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Am J Physiol Regul Integr Comp Physiol 275: R986-R994, 1998;
0363-6119/98 $5.00
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Vol. 275, Issue 4, R986-R994, October 1998

Effects of costimulation of dopamine D1- and D2-like receptors on renal function

Pedro A. Jose1, Laureano D. Asico1, Gilbert M. Eisner2,3, Felice Pocchiari4, Claudio Semeraro4, and Robin A. Felder5

1 Department of Pediatrics and 2 Department of Medicine, Georgetown University Medical Center; 3 Department of Medicine, Washington Hospital Center, Washington, District of Columbia 20007; 4 Department of Biochemistry, Zambon Group, Bresso, Italy 20091; and 5 Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

In vitro studies have suggested that dopamine D1- and D2-like receptors interact to inhibit renal sodium transport. We used Z-1046, a dopamine receptor agonist with the rank-order potency D3 >=  D4 > D2 > D5 > D1, to test the hypothesis that D1- and D2-like receptors interact to inhibit renal sodium transport in vivo in anesthetized rats. Increasing doses of Z-1046, administered via the right renal artery, increased renal blood flow (RBF), urine flow, and absolute and fractional sodium excretion without affecting glomerular filtration rate. For determination of the dopamine receptor involved in the renal functional effects of Z-1046, another group of rats received Z-1046 at 2 µg · kg-1 · min-1 (n = 10) in the presence or absence of the D2-like receptor antagonist domperidone and/or the D1-like antagonist SCH-23390. Domperidone alone had no effect but blocked the Z-1046-mediated increase in urine flow and sodium excretion; it enhanced the increase in RBF after Z-1046. SCH-23390 by itself decreased urine flow and sodium excretion without affecting RBF and blocked the diuretic, natriuretic, and renal vasodilatory effect of Z-1046. We conclude that the renal vasodilatory effect of Z-1046 is D1-like receptor dependent, whereas the diuretic and natriuretic effects are both D1- and D2-like receptor dependent.

dopamine receptors; sodium excretion; renal hemodynamics

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

DOPAMINE IS AN ENDOGENOUS catecholamine that modulates many cellular activities, including behavior, hormone synthesis and release, blood pressure, and transmembrane ion transport (22, 23, 37). Dopamine receptors in the brain have been divided classically into the D1- and D2-like subtypes on the basis of their interaction with the effector enzyme adenylyl cyclase; D1-like receptors stimulate adenylyl cyclase via the stimulatory G protein Gs, whereas D2-like receptors inhibit this enzyme via the inhibitory G protein Gi. The cloned dopamine receptors also fall into these categories; the DIA and DIB (also known as D1 and D5, respectively, in humans) are linked to stimulation of adenylyl cyclase, whereas the D2, D3, and D4 receptors are linked to inhibition of adenylyl cyclase (22, 23, 37). D1- and D2-like receptors also have been shown to interact with other signaling pathways and effector proteins, including potassium and calcium channels, phosphatidylinositol metabolism, and arachidonic acid release (22, 23, 37).

Pharmacological, biochemical, and molecular evidence also points to the existence of D1- and D2-like receptors in the kidney. Thus the D1A, D1B, D2 Long, D3, and D4 receptor genes are expressed in specific nephron segments and in kidney cell lines (8, 15, 16, 26, 27, 32, 43, 45). Most studies in vivo have shown that the natriuretic effect of dopamine is exerted mainly via D1-like receptors (reviewed in Ref. 23). The effect of D2-like receptors, independent of D1-like receptors, on tubular function remains to be settled. In anesthetized rats, bromocriptine, a D2-like agonist, has been reported to increase renal blood flow (RBF) and superficial nephron glomerular filtration rate (GFR) without affecting urinary sodium excretion (35, 40). However, in conscious, chronically catheterized dogs, the intrarenal administration of the D2-like receptor agonist quinpirole produced significant dose-dependent antidiuresis and antinatriuresis accompanied by a decrease in GFR, renal plasma flow, and sodium excretion (39). In agreement with the quinpirole data, in a similar preparation in dogs, the D2 antagonist YM-09151 increased sodium excretion, an effect that was blocked by the D2-like agonist quinpirole (38). In the isolated perfused kidney, haloperidol, a D2-like antagonist, also increased sodium excretion (2), and in the anesthetized rat, the antinatriuretic effect of the D1-like antagonist SCH-23390 was reversed by the D2 antagonist YM-09151 (12). These results indicate that D2-like receptors exert an effect on sodium excretion opposite to that of D1-like receptors.

