confirmed. In the remaining 17 patients the suspected diagnosis was finally rejected after a clinical decision had been made on the basis of clinical history, symptoms, laboratory and imaging tests. 131-I-MIBG scintigraphy apparently had a very high specificity (no false-positive results among the patients with rejected diagnosis), but showed the least sensitivity (3 of 14 tumours were not detected). Urine catecholamines showed two false-negative and three false-positive results. Plasma catecholamines had the highest sensitivity and gave only one false-positive result. Because of its high pathognomonic value 131-MIBG scintigraphy can be helpful not only for localization, but also for confirmation of diagnosis when catecholamine determination tests are contradictory. On the basis of our experience with false-positive results after interfering medication therapy, urine and plasma catecholamine determination tests should only be carried out after purification with thin layer chromatography or high performance liquid chromatography.

3-Iodobenzylguanidine↗
PubMed1981

Response of white adipocyte of mouse and rabbit to catecholamines and ACTH. 2. Stability and restoration of activity of hormone-sensitive adenylate cyclase of adipocyte plasma membrane.

The isolated intact white adipocyte of the Swiss mouse responds to both ACTH and catecholamines by an elevation of cAMP levels and an increase in lipolysis. However, in the isolated plasma membrane of the mouse adipocyte, adenylate cyclase loses its responsiveness to ACTH but retains its ability to respond to catecholamines. This lack of responsiveness to ACTH by adenylate cyclase of mouse adipocyte plasma membrane can be overcome, at least partially, by addition of GPP (NH)p, an analog of GTP, to the assay medium. The data on mouse adipocyte membrane suggests that the coupling of ACTH receptor to adenylate cyclase is dependent on GTP and that catecholamine-activation of adenylate cyclase is less dependent on this nucleotide. The isolated intact white adipocyte of adult New Zealand rabbit responds to ACTH, but does not (or only weakly) respond to catecholamines. In contrast to the mouse plasma membrane preparation, adenylate cyclase of adipocyte membrane of the rabbit responds to ACTH. And the addition of GPP(NH)P is not required to demonstrate the CTH: sensitive adenylate cyclase activity. The difference between mouse and rabbit adipocyte membrane in the requirement for GPP(NH)P in ACTH action is not readily explained. The lack of catecholamine sensitivity of rabbit membrane enzyme cannot be reversed by addition of GPP(NH)P or adenosine deaminase. These two adenylate cyclase model systems using mouse and rabbit adipocyte plasma membrane may be useful tools for the study of the specificity and mechanism of action of lipolytic hormones such as ACTH and catecholamines.

Adenylyl Cyclases↗
PubMed1975

Hypercalcemic effect of catecholamines and its prevention by thyrocalcitonin.

Earlier work by others has shown that the catecholamines, epinephrine and isoproterenol, can raise blood calcium levels in parathyroidectomized but not intact rats, and can restrict the hypocalcemic effect of injected thyrocalcitonin (TCT). The present findings support this earlier work, further showing that such catecholamines can produce hypercalcemia in rats after removal of the thyroid gland by acute thyroparathyroidectomy (TPTX) and indicating that these drugs may raise blood calcium by mobilizing calcium from bone. Rats were fasted overnight, subjected to TPTX and concurrently injected with adrenergic agonist or antagonist drugs alone or in combination. Epinephrine, isoproterenol, and the beta-2 adrenergic agonist, salbutamol, in doses greater than or equal to 1 mg/kg raised blood calcium from low normal levels (approximately 9-10 mg/100 ml) by 1.5 to 2 mg/100 ml (p less than 0.01). Hypercalcemia was apparent by 1 hour after injection and lasted for 1-4 hours. The extent of Ca elevation was dose-related. Pretreatment of rats with the alpha-adrenergic antagonist, phenoxybenzamine, enhanced the effect of epinephrine while pretreatment with the beta-antagonist, propranolol, reduced the effect of isoproterenol. The more selective beta-2 antagonist, butoxamine, but not the beta-1 antagonist, practolol, also reduced the hypercalcemic effect of isoproterenol in TPTX rats. These results suggest that catecholamine-induced hypercalcemia in TPTX rats is mediated by beta-2 adrenergic receptors. Related studies using rats prelabeled with 45Ca further suggest that the catecholamines, like parathyroid hormone, may act to raise blood calcium by mobilizing calcium from bone. The fact that these catecholamines could induce marked hypercalcemia in acutely TPTX rats but not in intact rats indicated that endogenous TCT protects the thyroid intact rat against hypercalcemia. The present findings support this idea in showing that isoproterenol and salbutamol raised levels of immunoreactive rat TCT in both thyroid venous and peripheral blood. Catecholamines apparently can promote TCT secretion, either directly or by a small transient increase in blood calcium. This, in turem, acts to combat hypercalcemia in thhroid-intact rats.

