Effect of inhibition of MAO and COMT on intrarenal dopamine and serotonin and on renal function

The purpose of the present investigation was to study the effects of inhibition of monoamine oxidase (MAO) and/or catechol-O-methyltransferase (COMT), enzymes involved in the degradation of dopamine (DA) and serotonin (5-HT), on intrarenal DA and 5-HT, as reflected in the renal interstitial fluid (RIF) microdialysate and urine, and on renal function. Inhibition of MAO selectively increased RIF 5-HT from 3.16 +/- 0.38 to 8.03 +/- 1.83 pg/min (n = 7, P < 0.05), concomitant with decreases in mean arterial blood pressure and glomerular filtration rate (2.09 +/- 0. 18 to 1.57 +/- 0.22 ml/min, n = 7, P < 0.05). Inhibition of COMT significantly increased RIF DA (3.47 +/- 0.70 to 8.68 +/- 1.96 pg/min, n = 9, P < 0.05), urinary DA (2.00 +/- 0.16 to 2.76 +/- 0.26 ng/min, n = 9, P < 0.05), and absolute excretion of sodium (6.42 +/- 2.00 to 9.82 +/- 1.62 micromol/min, n = 10, P < 0.05). Combined inhibition of MAO and COMT significantly increased RIF DA, urinary DA, and urinary 5-HT, which was accompanied with increases in urine flow rate, and absolute (3.03 +/- 0.59 to 8.40 +/- 1.61 micromol/min, n = 9, P < 0.01) and fractional excretion of sodium. We conclude that inhibition of MAO selectively increases RIF 5-HT. COMT appears to be more important than MAO in the metabolism of intrarenal DA. Physiological increases in intrarenal DA/5-HT induced by inhibition of their degrading enzymes are accompanied with significant alterations of renal function.     

Atrial natriuretic factor decreases renal dopamine turnover and catabolism without modifying its release

Atrial natriuretic factor (ANF) and dopamine (DA) are both important regulators of sodium and water transport across renal proximal tubules. Many evidences suggest that some of ANF inhibitory effects on sodium and water reabsorption are mediated by dopaminergic mechanisms. We have previously reported that ANF stimulates extraneuronal DA uptake in external renal cortex by activation of NPR-A receptors coupled to cGMP signal and PKG. Moreover, ANF enhanced DA-induced inhibition of Na(+)-K(+) ATPase activity. The aim of the present study was to evaluate if ANF could alter also renal DA release, catabolism and turn over. The results indicate that ANF did not affect basal secretion of the amine in external renal cortex or its KCl-induced release, but diminished DA turn over. Moreover, ANF diminished COMT and did not alter MAO activity. In conclusion, present results as well as previous findings show that ANF modifies DA metabolism in rat external renal cortex by enhancing DA uptake and decreasing COMT activity. All those effects, taken together, may favor DA accumulation into renal cells and increase its endogenous content and availability. This would permit D1 receptor recruitment and stimulation and in turn, Na(+), K(+)-ATPase activity over inhibition that results in decreased sodium reabsorption. Therefore, ANF and DA could act via a common pathway to enhance natriuresis and diuresis.     

Relationship Between Catechol-O-Methyltransferase and Phenolsulfotransferase in the Metabolism of Dopamine in the Rat Brain

The relationship between phenolsulfotransferase (PST) and catechol-O-methyltransferase (COMT) in the metabolism of free 3,4-dihydroxyphenylethylamine (DA, dopamine) in the rat brain was studied. In rats not pretreated with a monoamine oxidase (MAO) inhibitor a huge increase of free DA in the brain, following an intraperitoneal injection of L-3,4-dihydroxyphenylalanine (L-DOPA) or an intraventricular injection of free DA, did not lead to any noticeable change in DA sulfate or 3-methoxytyramine (3-MT), which remained undetectable by the present HPLC method. However, in rats previously treated with the MAO inhibitors pargyline or tranylcypromine, the same L-DOPA or free DA treatment resulted in significant increases in both 3-MT and DA sulfate in the hypothalamus, brainstem, and striatum. This response of COMT and PST was not affected by prior treatment of the rats with 6-hydroxydopamine, which suggests that O-methylation and sulfoconjugation occur outside adrenergic neurons not destroyed by the neurotoxin. Inhibition of COMT activity did not lead to any increase in DA sulfate, which showed that despite their common mode of action (both enzymes react preferentially at the same hydroxyl group in the DA molecule), the two enzymes are not competitive. After MAO inhibition there were strong correlations between an increase in DA sulfate and 3-MT on the one hand, and between free DA and 3-MT on the other. Because 3-MT is a marker of central DA release, these data suggest that inhibition of MAO activity not only affects DA metabolism by this enzyme but also influences DA release in the rat brain.     

