The role of dopamine-metabolizing enzymes in the regulation of renal sodium excretion in the rat.

The intrarenal natriuretic hormone dopamine (DA) is metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). We have previously shown that inhibition of COMT by entacapone results in a potent D1-like receptor-mediated natriuretic response. The present study was performed using anaesthetized rats to compare the importance of MAO and COMT in DA-mediated natriuresis by use of the MAO inhibitor phenelzine. Urinary sodium and DA excretion remained unchanged after MAO inhibition, while excretion of the main metabolite dihydroxyphenylacetic acid (DOPAC) decreased by 55%. The response was unaltered if 5-hydroxytryptamine receptors (5-HT1A) were blocked during MAO inhibition. We also investigated the specific renal activities of MAO and COMT in rat renal cortex during DA-influenced natriuresis. Specific COMT activity in the renal cortex was reduced by 13% after isotonic sodium loading (5% of body mass) whereas renal MAO-A and MAO-B activities remained unaltered. Furthermore, preliminary data obtained from spontaneously hypertensive rats, whose basal urinary DA excretion is higher than that of normotensive Wistar-Kyoto rats, show a tendency for renal COMT activity to be lower. It is concluded that MAOinhibition by phenelzine does not alter sodium excretion. Furthermore, specific renal cortical COMT activity is reduced during partly D1-like receptor-mediated natriuresis, whereas MAO activity remains unchanged. The results suggest that MAO is less important than COMT in regulating DA-mediated natriuresis in the rat kidney.

Changing dopaminergic activity through different pathways: consequences for renal sodium excretion, regional blood flow and oxygen tension in the rat.

Dopamine (DA) is an intrarenal natriuretic hormone involved in sodium homeostasis, but the regulation of renal dopaminergic tonus is unclear. We evaluated different pathways for elevating DA tonus to determine which are important for the ability of the kidney to produce natriuresis and studied the accompanying effects on regional renal blood flow and oxygen tension. Thus, we compared the effects of a catechol-O-methyl transferase (COMT)-inhibitor, an unspecific monoamine oxidase (MAO)-inhibitor, a D1-like receptor agonist and a DA precursor in anaesthetized rats. Sodium excretion increased sixfold after COMT inhibition, eightfold after administration of the D1-like agonist, whereas it was similar to control after MAO inhibition and infusion of DA precursor. Urinary dopamine excretion increased 42% by COMT inhibition, 55% by MAO inhibition and 12-fold after DA precursor, but remained unchanged after infusion of the D1-like agonist. The D1-like receptor agonist led to a 38% increase in the cortical blood flow and a 21% increase in outer medullary blood flow. Regional renal blood flow was unaffected by all other treatments. Cortical and outer medullary oxygen tension was unaffected in all treatment groups. To conclude, the natriuretic and haemodynamic properties of an elevation in DA tonus depends on the route by which the elevation occurred. Systemic administration of a D1-like receptor agonist, results in a natriuretic response which, as opposed to the natriuresis seen after COMT inhibition, coincides with an increase in renal cortical and outer medullary blood flow. Precursor delivery or MAO inhibition did not change neither urinary sodium excretion nor renal blood flow.

Hyaluronan content in the kidney in different states of body hydration.