Dopamine influences sodium transport by regulation of Na+/H+ exchanger (NHE) activity in brush border membranes and Na+-K+-ATPase activity in basolateral membranes (3, 7, 33). D1-like receptors inhibit NHE activity, whereas D2-like receptors may increase its activity (23). The effect of dopamine receptor subtypes on Na+-K+-ATPase is controversial. For example, D1-like receptors, independent of D2-like receptors, inhibit the sodium pump, whereas the D2-like agonist bromocriptine has been shown to stimulate Na+-K+-ATPase activity in renal proximal tubule cells (20). The ability of D2-like receptors to stimulate sodium transport is, at first glance, at variance with the reports of Bertorello and Aperia (3) and Satoh et al. (33). These investigators reported that D2-like receptors, in concert with D1-like receptors, inhibited Na+-K+-ATPase activity in renal proximal tubules and neuronal cells (3, 4, 33). In the LTK- cell transfected with either the rat D1A or D2 Long cDNA, it was found that D1-like receptor stimulation decreased Na+-K+-ATPase activity, whereas D2-like receptor stimulation produced the opposite effect; these effects were transduced by increases or decreases in cAMP production, respectively (18, 44). However, in the LTK- cell transfected with both rat D1A and D2 Long cDNA, D2-like agonists enhanced the ability of D1-like agonists to stimulate cAMP production (42). In heterologously transfected Chinese hamster ovary (CHO) cells expressing 10 times more D2 than D1 receptors, stimulation of either receptor resulted in a potentiation of arachidonic acid release compared with those cells expressing only one receptor (30). Although neither the D1 nor the D2 receptor alone stimulated arachidonic acid, dopamine and other Gi-coupled receptors amplified ATP receptor-stimulated arachidonic acid release (9, 24). Arachidonic acid cytochrome P-450 products have been shown to inhibit renal sodium transport (21, 28). Both protein kinase A and protein kinase C are involved in the transduction of dopamine-mediated arachidonic acid release (9, 25). It is of interest that D1-like receptors increase renal phospholipase C and protein kinase C activity (11, 24). Thus D1-D2 synergism in the production of cAMP, phosphoinositide, and arachidonic acid products may explain the synergism of D1-like and D2-like agonists in their inhibition of Na+-K+-ATPase activity.