Contribution of Sulfate Conjugation, Deamination, and O-Methylation to Metabolism of Dopamine and Norepinephrine in Human Brain

Abstract: The kinetic constants were determined for dopamine (DA) and norepinephrine (NE) metabolism by phenolsulfotransferase (PST), type A and B monoamine oxidase (MAO), and membrane-bound and soluble catechol- O - methyltransferase (COMT) in frontal lobe preparations of human brain. PST and membrane-bound COMT were found to have the lowest K _m, values for both catecholamines. By means of the appropriate rate equations and the calculated kinetic constants for each enzyme, the activity of each enzymatic pathway was determined at varying concentrations of DA and NE. Results indicate that deamination by MAO is the principal pathway for the enzymatic inactivation of DA whereas NE is largely metabolized by MAO type A and membrane-bound COMT under the in vitro assay conditions used. At concentrations less than 100 μ M , soluble COMT'contributes less than 5% to the total catabolism of either catecholamine. PST can contribute up to 15% of the total DA metabolism and 7% of NE metabolism.     

Evaluation of nitrocatechol chalcone and pyrazoline derivatives as inhibitors of catechol-O-methyltransferase and monoamine oxidase

Literature reports that chalcones inhibit the monoamine oxidase (MAO) enzymes, mostly with specificity for the MAO-B isoform, while nitrocatechol compounds are established inhibitors of catechol–O-methyltransferase (COMT). Based on this, nitrocatechol derivatives of chalcone have been proposed to represent dual-target-directed compounds that may inhibit both MAO-B and COMT. Both these enzymes play key roles in the metabolism of dopamine and levodopa, and inhibitors are thus relevant to the treatment of Parkinson’s disease. The present study expands on the discovery of dual MAO-B/COMT inhibitors by synthesising additional nitrocatechol derivatives of chalcones which include heterocyclic derivatives, and converting them to the corresponding pyrazoline derivatives. The newly synthesised chalcone and pyrazoline compounds were evaluated as inhibitors of human MAO and rat COMT, and the inhibition potencies were expressed as IC₅₀ values. A pyrazoline derivative, compound 8b, was the most potent COMT inhibitor with an IC₅₀ value of 0.048 μM. This is more potent than the reference COMT inhibitor, entacapone, which has an IC₅₀ value of 0.23 μM. The results indicated that the pyrazoline derivatives (IC₅₀ = 0.048–0.21 µM) are more potent COMT inhibitors than the chalcones (IC₅₀ = 0.14–0.29 µM). Unfortunately, the chalcone and pyrazoline derivatives were weak MAO inhibitors with IC₅₀ values > 41.4 µM. This study concludes that the nitrocatechol derivatives investigated here are promising COMT inhibitors, while not being suitable as MAO inhibitors. Using molecular docking, potential binding modes and interactions of selected inhibitors with COMT are proposed.     