Albuterol↗
PubMed2005

Selective blockade of nicotinic acetylcholine receptors by pimobendan, a drug for the treatment of heart failure: reduction of catecholamine secretion and synthesis in adrenal medullary cells.

Pimobendan, a Ca(2+) sensitizer, is used clinically in the treatment of chronic heart failure. Although chronic heart failure is associated with activation of the sympathetic nervous system, it remains unknown whether pimobendan affects the function of sympathetic neurons and the adrenal medulla. Here, we report the inhibitory effects of pimobendan on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. Pimobendan decreased the catecholamine secretion (IC(50)=29.5 microM) elicited by carbachol, an agonist at nicotinic acetylcholine receptors, but not that elicited by veratridine, an activator of voltage-dependent Na(+) channels, or by high K(+), an activator of voltage-dependent Ca(2+) channels. Pimobendan also inhibited carbachol-induced influx of (22)Na(+) (IC(50)=25.9 microM) and (45)Ca(2+) (IC(50)=26.0 microM), but not veratridine-induced (22)Na(+) influx or high K(+)-induced (45)Ca(2+) influx. The reduction of catecholamine secretion caused by pimobendan was not overcome by increasing the concentration of carbachol. UD-CG 212, an active metabolite of pimobendan, lowered carbachol-induced catecholamine secretion with a concentration/inhibition curve similar to that of pimobendan. In experiments in situ, pimobendan suppressed both basal and carbachol-stimulated (14)C-catecholamine synthesis (IC(50)=5.3 and 4.9 microM) from [(14)C] tyrosine [but not from L: -3, 4-dihydroxyphenyl [3-(14)C] alanine ([(14)C]DOPA)], as well as tyrosine hydroxylase activity (IC(50)=3.8 and 4.3 microM). These findings suggest that pimobendan inhibits carbachol-induced catecholamines secretion and synthesis through suppression of nicotinic acetylcholine receptors.

Adrenal Medulla↗
PubMed2006

Capsaicin inhibits catecholamine secretion and synthesis by blocking Na+ and Ca2+ influx through a vanilloid receptor-independent pathway in bovine adrenal medullary cells.

We report here the effects of capsaicin, a flavoring ingredient in the hot pepper Capsicum family, on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. Capsaicin inhibited catecholamine secretion (IC(50)=9.5, 11.8, and 62 microM) stimulated by carbachol, an agonist of the nicotinic acetylcholine receptor, by veratridine, an activator of voltage-dependent Na(+) channels, and by high K(+), an activator of voltage-dependent Ca(2+) channels, respectively. Capsaicin also suppressed carbachol-induced (22)Na(+) influx (IC(50)=5.0 microM) and (45)Ca(2+) influx (IC(50)=24.4 muM), veratridine-induced (22)Na(+) influx (IC(50)=2.4 microM) and (45)Ca(2+) influx (IC(50)=1.1 microM), and high K(+)-induced (45)Ca(2+) influx (IC(50)=5.8 microM). The reduction in catecholamine secretion caused by capsaicin was not overcome by increasing the concentration of carbachol. Furthermore, capsazepine (10 microM), a competitive antagonist for the transient receptor potential vanilloid 1, and ruthenium red (30 microM), a nonselective cation channel antagonist, did not block the inhibition by capsaicin of catecholamine secretion. Capsaicin also suppressed both basal and carbachol-stimulated (14)C-catecholamine synthesis (IC(50)=10.6 and 26.4 microM, respectively) from [(14)C] tyrosine but not from L: -3, 4-dihydroxyphenyl [3-(14)C] alanine ([(14)C] DOPA) as well as tyrosine hydroxylase activity (IC(50)=8.4 and 39.0 microM, respectively). The present findings suggest that capsaicin inhibits catecholamine secretion and synthesis via suppression of Na(+) and Ca(2+) influx through a vanilloid receptor-independent pathway.

Adrenal Medulla↗
PubMed1999

Modification of low density lipoprotein potentiates its inhibitory effect on catecholamine secretion in cultured bovine adrenal medullary cells.