The effect on sodium excretion of the interaction between a D1- and D2-like agonist has not been studied in vivo, due in part to the lack of availability of a drug that is selective to D1- and D2-like receptor subtypes without affinity to adrenergic or serotonergic receptors. This limitation has been overcome with the availability of Z-1046, a dopaminergic agonist with rank-order potency in transfected CHO cells of D3 >=  D4 > D2 > D5 > D1 (34). In these transfected cells, the inhibition constants for the D1-like receptors assessed by [3H]SCH-23390 binding were 25.4 ± 9.3 nM for D1 and 11.9 ± 9.3 for D5 (corresponding values for dopamine were much higher: D1 = 1199 ± 137.6 nM and D5 = 312 ± 37.2 nM). The inhibition constants for D2-like receptors assessed by [3H]spiperone binding were 9.9 ± 3.9 nM for D2, 0.7 ± 0.1 nM for D3, and 1.9 ± 0.6 nM for D4 [corresponding values for dopamine were much higher (D2 = 4970 ± 871 nM, D3 = 58.1 ± 2.8 nM, and D4 = 123.7 ± 31 nM)]. It must be pointed out that the high inhibition constants for dopamine are close to the concentrations of dopamine found in renal proximal tubule lumen and urine (17, 23). Z-1046 had no agonist effect on either beta 1- or beta 2-adrenergic, alpha 1-adrenergic, or 5-hydroxytryptamine 2 receptors but had an alpha 1-adrenergic receptor antagonist effect (unlike dopamine, which is an agonist at alpha 1-adrenergic receptors) (13, 17). Z-1046 also has an alpha 2-adrenergic agonist activity (comparable to dopamine), which was assessed by inhibition of electrically induced tachycardia in guinea pig atria (17, 34). We therefore tested, using Z-1046, the hypothesis that D1- and D2-like receptors interact to inhibit renal sodium transport in vivo. We determined the effect of Z-1046 on various parameters of renal function, including RBF, GFR, urine flow (V) and absolute (UNaV) and fractional (FENa) sodium excretion. The role of D2-like receptors was determined by the use of the D2-like antagonist domperidone, which is devoid of central nervous system effects (41). The role of D1-like receptors was determined by the use of the D1-like antagonist SCH-23390 (22). To minimize confounding systemic effects (e.g., arterial pressure), we infused drugs into the right renal artery of anesthetized rats.

    MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Male Wistar-Kyoto rats (Taconic Farms, Germantown, NY) ranging in age from 9 to 16 wk, on a regular Purina rat chow diet, were used. Food but not water was withheld 24 h before the study. The rats were anesthetized with pentobarbital sodium (50 mg/kg body wt ip), placed on a heated table to maintain rectal temperature between 36 and 37°C, and tracheotomized (PE-240). Anesthesia was maintained by the infusion of pentobarbital sodium at 0.8 mg · 100 g body wt-1 · h-1 (10). Catheters (PE-50) were placed into the external jugular and femoral veins and left carotid artery. Systemic arterial pressure was monitored electronically using Cardiomax II (Columbus Instruments, Columbus, OH). Laparotomy was performed, and both the right and left ureters were catheterized (PE-10). The right renal artery was exposed, and the right suprarenal artery (which originates from the right renal artery) was catheterized (PE-10 heat stretched to 180 µm) (10). After a Transonic Systems flow probe was secured around the right renal artery (Transonic Systems, Ithaca, NY), the abdomen was closed with surgical clips. The duration of these surgical procedures was ~60 min. Fluid losses during surgery were replaced with 5% albumin at 1% body weight over 30 min. For the determination of GFR, the animals received an intravenous infusion of normal saline containing [14C]inulin (0.01 mCi/10 ml infusate; NEN, Boston, MA) at a rate of 5 ml/100 g body wt for 30 min, followed by a rate of 0.8 ml · 100 g body wt-1 · h-1 until the end of the experiment. After an equilibration period of 120 min, 40-min urine collections for clearance determinations were begun and eight collections were obtained.

Studies on Renal Function In Vivo

Control group. In the control group, normal saline, the vehicle, was infused alone into the right suprarenal artery at a rate of 40 µl/h for eight collection periods. The rates for both intravenous and intrarenal arterial infusions were the same in all groups.

Z-1046 group. In preliminary studies, after two baseline periods, this group received the D1/D2 agonist Z-1046 at a dose of 0.03 µg · kg-1 · min-1 (period 3), 0.30 µg · kg-1 · min-1 (period 4), and 3.0 µg · kg-1 · min-1 (period 5). Thereafter, the infusate was changed to the vehicle (periods 6-8, recovery periods). After establishing an intrarenal dose of Z-1046 that produced a diuresis and natriuresis, we determined the dopamine receptor involved in subsequent studies. In these studies, after two baseline periods, Z-1046 was infused at 2 µg · kg-1 · min-1 for three periods followed by two recovery periods. All infusions were given at a rate of 40 µl/h. To account for the dead space in the renal arterial catheter, we changed the infusate 10 min before each period.