Low-dose dopamine as an activator of renal catecholamine receptors of different classes. II. Studies in water-saline depletion and associated adrenergic blockade

The renal function in healthy man with salt and water depletion (natriuretic pretreatment) associated with adrenergic blocking agents administration was explored during steady hypotonic polyuria. Four 15 min clearance (cl.) periods, before, during and after dopamine (DA) infusion in a subpressor dose, were performed. The 9 subjects treated with prazosin showed different renal hemodynamic responses in the early stage of DA infusion i.e. hyperemic (6 subjects, subgroup A) or ischemic (3 subjects, subgroup B). The whole group of 6 subjects treated with propranolol showed an hyperemic response DA infusion. A natriuretic effect and a trend towards tubular sodium reabsorption inhibition, in particular at the diluting segment level, were associated with the DA vasodilatory responses. The ischemic responses to DA occurred in the presence of incomplete alpha-adrenergic receptors blockade; nevertheless in the same circumstances DA failed to increase the diluting segment sodium reabsorption.     

THE EFFECTS OF METOPIRONE AND ADRENALECTOMY ON THE REGULATION OF THE ENZYMES MONOAMINE OXIDASE AND CATECHOL-O-METHYL TRANSFERASE IN DIFFERENT BRAIN REGIONS

Abstract— The role of glucocorticoids in the regulation of the enzymes monoamine oxidase (MAO) and catechol- O -methyltransferase (COMT) in brain regions has been studied. Glucocorticoids were blocked by Metopirone. The activities of MAO and COMT were determined in the hypophysis, hypothalamus, pineal gland and in the rest of brain. All the cerebral tissues except the pineal gland demonstrated highest MAO activity 8 h after Metopirone administration, when glucocorticoids were at the lowest level. Prolonged treatment for 10 days significantly augmented MAO activity in brain, hypophysis and hypothalamus, and COMT in the hypophysis increased by 56 per cent. The COMT activity in the rest of the brain did not change significantly with either short or prolonged administration. Complete ablation of the adrenal cortex resulted in a 167 per cent rise in MAO activity of the hypophysis. Metopirone and hydrocortisone inhibit MAO and COMT in vitro. The results suggest that glucocorticoids in the circulation of normal animals inhibit the activities of MAO and COMT. The inhibition or ablation of these hormones removes this rate-limiting control of catecholamine degradation resulting in higher activities of MAO and COMT. Metopirone, an inhibitor of MAO and COMT in vitro , acts in the opposite direction in vivo due to its inhibitory effects on corticoid biosynthesis.     

Effects of acute and sub-chronic l-dopa therapy on striatal l-dopa methylation and dopamine oxidation in an MPTP mouse model of Parkinsons disease

Aims

The molecular mechanisms for the loss of 3,4-dihydroxyphenylalanine (l-dopa) efficacy during the treatment of Parkinson's disease (PD) are unknown. Modifications related to catecholamine metabolism such as changes in l-dopa and dopamine (DA) metabolism, the modulation of catecholamine enzymes and the production of interfering metabolites are the primary concerns of this study.

Main methods

Normal (saline) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) pre-treated mice were primed with 100 mg/kg of l-dopa twice a day for 14 days, and a matching group remained l-dopa naïve. l-dopa naive and primed mice received a challenge dose of 100 mg/kg of l-dopa and were sacrificed 30 min later. Striatal catecholamine levels and the expression and activity of catechol-O-methyltransferase (COMT) were determined.

Key findings

Normal and MPTP pre-treated animals metabolize l-dopa and DA similarly during l-dopa therapy. Administration of a challenge dose of l-dopa increased l-dopa and DA metabolism in l-dopa naïve animals, and this effect was enhanced in l-dopa primed mice. The levels of 3-OMD in MPTP pre-treated animals were almost identical to those in normal mice, which we found are likely due to increased COMT activity in MPTP pre-treated mice.

Significance

The results of this comparative study provide evidence that sub-chronic administration of l-dopa decreases the ability of the striatum to accumulate l-dopa and DA, due to increased metabolism via methylation and oxidation. This data supports evidence for the metabolic adaptation of the catecholamine pathway during long-term treatment with l-dopa, which may explain the causes for the loss of l-dopa efficacy.     