Low density lipoprotein (LDL) and lipoprotein(a) suppress catecholamine secretion in cultured adrenal medullary cells. Modification of LDL by oxidation or acetylation potentiates various atherogenic actions of LDL. In the present study, we investigated whether the modification of LDL influences catecholamine secretion in cultured bovine adrenal medullary cells. The exposure of LDL to CuSO4 caused a time-dependent oxidation of LDL. Maximal oxidation of LDL was observed after exposure to CuSO4 for 24 h. Native LDL inhibited catecholamine secretion induced by carbachol to 68.5% of control. Oxidized LDL caused further inhibition of carbachol-evoked secretion to 37.6% of control. Acetylated LDL inhibited it to 41.0% of control. There was a good correlation between the extent of LDL oxidation and the inhibition of catecholamine secretion. These results suggest that oxidation or acetylation of LDL augments its inhibitory effect on the secretion of catecholamines. Since catecholamines are a risk factor of atherosclerosis, the inhibitory effect by such modified LDL may be a mechanism inhibiting atherosclerotic progression.

Adrenal Medulla↗
PubMed2006

Pretreatment and one-shot separating analysis of whole catecholamine metabolites in plasma by using LC/MS.

Catecholamines are biogenic amines that play an important role in the nervous system. Some catecholamines have been used as tumor makers of phenochromocytoma, paraganglioma and neuroblastoma. The analysis of total catecholamine metabolites should be useful for one-shot screening of multiple aspects of diseases; however, it is difficult to do this, because the catecholamine metabolites are divided into three groups: five amines, one amino acid and three carbonic acids. Catecholamines and small molecules were separated from plasma proteins by an internal-surface reversed-phase column (protein-coated octadeyclsilica column) and were analyzed by liquid chromatography (LC)/mass spectrometry (MS) using electrospray ionization time-of-flight MS. Using a reversed-phase column and hydrophilic mobile phases, we succeeded in the separation of nine catecholamines, all of which had similar structures. These nine substances were eluted in the following order: norepinephrine, epinephrine, normetanephrine, dopamine, metanephrine, 3,4-dihydroxyphenylalanine, vanillomandelic acid, 3,4-dihydroxyphenylacetic acid and homovanillic acid. The reproducibility of this method was acceptable. The highest coefficient of variation was 7.4%. In addition, various types of compounds were separated from and detected in plasma proteins by applying LC/MS. The plasma direct injection method, which uses an internal-surface reversed-phase column and an ion-pair reagent, allowed us to separate small molecules from plasma proteins. MS detected some compounds that high-performance LC could not succeed in separating and detecting with UV detection. We think that the method can be applied to find new markers in neuroblastoma, by comparing the plasma of patients with that of normal infants. The method can be also used to help in making a diagnosis of other diseases and finding their new makers.

Catecholamines↗
PubMed1979

Plasma catecholamines in acute myocardial infarction.

Plasma catecholamine levels were determined in 26 cases of uncomplicated myocardial infarction within 24 hours of onset of acute chest pain. Blood samples were collected at time of entry and at 4-hour intervals during the 48 hours following admission. Average values of plasma catecholamines within 1 hour of onset of pain were 0.87 ng./ml +/- 0.21 and remained elevated during the first 24 hours period. A gradual fall in catecholamine values was observed during the second 24-hour period. Catecholamines were higher in patients with sinus tachycardia and lower in patients with sinus bradycardia, and were higher in patients with anterior or anterolateral infarction. Catecholamine values were significantly higher when determined while patients presented ventricular ectopic beats or ventricular tachycardia. Sinus tachycardia, ventricular arrhythmias, and elevated plasma catecholamine values may be considered indicators of pain, anxiety, and/or left ventricular dysfunction without necessarily being causally related between themselves.

Adult↗
PubMed1986

High-performance liquid chromatographic determination of urinary catecholamines by pre-column solid-phase dansylation on alumina.

Sensitive and selective high-performance liquid chromatographic determination of catecholamines by pre-column solid-phase dansylation is described. After catecholamines are adsorbed on alumina, the amino groups not responsible for adsorption are dansylated by a solid-phase reaction. The excess reagent and fluorescent contaminants are washed out, and the dansylated catecholamines are eluted and separated by reversed-phase high-performance liquid chromatography. The four catecholamine derivatives can be separated within 10 min and no major interfering peak is observed on chromatograms. The response of each catecholamine is linear from 10 to 500 pmol per sample and the detection limit is 0.5 pmol. This method was applied to determination of catecholamines in human urine.