SCH-23390 group. After one baseline period, this group received the D1 antagonist SCH-23390 at 120 ng · 300 g body wt-1 · min-1 for four periods (periods 2-5). Thereafter, the infusate was changed to the vehicle (periods 6-8, recovery periods). This dose of SCH-23390 has been shown to be effective in blocking the diuretic and natriuretic effect of up to 120 ng · 300 g body wt-1 · min-1 of the D1-like agonist SKF-38393 in anesthetized rats (12).

Z-1046 and SCH-23390 group. After a baseline period, this group received the D1 antagonist SCH-23390 at 120 ng · 300 g body wt-1 · min-1 for four periods (periods 2-5). From periods 3 to 6, Z-1046 was infused at the same rate as described for the Z-1046 group. Thereafter, the infusate was changed to the vehicle (periods 7 and 8, recovery periods).

Domperidone group. After a baseline period, this group received the D2 antagonist domperidone at 1 µg · kg body wt-1 · min-1 for four periods (periods 2-5). Thereafter, the infusate was changed to the vehicle (periods 6-8, recovery periods).

Z-1046 and domperidone group. After a baseline period, this group received the D1 antagonist domperidone at 1 µg · kg body wt-1 · min-1 for four periods (periods 2-5). From periods 3 to 6, Z-1046 was infused at 2 µg · kg-1 · min-1 as described for the Z-1046 group. Thereafter, the infusate was changed to the vehicle (periods 7 and 8, recovery periods).

Blood samples were obtained before the first collection period, before the fifth collection period, and at the end of the experiment. Radioactivity and sodium and potassium concentrations were assayed in the blood and urine samples.

At the conclusion of the experiment, the position of the intrarenal arterial catheter was verified with lissamine green infusion.

The rats were killed by an overdose of pentobarbital sodium (100 mg/kg body wt). The kidneys were removed, blotted, and weighed for calculation of corrected GFR. Within-group comparisons were made using ANOVA for repeated measures (ANVR) or paired t-test with Bonferroni correction, and among-group comparisons were made using one-way ANOVA. Scheffé's test was used post hoc in both instances. When the left and right kidney were being compared, a paired t-test was used. P < 0.05 was considered significant.

    RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Effect of Vehicle on Renal Function

Table 1 shows that the intrarenal arterial infusion of the vehicle into the right kidney had no effect on mean arterial pressure (MAP), RBF, GFR, V, UNaV, or FENa.

                              
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  		Table 1.   Effect of vehicle on renal function in infused right kidney of WKY rats

Dose Response Effect of Z-1046 on Renal Function

Z-1046 (0.03, 0.3, and 3.0 µg · kg-1 · min-1; n = 8, with each dose administered for 40 min into the right kidney) increased RBF, V, UNaV, and FENa without affecting GFR; the changes were significant at the dose of 3.0 µg · kg-1 · min-1 (Table 2). Significant diuresis and natriuresis also occurred in the contralateral noninfused left kidney, indicating recirculation (data not shown), although neither MAP (Table 2) nor heart rate (data not shown) was affected by the drug infusion.

                              
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  		Table 2.   Effect of Z-1046 (0.03, 0.3, or 3.0 µg · kg-1 · min- 1) on renal function in infused right kidney of WKY rats

To determine the dopamine receptor subtype involved in the renal hemodynamic and functional effects of Z-1046, we studied the intrarenal effects of Z-1046 infused at 2 µg · kg-1 · min-1 (Table 3). Z-1046 increased V (Fig. 1), UNaV (Fig. 2), and FENa (Fig. 3); the changes were significant after 80 min of Z-1046 infusion. Z-1046 also increased RBF in absolute terms and as percent change from the baseline period (Fig. 4); a percent change in RBF is shown because the baseline RBF varied from group to group. GFR significantly increased after 80 but not after 120 minutes of infusion (Fig. 5). There was recirculation of the Z-1046 affecting renal function in the contralateral noninfused left kidney, but neither MAP nor heart rate was affected by Z-1046 infusion (data not shown).