Dopamine Synthesis Precedes Dopamine Uptake in Embryonic Rat Mesencephalic Neurons

We have measured [3H]dopamine ([3H]DA) uptake and tyrosine hydroxylase-immunopositive immunostaining in cells acutely dissociated from the embryonic ventral mesencephalon (MSC). DA and its metabolites as well as catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) activities were determined in homogenates taken from the MSC and striatum (STR). In the embryonic ventral MSC measurable DA and tyrosine hydroxylase (TH) immunostaining were present as early as embryonic day (E) 12.5. At E14 the number of TH+ neurons was about 50% of the values at E18. In the MSC, DA concentration increased sharply at E16 and reached a plateau before birth that was 10-fold lower than adult values. In the STR, DA was first detected at E16, suggesting that DA fibers reach the STR at this embryonic stage. High-affinity DA uptake appeared in the MSC only at E16, concomitantly with the arrival of DA fibers in the STR, increased sharply between E16 and E18, and reached a plateau before birth. This uptake mechanism was not selective for catecholamine uptake inhibitors. Thus, DA synthesis in the MSC preceded the onset of high-affinity uptake mechanism, which could be correlated to the beginning of striatal DA innervation. Measurable MAO and COMT activities were detected as early as E13 (MSC) and E15 (STR), but not DA metabolites, which appeared later. We conclude that the high-affinity DA uptake mechanism in MSC DA neurons develops coincident with the arrival of DA fibers to the STR. The sharp increase of DA uptake between E16 and E18 is due only in part to an increase in the number of TH+ cells. These results support the hypothesis that in vivo the target STR neurons regulate the maturation of MSC DA cells.     

Signaling pathways involved in atrial natriuretic factor and dopamine regulation of renal Na+, K+ -ATPase activity

Dopamine (DA) and atrial natriuretic factor (ANF) share a number of physiological effects. We hypothesized that ANF and the renal dopaminergic system could interact and enhance the natriuretic and diuretic effects of the peptide. We have previously reported that the ANF-stimulated DA uptake in renal tubular cells is mediated by the natriuretic peptide type-A receptor (NPR-A). Our aim was to investigate the signaling pathways that mediate ANF effects on renal 3H-DA uptake. Methylene blue (10 microM), an unspecific inhibitor of guanylate cyclase (GC), blunted ANF elicited increase of DA uptake. ODQ (10 microM) a specific inhibitor of soluble GC, did not modify DA uptake and did not reverse ANF-induced increase of DA uptake; then the participation of nitric oxide-dependent pathways must be discarded. The second messenger was the cGMP since the analogous 125 microM 8-Br-cGMP mimicked ANF effects. The specific inhibitor of the protein kinase G (PKG), KT 5823 (1 microM) blocked ANF effects indicating that PKG is involved. We examined if ANF effects on DA uptake were able to modify Na+, K+ -adenosine triphosphatase (Na+, K+ -ATPase) activity. The experiments were designed by means of inhibition of renal DA synthesis by carbidopa and neuronal DA uptake blocked by nomifensine. In these conditions renal Na+, K+ -ATPase activity was increased, in agreement with the decrease of DA availability. When in similar conditions, exogenous DA was added to the incubation medium, the activity of the enzyme tended to decrease, following to the restored availability of DA. The addition of ANF alone had similar effects to the addition of DA on the sodium pump, but when both were added together, the activity of Na(+), K(+)-ATPase was decreased. Moreover, the extraneuronal uptake blocker, hydrocortisone, inhibited the latter effect. In conclusion, ANF stimulates extraneuronal DA uptake in external cortex tissues by activation of NPR-A receptors coupled to GC and it signals through cGMP as second messenger and PKG. Dopamine and ANF may achieve their effects through a common pathway that involves reversible deactivation of renal tubular Na+, K+ -ATPase activity. This mechanism demonstrates a DA-ANF relationship involved in the modulation of both decreased sodium reabsorption and increased natriuresis.     