Adult↗
PubMed1982

Reverse trans-synaptic regulation of catecholamine synthesis in adrenergic neurones.

It was established that the blocking agent of beta-adrenoceptors, propanolol (1 X 10(-6)M), activates [3H] catecholamine synthesis from [3H] tyrosine in isolated rat organs (vas deferens and atrium) by 40-80%. The blocking agent of alpha-adrenoceptors, phentolamine (1 X 10(-6)M) activates [3H] catecholamine synthesis by 30-60% only in the organ possessing postsynaptic alpha-adrenoceptors (vas deferens). The activator of beta-adrenoceptors, isopropylnoradrenaline (1 X 10(-6)M), was shown to produce a decrease in [3H] catecholamine synthesis by 30-40% in both organs investigated. The substance activating alpha-adrenoceptors, phenylephrine (1 X 10(-5)M), inhibits [3H] catecholamine synthesis in the organ with postsynaptic alpha-adrenoceptors by 40-50%. Activation and inhibition of [3H] catecholamine synthesis induced by adrenotropic drugs is due to the release of chemical factors from he effector cell and their influence on the adrenergic neurone. The formation of chemical factors changing the intensity of catecholamine synthesis is related to the activation of protein synthesis in the effector cell. The processes which proceed in the adrenergic neurone are not connected with protein synthesis de novo. Existence of the common mechanism for trans-synaptic regulation of noradrenergic synthesis and uptake via the adrenoceptors of the effector cell is discussed.

Adrenergic Fibers↗
PubMed1984

Effects of inhibitors of arachidonic acid metabolism on calcium uptake and catecholamine release in cultured adrenal chromaffin cells.

The possibility that arachidonic acid metabolism is involved in the secretory process in cultured adrenal chromaffin cells was investigated by studying the effects of lipoxygenase inhibitors and cyclooxygenase inhibitors on 45Ca2+ uptake and catecholamine release. Lipoxygenase inhibitors, which have different chemical structures, such as nordihydroguaiaretic acid (NDGA), 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline (BW755C) and 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861) all prevented the catecholamine release evoked by carbamylcholine and high K+. In contrast, cyclooxygenase inhibitors, such as aspirin and indomethacin failed to inhibit the carbamylcholine-evoked catecholamine release. Lipoxygenase inhibitors also inhibited 45Ca2+ uptake into the cells stimulated by carbamylcholine and high K+. Lipoxygenase inhibitors inhibited 45Ca2+ uptake and catecholamine release with similar potency. Slightly higher concentrations of lipoxygenase inhibitors were required to inhibit high K+-evoked effects compared to those evoked by carbamylcholine. The inhibitory effects of these inhibitors on carbamylcholine-evoked catecholamine release was different in its nature from the inhibitory effect of verapamil, a blocker of the Ca2+ channel, and was not due to a competitive antagonism at cholinergic receptor site. Moreover, these lipoxygenase inhibitors did not inhibit the binding of [3H]nitrendipine to chromaffin cell homogenate. The data suggest that lipoxygenase inhibitors prevent the catecholamine release from cultured adrenal chromaffin cells by blocking Ca2+ uptake. It might be possible that lipoxygenase product(s) is involved in the Ca2+ translocation system in these cells.

Adrenal Glands↗
PubMed1986

Monensin-induced influx of 22Na and the release of catecholamines in cultured bovine adrenal medulla cells and isolated chromaffin granules.

In cultured bovine adrenal medulla cells, monensin caused the release of catecholamines simultaneous with the influx of 22Na to the cells. The release of catecholamines by monensin was dependent on Na but not on Ca in the medium. Release of catecholamines and the influx of 22Na caused by monensin were not inhibited by tetrodotoxin. Monensin did not cause the release of dopamine beta-hydroxylase from the cells showing that monensin caused the release of catecholamines by a nonexocytotic mechanism. Similarly, in isolated chromaffin granules, monensin caused Na-dependent release of catecholamines, simultaneously with the influx of 22Na to the granules. Basing on these findings, monensin seems to cause a nonexocytotic release of catecholamines by acting as an Na ionophore both at cell membranes and chromaffin granule.

Adrenal Medulla↗
PubMed1987

Effects of alpha 2-adrenergic agonists on carbachol-stimulated catecholamine synthesis in cultured bovine adrenal medullary cells.