                              
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  		Table 3.   Effect of Z-1046 (2 µg · kg-1 · min- 1) on renal function in infused right kidney of WKY rats


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  		Fig. 1.   Effect of saline (open circle , n = 6), preferential D2-like agonist Z-1046 alone (black-down-triangle , 2 µg, n = 10), D1-like antagonist SCH-23390 alone (star , 120 ng, n = 7), and D2-like antagonist domperidone alone (down-triangle, 1 µg, n = 9) or in combination (domperidone + Z-1046, , n = 6; SCH-23390 + Z-1046, +, n = 5) on urine flow (V) rate in anesthetized saline-loaded Wistar-Kyoto rats. All drugs were infused into 1 renal artery to minimize confounding systemic effects, as described in MATERIALS AND METHODS. Periods over which each drug was infused are shown as lines at top. Z-1046 (2 µg · kg-1 · min-1) by itself increased V, and SCH-23390 (120 ng · 300 g body wt-1 · min-1) by itself decreased V, whereas domperidone (1 µg · kg-1 · min-1) by itself was without effect. Increase in V due to Z-1046 was no longer evident when domperidone or SCH-23390 was combined with Z-1046. Data are means ± SE. * P < 0.05 vs. baseline period (1) or recovery (6-8) by ANVR and Scheffé's test. # P < 0.05 vs. other groups by ANOVA and Scheffé's test. a P < 0.05 vs. others except domperidone and Z-1046 by ANOVA and Scheffé's test.


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  		Fig. 2.   Effect of saline (open circle , n = 6), preferential D2-like agonist Z-1046 alone (black-down-triangle , 2 µg, n = 10), D1-like antagonist SCH-23390 alone (star , 120 ng, n = 7), and D2-like antagonist domperidone alone (down-triangle, 1 µg, n = 9) or in combination (domperidone + Z-1046, , n = 6; SCH-23390 + Z-1046, +, n = 5) on sodium excretion (UNaV) in anesthetized saline-loaded Wistar-Kyoto rats. All drugs were infused into 1 renal artery to minimize confounding systemic effects, as described in MATERIALS AND METHODS. Periods over which each drug was infused are shown as lines at top. Z-1046 (2 µg · kg-1 · min-1) by itself increased UNaV, and SCH-23390 (120 ng · 300 g body wt-1 · min-1) by itself decreased UNaV, whereas domperidone (1 µg · kg-1 · min-1) by itself was without effect. Increase in UNaV due to Z-1046 was no longer evident when domperidone or SCH-23390 was combined with Z-1046. Data are means ± SE. * P < 0.05 vs. baseline period (1) or recovery (6-8) by ANVR and Scheffé's test. a P < 0.05 vs. others except domperidone and Z-1046 by ANOVA and Scheffé's test.


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  		Fig. 3.   Effect of saline (open circle , n = 6), preferential D2-like agonist Z-1046 alone (black-down-triangle , 2 µg, n = 10), D1-like antagonist SCH-23390 alone (star , 120 ng, n = 7), and D2-like antagonist domperidone alone (down-triangle, 1 µg, n = 9) or in combination (domperidone + Z-1046, , n = 6; SCH-23390 + Z-1046, +, n = 5) on fractional sodium excretion (FENa) in anesthetized saline-loaded Wistar-Kyoto rats. All drugs were infused into 1 renal artery to minimize confounding systemic effects, as described in MATERIALS AND METHODS. Periods over which each drug was infused are shown as lines at top. Z-1046 (2 µg · kg-1 · min-1) by itself increased FENa, and SCH-23390 (120 ng · 300 g body wt-1 · min-1) by itself decreased FENa, whereas domperidone (1 µg · kg-1 · min-1) by itself was without effect. Increase in FENa due to Z-1046 was no longer evident when domperidone or SCH-23390 was combined with Z-1046. There was a tendency for FENa to overshoot after discontinuation of SCH-23390 both alone and in combined Z-1046 and SCH-23390 infusion, but changes were not significant. Data are means ± SE. * P < 0.05 vs. baseline period (1) or recovery (6-8) by ANVR and Scheffé's test. b P < 0.05 Z-1046 vs. baseline period (1) and SCH by ANOVA and Scheffé's test.