Atrial natriuretic factor stimulates renal dopamine uptake mediated by natriuretic peptide-type A receptor

To determine the effects of atrial natriuretic factor (ANF) on renal dopamine (DA) metabolism, 3H-DA and 3H-L-DOPA uptake by renal tubular cells was measured in experiments carried out in vitro in Sprague-Dawley rats. The receptor type involved was also analyzed. The results indicate that ANF increased at 30 min, DA uptake in a concentration-response fashion having 10 pM ANF as the threshold concentration. Conversely, the uptake of the precursor L-DOPA was not modified by the peptide. ANF effects were observed in tissues from external and juxtamedullar cortex and inner medulla. On this basis, 100 nM ANF was used to continue the studies in external cortex tissues. DA uptake was characterized as extraneuronal uptake, since 100 microM hydrocortisone blocked ANF-induced increase of DA uptake. Renal DA uptake was decreased at 0 degrees C and in sodium-free medium. The effects of ANF in these conditions were not present, confirming that renal DA uptake is mediated by temperature- and sodium-dependent transporters and that the peptide requires the presence of the ion to exhibit its actions on DA uptake. The biological natriuretic peptide type A receptor (NPR-A) mediates ANF effects, since 100 nM anantin, a specific blocker, reversed ANF-dependent increase of DA uptake. The natriuretic peptide type C receptor (NPR-C) is not involved, since the specific analogous 100 nM 4-23 ANF amide has no effect on renal DA uptake and does not alter the effects of 100 nM ANF. In conclusion, ANF stimulates DA uptake by kidney tubular cells. ANF effects are mediated by NPR-A receptors coupled to guanylate cyclase and cGMP as second messenger. The process involved was characterized as a typical extraneuronal uptake, and characterized as temperature- and sodium-dependent. This mechanism could be related to DA effects on sodium reabsorption and linked to ANF enhanced natriuresis in the kidney. The increment of endogenous DA into tubular cells, as a consequence of increased DA uptake, would permit D1 receptor recruitment and Na+,K+-ATPase activity inhibition, which results in decreased sodium reabsorption and increased natriuresis.     

Selective increase of brain dopamine induced by gamma-hydroxybutyrate: study of the mechanism of action

Abstract— γ-Hydroxybutyrate (γ-OH) produces a selective accumulation of brain DA not only in normal animals but also in reserpinized animals. This is especially evident after the administration of DOPA; while in parallel experiments γ-OH does not influence significantly the amount of 5-HT present in brain after 5-HTP treatment. γ-OH does not raise DA in rats after inhibition of tyrosine hydroxylase. The accumulation of brain DA is not due to inhibition of MAO or COMT activity.     

Comparative Analysis of Expression of Genes Encoding Enzymes of Catecholamine Catabolism and Renalase in Tissues of Normotensive and Hypertensive Rats

Comparative analysis of expression of genes encoding enzymes of catecholamine catabolism (monoamine oxidases A and B (MAO A and MAO B) and catechol-O-methyl transferase (COMT)) and renalase has been carried out in tissues of normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Among investigated tissues the highest level of mRNA of genes encoding key enzymes of catecholamine catabolism (MAO A, MAO B, COMT) was found in the heart of WKY rats. In SHR the mRNA levels of these genes were lower (p < 0.05–0.01), however, no similar changes were observed in the tissues studied in dependence of hypertension. The relative mRNA levels of the studied genes normalized versus actin mRNA significantly varied. In heart and kidney the relative level of COMT mRNA significantly exceeded the relative levels of both MAO A mRNA and MAO B mRNA. In the brain differences in mRNAs of MAOA, MAOB, and COMT were less pronounced. However, in all examined tissue the renalase mRNA level was much (at least 10–20-fold) lower than any other mRNA studied. Taking into consideration known correlations between mRNAs and corresponding protein products reported in the literature for many genes these results suggest that in the case of any catalytic scenarios proposed or even proved for renalase this protein cannot contribute to catecholamine degradation. It is also unlikely that the products of the renalase reaction, β-NAD(P)⁺ and hydrogen peroxide, can exhibit a hypotensive effect due to low expression of the renalase encoding gene.     