We examined the effects of alpha 2- and alpha 1-adrenergic agonists on synthesis of catecholamines in cultured bovine adrenal medullary cells. Clonidine, an alpha 2-adrenergic agonist, inhibited carbachol-stimulated synthesis of [14C]catecholamines from [14C]tyrosine in a concentration-dependent manner. Clonidine also inhibited carbachol-induced uptake of 45Ca2+ into cells at concentrations similar to those that inhibited the synthesis of [14C]catecholamines. Other alpha 2-adrenergic agonists, oxymetazoline and guanfacine, also strongly inhibited carbachol-stimulated synthesis of [14C]catecholamines. alpha 1-Adrenergic agonists, phenylephrine and norfenefrine, did not affect the synthesis. Tyrosine hydroxylase (EC 1.14.16.2) activity in a soluble fraction of cultured bovine adrenal medullary cells was assayed after gel filtration on a Sephadex G-25 column. Stimulation of the cells with carbachol increased the activity of tyrosine hydroxylase. Clonidine, oxymetazoline, and guanfacine all suppressed the carbachol-induced increase in activity of tyrosine hydroxylase in the cells. These results suggest that alpha 2-adrenergic agonists inhibit carbachol-stimulated synthesis of catecholamines by suppression of tyrosine hydroxylase activity, probably through the inhibition of Ca2+ uptake. However, the involvement of alpha 2-adrenoceptors in the inhibitory effects of alpha 2-agonists on catecholamine synthesis is still unsettled, since yohimbine failed to antagonize the inhibitory effect of clonidine on the synthesis in cultured bovine adrenal medullary cells.

2-Hydroxyphenethylamine↗
PubMed1987

Effects of DJ-7141, a new alpha 2-adrenoceptor agonist, on catecholamine secretion from isolated bovine adrenal medullary cells.

The effects of a newly synthesized alpha 2-adrenoceptor agonist (an imidazole derivative, DJ-7141) on catecholamine secretion from isolated bovine adrenal medullary cells were examined. DJ-7141 did not affect basal catecholamine secretion, but inhibited catecholamine secretion induced by stimulation of the nicotinic ACh receptor. This inhibitory effect of DJ-7141 was less than that of clonidine, another alpha 2-agonist. DJ-7141 also inhibited [45Ca]2+ uptake by the cells induced by nicotinic stimulation. DJ-7141 did not affect catecholamine secretion induced by high K+ concentration. Its inhibitory effect on nicotine-induced catecholamine secretion was not restored by increase in either the nicotine or Ca2+ concentration of the medium, suggesting that it interfered with the coupling between nicotinic ACh receptor stimulation and Ca2+-channel activation. The inhibitory effect of DJ-7141 seemed to be independent of its effect on alpha 2-adrenoceptors, because its effect was not antagonized by the alpha 2-adrenoceptor antagonists yohimbine and DG-5128, which both had no effect on either basal or nicotine-induced catecholamine secretion.

Adrenal Medulla↗
PubMed1994

Differential induction of gene expression of catecholamine biosynthetic enzymes and preferential increase in norepinephrine by forskolin.

We examined the effect of forskolin, an adenylate cyclase activator, on gene expression and the activities of the three enzymes specific for catecholamine biosynthesis [tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT)] and on the amounts of available catecholamines in primary cultured bovine adrenomedullary chromaffin cells. The results showed that TH was increased by 4.7 +/- 0.7-fold and 69% in mRNA and activity levels, respectively, compared with the untreated control. DBH was elevated by 3.2 +/- 0.2-fold in mRNA and 45% in activity. The increase in PNMT, on the other hand, was smaller: 1.7 +/- 0.2-fold in mRNA and 13% in activity. This relatively small increase in PNMT was reflected in the catecholamine levels in that the total epinephrine (EPI) was elevated by only 16% while norepinephrine (NE) was elevated by 99%, which caused a shift in the molar ratio of EPI to NE from 7.0 in the untreated control to 4.1 after forskolin treatment. A large portion of the elevated catecholamines was found in the medium, which represented a 10.1-fold increase for NE and a 6.4-fold increase for EPI compared with the control. Interestingly, this caused the remaining intracellular NE and EPI to be only 117 and 66% of the control, respectively. Thus, forskolin caused coordinate up-regulation of gene expression and enzyme activities of the three catecholamine-synthesizing enzymes but to different degrees, resulting in a relatively larger increase in NE than in EPI, both of which were released dramatically. This large enhancement of catecholamine release, as well as the dramatic shift in their ratio, implicates an important physiological role for cAMP in the regulation of in vivo sympathetic activities.

Adrenal Medulla↗