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  		Fig. 4.   Effect of saline (open circle , n = 6), preferential D2-like agonist Z-1046 alone (black-down-triangle , 2 µg, n = 7), D1-like antagonist SCH-23390 alone (star , 120 ng, n = 7), and D2-like antagonist domperidone alone (down-triangle, 1 µg, n = 6) or in combination (domperidone + Z-1046, , n = 4; SCH-23390 + Z-1046, +, n = 3) on renal blood flow (RBF) in anesthetized saline-loaded Wistar-Kyoto rats. All drugs were infused into 1 renal artery to minimize confounding systemic effects, as described in MATERIALS AND METHODS. Periods over which each drug was infused are shown as lines at top. Because baseline RBF varied from group to group, results are expressed as percent change from baseline. Z-1046 (2 µg · kg-1 · min-1) by itself increased RBF, and neither SCH-23390 (120 ng · 300 g body wt-1 · min-1) nor domperidone (1 µg · kg-1 · min-1) infused alone had any effect. Increase in RBF due to Z-1046 was no longer evident when SCH-23390 was combined with Z-1046. In contrast, renal vasodilatory effect of Z-1046 was enhanced in presence of domperidone. Data are means ± SE. * P < 0.05 vs. baseline period (2) by ANVR and Scheffé's test, # P < 0.05 vs. other groups by ANOVA and Scheffé's test, a P < 0.05 vs. others except domperidone, c P < 0.05 vs. others except Z-1046, d P < 0.05 Z-1046 vs. others except combination of domperidone and Z-1046 infusion by ANOVA and Scheffé's test.


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  		Fig. 5.   Effect of saline (open circle , n = 6), preferential D2-like agonist Z-1046 alone (black-down-triangle , 2 µg, n = 10), D1-like antagonist SCH-23390 alone (star , 120 ng, n = 7), and D2-like antagonist domperidone alone (down-triangle, 1 µg, n = 9) or in combination (domperidone + Z-1046, , n = 6; SCH-23390 + Z-1046, +, n = 5) on glomerular filtration rate (GFR) in anesthetized saline-loaded Wistar-Kyoto rats. All drugs were infused into 1 renal artery to minimize confounding systemic effects, as described in MATERIALS AND METHODS. Periods over which each drug was infused are shown as lines at top. Z-1046 (2 µg · kg-1 · min-1) by itself transiently increased GFR, and neither SCH-23390 (120 ng · 300 g body wt-1 · min-1) nor domperidone (1 µg · kg-1 · min-1) infused alone had any effect. Transient increase in GFR due to Z-1046 was no longer evident when SCH-23390 was combined with Z-1046. Data are means ± SE. e P < 0.05 baseline period 2 vs. period 4 (Z-1046) by ANVR and Scheffé's test, f P < 0.05 baseline period 2 vs. recovery period 8 (SCH-23390) by ANVR and Scheffé's test.

Effect of D2-Like Blockade on Z-1046

Domperidone, a D2-like antagonist, infused by itself at 1.0 µg · kg-1 · min-1 did not affect V, UNaV, FENa, RBF, or GFR in the infused (Table 4 and Figs. 1-5) or noninfused kidney (data not shown). To determine further if a D2-like antagonist can indeed block the diuretic and natriuretic effect of Z-1046, domperidone was coadministered with Z-1046 (2.0 µg · kg-1 · min-1). In this setting, the ability of Z-1046 to increase V, UNaV, and FENa was no longer evident (Table 5 and Figs. 1-3). Thus D2-like receptors are important in the diuretic and natriuretic effect of Z-1046. In contrast, the increase in RBF after Z-1046 (2 µg · kg-1 · min-1) was enhanced by domperidone (Table 5 and Fig. 4). These results suggest that Z-1046, via D2-like receptors, has a vasoconstrictor effect (19, 38).