Renal effects of dopamine and ANP in high volume expanded rats

Both dopamine (DA) and atrial natriuretic peptide (ANP) have been postulated to exert similar effects on the kidney, participating in the regulation of body fluid and sodium homeostasis. In the present study, experiments were performed in anesthetized and isotonic sodium chloride volume expanded rats. After acute volume expansion at 15 % of body weight during 30 min, glomerular filtration rate, urine output, sodium excretion, fractional sodium excretion, proximal and distal sodium excretion and blood pressure were measured. In additional groups we administered ANP or haloperidol or the combination of both to volume expanded animals. Blockade of DA receptors with haloperidol, attenuated diuretic and natriuretic responses to volume load. Proximal sodium excretion was not modified by haloperidol in all experimental groups of rats. Reduction in distal tubular excretion was induced by haloperidol in saline infusion expanded rat but not in ANP treated expanded animals. In conclusion, when exaggerated volume expansion is provoked, both DA and ANP exert renal tubular events, but ANP have a major central role in the regulation of renal sodium handling.     

Renal dopaminergic system activity in rat remnant kidney up to twenty-six weeks after surgery

AimsIn 3/4 nephrectomized (3/4nx) rats the renal dopaminergic system was suggested to be involved in the adaptive increase of sodium excretion two weeks after renal mass ablation. The aim of the present study was to evaluate the renal adaptations in sodium handling and renal dopaminergic system activity in 3/4nx rats up to twenty-six weeks after surgery.Main methodsThe rats were placed in metabolic cages for the collection of 24 h urine for evaluation of sodium, dopamine, dopamine precursor and metabolites. Blood pressure, aromatic L-amino acid decarboxylase (AADC) activity in proximal tubules and the effect of dopamine D₁ receptor selective antagonist (Sch-23390) on natriuresis was evaluated.Key findingsA time-dependent increase in both systolic and diastolic blood pressure was observed in 3/4nx rats, and this was accompanied by a decrease in urinary levels of dopamine and in renal AADC activity at twenty-six weeks after renal mass ablation. In contrast to what has been found two weeks after renal mass ablation, the natriuretic response to volume expansion was progressively reduced in 3/4nx rats at ten and twenty-six weeks after surgery and this was accompanied by insensitivity of natriuresis to Sch-23390.SignificanceIn conclusion the renal dopaminergic system activity is compromised in 3/4nx rats in a time-dependent manner after renal mass ablation. It is suggested that this may contribute to compromise sodium excretion and increase blood pressure, in chronic renal insufficiency.     

Age-related motor and catecholomine alterations in mice on levodopa supplemented diet

Old mice reared on regular diet show reduced motor activity, decreased basal adenylate cyclase, and increased MAO activities compared to adults. Brain DDC and COMT activities, DA, NE levels and DA-stimulated adenylate cyclase remained unchanged. By contrast, mice fed levodopa for life did not develop decreased motor activity with aging, lived about 50% longer, had slightly elevated whole brain DA and NE levels and failed to develop the expected rise in MAO activity with aging. Levodopa did not alter the number of dopaminergic and muscarinic cholinergic receptors or the adenylate cyclase activity in the striatum during aging. On levodopa, hepatic and renal DA, dopa, and HVA increased but the latter two returned to basal levels by mid life. In liver, DDC was unchanged but MAO tended to be higher in levodopa-fed mice. Thus, motor impairment is an age-related phenomenon in mice associated with selective alterations in brain dopaminergic systems, which may be prevented by dietary levodopa. Extracerebral tissues, through possibly adaptive metabolic mechanisms, play a significant role in regulating brain catecholamines during chronic administration of large doses of levodopa.     

Role of 20-hydroxyeicosatetraenoic acid in mediating hypertension in response to chronic renal medullary endothelin type B receptor blockade

Background

The renal medullary endothelin (ET-1) system plays an important role in the control of sodium excretion and arterial pressure (AP) through the activation of renal medullary ET-B receptors. We have previously shown that blockade of endothelin type B receptors (ET-B) leads to salt-sensitive hypertension through mechanisms that are not fully understood. One possible mechanism is through a reduction in renal medullary production of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a metabolite of arachidonic acid, has natriuretic properties similar to ET-B activation. While these findings suggest a possible interaction between ET-B receptor activation and 20-HETE production, it is unknown whether blockade of medullary ET-B receptors in rats maintained on a high sodium intake leads to reductions in 20-HETE production.