BACKGROUND: Growing evidence suggests that the interstitial hyaluronan (HA) content is a determinant of the fluid exchange barrier in tissues through its high resistance to water flow. This study addressed the possible involvement of renal papillary HA in water balance regulation. METHODS: In anesthetized rats during different states of renal water handling (euvolemia, water diuresis, antidiuresis), in desert rodents, and in Brattleboro rats (diabetes insipidus) with a hereditary difference in water handling, regional renal HA and water contents were measured. RESULTS: The intrarenal HA distribution is heterogeneous, with 100 times larger amounts in the papilla than in the cortex. Compared with control rats, two hours of water diuresis increased the papillary HA content by 48% and that in the outer medulla by 52%, leaving the cortex unaffected. After 24 hours of water deprivation, papillary HA was decreased by 17%, while outer medullary HA remained unchanged. In gerbils, papillary and outer medullary HA contents were only 25 and 13%, respectively, of those in normal rats, while the cortical content was similar. In Brattleboro rats, the outer medullary HA content was significantly higher (285%) than in the normal rat, while the papillary content was similar. Generally, papillary HA was positively correlated to water content but was inversely related to urine osmolality. CONCLUSIONS: The amount of renal papillary HA changes in response to water balance of the organism. When excess water needs to be excreted, increased papillary interstitial HA could antagonize water reabsorption. The opposite occurs during water conservation. HA may play a role in renal water handling by affecting physicochemical characteristics of the papillary interstitial matrix and influencing the interstitial hydrostatic pressure, thereby determining interstitial water diffusion.

Regulation of dopamine-induced natriuresisby the dopamine-metabolizing enzyme catechol-O-methyltransferase.

Dopamine (DA) is an intrarenal natriuretic hormone involved in sodium homeostasis. A study was performed to elucidate two possible regulatory pathways of DA-induced natriuresis, i.e., metabolism and precursor delivery. This was done by use of an intraperitoneal injection of a catechol-O-methyltransferase (COMT) inhibitor, entacapone, or intravenous infusion of the DA precursor, L-dopa. Entacapone (30 mg/kg i.p.) induced a more than fivefold increase in renal sodium excretion which occurred without changes in renal haemodynamics. The natriuretic response was highly dependent on DA D(1)-like receptor activation, since the selective D(1)-like receptor antagonist SCH23390 attenuated the natriuretic response by 61%, while the selective D(2)-like receptor antagonist sulpiride was ineffective. The urinary excretion of DA did not increase. Infusion of L-dopa (60 microg/h/kg) only induced a twofold increase in sodium excretion, but the urinary excretion of DA increased more than 17-fold. The L-dopa-induced natriuretic response occurred without increments in glomerular filtration rate and could be blocked with the D(1)-like receptor antagonist SCH23390. It is concluded that the DA-metabolizing enzyme COMT is involved in the regulation of the natriuretic effect of intrarenal DA. It may be speculated that intrarenal DA activity is not primarily determined on the basis of delivered precursor, but on that of the level of DA metabolism.

Different renal effects of two inhibitors of catechol-O-methylation in the rat: entacapone and CGP 28014.

Dopamine is a natriuretic hormone that is abundantly synthesized in the kidney and is involved in sodium homeostasis. It is metabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) to form 3-methoxytyramine and dihydroxyphenylacetic acid (DOPAC) and finally homovanillic acid (HVA). In order to investigate whether dopamine metabolism is involved in renal sodium regulation, we tested the renal effects of the nitrocatechol entacapone (COMT inhibitor), in comparison with those of the pyridine derivative CGP 28014, in the anaesthetized rat. Entacapone injection resulted in a more than 5-fold increase in sodium excretion, while the renal excretion of dopamine only transiently increased by 20%. DOPAC excretion showed a more than 2-fold increase which persisted throughout the study. Pretreatment with the selective dopamine DA1-receptor antagonist SCH23390 reduced the entacapone-induced natriuretic response by 69%. Glomerular filtration rate (GFR) and mean arterial blood pressure (MAP) remained unchanged. Injection of CGP 28014 did not produce a natriuretic response; nevertheless, both dopamine and DOPAC excretion increased by 78% and more than 2-fold, respectively. GFR and MAP remained unchanged. In conclusion, COMT inhibition using entacapone results in a mainly DA1 receptor mediated natriuresis involving inhibition of tubular transport processes, supporting a role for dopamine metabolism in sodium homeostasis. Although CGP 28014 increases the renal excretion of both dopamine and DOPAC it does not affect renal sodium handling indicating a different mechanism of action.