                              
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  		Table 4.   Effect of D2-like antagonist domperidone on renal function in infused right kidney of WKY rats

                              
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  		Table 5.   Effect of Z-1046 (2 µg · kg-1 · min- 1) and domperidone on renal function in infused right kidney of WKY rats

Effect of D1-Like Antagonist

Infusion of the D1-like antagonist SCH-23390 alone at 120 ng · 300 g body wt-1 · min-1 decreased V, UNaV, and FENa after 40 min of infusion without affecting RBF and GFR (Table 6 and Figs. 1-5). The ability of SCH-23390 to decrease water and sodium excretion is in agreement with previous studies, supporting the hypothesis that D1-like receptors are important in the regulation of sodium excretion in volume-expanded animals (12, 23).

                              
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  		Table 6.   Effect of D1-like antagonist SCH-23390 on renal function in infused right kidney of WKY rats

SCH-23390 also blocked the increases in V, UNaV, and FENa induced by Z-1046 (2 µg · kg body wt-1 · min-1; Table 7 and Figs. 1-3). Moreover, SCH-23390 also blocked the ability of Z-1046 to increase RBF and GFR (Table 7 and Figs. 4 and 5). These studies suggest that D1-like receptors are involved in the hemodynamic, diuretic, and natriuretic effects of Z-1046.

                              
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  		Table 7.   Effect of Z-1046 (2 µg · kg-1 · min-1) and SCH-23390 on renal function in infused right kidney of WKY rats

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

These studies show that Z-1046, a dopamine receptor agonist with the rank-order potency D3 >=  D4 > D2 > D5 > D1, increases RBF, GFR, V, and sodium excretion in a dose-dependent manner (34). These changes are independent of perfusion pressure. However, the effects of Z-1046 on renal hemodynamics and GFR can be dissociated from its effects on V and sodium excretion. Thus the diuretic and natriuretic effects of Z-1046 occur only during the infusion periods (Figs. 1-3, periods 2-5), whereas the renal vasodilatory effect of Z-1046 persists for several hours thereafter. These studies suggest that Z-1046 may have direct effects on the renal tubule.

D1- and D2-like receptors in the kidney are known to influence renal hemodynamics. In vivo, D1-like receptor occupancy in renal resistance vessels leads to vasodilation that becomes more evident under sodium-replete conditions (14, 31). The effect of D2-like receptors on renal hemodynamics is not as straightforward as with D1-like receptors. As with D1-like receptors, the effect is influenced by sodium balance (5). In anesthetized hydropenic rats, quinpirole also increases RBF via D2-like receptors (35). Because sympathetic nervous system activity is increased in hydropenia, stimulation of D2-like presynaptic receptors in renal nerves could lead to an increase in RBF (see references in Ref. 23). In the current studies in anesthetized rats acutely loaded with saline at 5% of body wt, the D2 agonist domperidone by itself has no effect on renal hemodynamics, GFR, V, or sodium excretion. Z-1046, which has a higher affinity to D2-like than to D1-like receptors, increased RBF. The renal vasodilatory effect of Z-1046 at a dose of 2 µg · kg-1 · min-1 in volume-expanded rats was mediated by D1-like rather than D2-like receptors. However, the increase in RBF after Z-1046 (2 µg · kg-1 · min-1) was enhanced by domperidone (Fig. 4). These results suggest that Z-1046, via D2-like receptors, has a vasoconstrictor effect (19, 38). The detection of a vasoconstrictor effect of D2-like receptors might have been uncovered by the volume-expanded experimental conditions (5).