Methodology/Principal Findings

The effect of increasing sodium intake from low (NS = .8%) to high (HS = 8%) on renal medullary production of 20-HETE in the presence and absence of renal medullary ET-B receptor antagonism was examined. Renal medullary blockade of ET-B receptors resulted in salt sensitive hypertension. In control rats, blood pressure rose from 112.8±2.4 mmHg (NS) to 120.7±9.3 mmHg (HS). In contrast, when treated with an ET-B receptor blocker, blood pressure was significantly elevated from 123.7±3.2 (NS) to 164.2±7.1 (HS). Furthermore, increasing sodium intake was associated with elevated medullary 20-HETE (5.6±.8 in NS vs. 14.3±3.7 pg/mg in HS), an effect that was completely abolished by renal medullary ET-B receptor blockade (4.9±.8 for NS and 4.5±.6 pg/mg for HS). Finally, the hypertensive response to intramedullary ET-B receptor blockade was blunted in rats pretreated with a specific 20-HETE synthesis inhibitor.

Conclusion

These data suggest that increases in renal medullary production of 20-HETE associated with elevating salt intake may be, in part, due to ET-B receptor activation within the renal medulla.     

Low-dose dopamine as an activator of renal catecholamine receptors of different classes. I. Studies in water-salt depletion

The renal function in healthy man with salt and water depletion induced by natriuretic treatment was explored during steady hypotonic polyuria. Four 15 min clearance (cl.) periods, before, during and after dopamine (DA) infusion in a subpressor dose were performed. The 12 examined subjects showed different renal hemodynamic responses in the early stage of DA infusion, i.e. hyperemic (4 subjects, subgroup A) or ischemic (8 subjects, subgroup B). A decrease in urinary sodium excretion and increase in tubular sodium reabsorption, in particular at the diluting segment level, were induced by DA in both subgroups, at least in the late stage of infusion. During the control cl. period in subgroup A as compared with B the renal plasma flow was lower and the tubular sodium reabsorption higher, suggesting a relatively higher level of renal adrenergic activity.     

Effects of intrastriatal kainic acid injection on [3H]dopamine metabolism in rat striatal slices: evidence for postsynaptic glial cell metabolism by both the type A and B forms of monoamine oxidase

Abstract: Intrastriatal injections of kainic acid (KA) were utilized to investigate the cellular localization of postsynaptic dopamine (DA) metabolism by type A and B monoamine oxidase (MAO) in rat striatum. At 2 days postinjection, maximal degeneration of cholinergic and γ-aminobutyric acid (GABA)ergic neurons was observed and found to be associated with a significant decrease in both type A and B MAO activity. However, over the next 8-day period, when only the process of gliosis appeared to be occurring, a selective return to control of type B MAO activity was seen. When the metabolism of [³H]DA (10^?7 M) was examined in 8-day KA-lesioned rat striatal slices, an increase in [³H]dihydroxyphenylacetic acid (DOPAC) and [³H]homovanillic acid (HVA) formation was observed. The KA-induced elevation of [³H]DOPAC formation (but not [³H]HVA) was abolished by the DA neuronal uptake inhibitor nomifensine. This is consistent with earlier findings suggesting that HVA is formed exclusively within sites external to DA neurons. Experiments with clorgyline and/or deprenyl revealed that the relative roles of type A and B MAO in striatal DA deamination remained unchanged following KA (90% deamination by type A MAO) even though total deamination was substantially enhanced. At high concentrations of [³H]DA (10^?5 M), deamination by type B MAO could be increased to 30% of the total MAO activity; however, this was observed in both control and KA-lesioned striata. These results suggest that KA-sensitive neurons contain type A and/or type B MAO. Moreover, whereas these neurons may metabolize DA, a major portion of postsynaptic DA deamination appears to occur within glial sites of rat striatal tissue. Furthermore, glial cells would appear to contain functionally important quantities of both type A and B MAO.