Both D1- and D2-like receptors in the kidney have also been found to regulate renal sodium handling. The current studies show that intrarenal blockade of D1-like receptors in volume-expanded rats decreases sodium transport independent of renal hemodynamics. These observations confirm our previous report and those of others that endogenous renal dopamine, via D1-like receptors, exerts a paracrine natriuretic function in volume-expanded states (reviewed in Ref. 23). Although the D1-like receptors are always associated with a diuretic and natriuretic action, the effect of stimulation of D2-like receptors, independent of D1-like receptors, on sodium excretion has ranged from antinatriuresis to no effect (reviewed in Ref. 23). Although bromocriptine has not been found to affect sodium excretion in vivo (40), it has been reported to increase Na+-K+-ATPase activity in renal proximal tubules in vitro (20). In anesthetized rats, the addition of a D2-like antagonist to the infusion of a D1-like antagonist reverses the antinatriuretic effect of the D1 antagonist (12). This observation is similar to the natriuretic effect of haloperidol in the isolated perfused rat kidney (2). In vivo, the intrarenal infusion of another D2-like agonist, YM-09151, in chronically instrumented conscious dogs on a moderate sodium diet also increases sodium excretion, whereas the infusion of the D2-like agonist quinpirole results in a decrease in V and sodium excretion (38, 39). These studies suggest an antinatriuretic effect of D2-like receptors.

However, in vitro studies have suggested that a D2-like agonist in concert with a D1-like agonist could synergistically act to decrease Na+-K+-ATPase and NHE activity in rat renal proximal tubules and brain striatal cells (3, 4, 33, 36) and inhibit sodium-phosphate cotransport in opossum kidney cells (29). A synergism between the D1A and the D2 receptor is also evident in LTK- and CHO cells expressing both dopamine receptor subtypes (30, 42). However, such synergism has not been demonstrated in vivo. The current studies show that diuretic and natriuretic effects of Z-1046 may also be due to synergism between D1- and D2-like receptors. However, synergism between D1- and D2-like receptors may be manifest only under volume expansion. The D2-like antagonist domperidone was unable to affect the natriuresis associated with either gludopa or dopamine in the non-volume-expanded state (14, 41). Investigation of the mechanism of this synergism was not an objective of this study. There are several potential explanations. Prevention of ANG II formation by angiotensin-converting enzyme inhibitors or blockade of ANG II receptors with losartan enhances the natriuretic and diuretic effects of fenoldopam, a D1-like agonist (6). D2-like receptors can decrease renin secretion in vivo in rats, and disruption of the D3 receptor gene in mice causes renin-dependent hypertension (1).

In summary, we have shown that Z-1046 increases RBF, V, and sodium excretion. The Z-1046-mediated increase in RBF is D1-like receptor dependent. In contrast, the Z-1046 inhibition of water and sodium transport is both D1- and D2-like receptor dependent.

Perspectives

Dopamine, via various D1- and D2-like receptors, regulates renal function. Usually D1- and D2-like receptors serve opposing functions. Under certain conditions, e.g., positive sodium balance, D2-like receptors may enhance the ability of D1-like receptors to inhibit sodium transport both in the renal proximal tubule and in more distal nephron segments. Thus, during volume expansion, D2-like receptors may facilitate D1-like receptor action by synergistic effects on signal transducers. D2-like receptors may also facilitate diuresis by antagonizing the hydrosmotic effect of vasopressin in cortical collecting duct (CCD) and may facilitate natriuresis in this nephron segment by inhibiting aldosterone secretion. The D1-like receptor action to antagonize aldosterone effects in the CCD may be enhanced by a D2-like receptor-mediated inhibition of aldosterone release in sodium-replete states. It is possible that the sodium retention seen in disease states such as hypertension may be due either to an abnormal D1- or D2-like receptor or to an abnormal interaction between them.

    ACKNOWLEDGEMENTS

These studies were supported by Grants HL-23081 and HL-58536 from the National Heart, Lung, and Blood Institute, DK-39308 and DK-44756 from the National Institute of Diabetes and Digestive and Kidney Diseases, and from the Zambon Group, Bresso, Italy.

    FOOTNOTES

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests: P. A. Jose, Dept. of Pediatrics, Georgetown Univ. Medical Center, PHC-2, 3800 Reservoir Road NW, Washington, DC 20007.

Received 23 February 1998; accepted in final form 22 June 1998.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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Am J Physiol Regul Integr Compar Physiol 275(4):R986-R994
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