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Comparison of the effects of fenoldopam, SK&F R-87516 and dopamine on renal arterioles in vitro
European Journal of Pharmacology, 126 (1986) 167-170
167
Elsevier
Short communication C O M P A R I S O N OF T H E EFFECTS OF F E N O L D O P A M , S K & F R-87516 A N D D O P A M I N E O N RENAL ARTERIOLES IN VITRO RICHARD M; EDWARDS Department of Pharmacology, Smith Kline and French Laboratories, L-521, 709 Swedeland Road, Swedeland, PA 19479, U.S.A.
Received 12 May 1986, accepted 20 May 1986
R.M. EDWARDS, Comparison of the effects of fenoldopam, S K & F R-87516 and dopamine on renal arterioles in vitro, European J. Pharmacol. 126 (1986) 167-170. The ability of the selective DA 1 agonists fenoldopam and SK&F R-87516 to relax norepinephrine-contracted afferent and efferent arterioles isolated from rabbit kidney was compared. In both arterioles, fenoldopam and SK&F R-87516 produced a concentration-dependent relaxation with a potency similar to that of dopamine. Fenoldopam also relaxed efferent arterioles contracted with angiotensin II. The selective DA 1 receptor antagonist, SK&F R-83566, caused parallel displacements in the concentration-response curves to SK&F 82526, corresponding to dissociation constants of 10.5 and 8.3 nM for afferent and efferent arterioles, respectively. The results provide direct evidence that the dopamine receptor present on renal resistance vessels is of the DA 1 subtype. Dopamine receptor
Renal vasculature
Afferent arteriole
1. Introduction Recent studies have demonstrated that the kidney contains dopamine receptors of both the DA 1 and DA 2 subtypes (Felder et al., 1984; Frederickson et al., 1985). Ligand binding studies have shown the presence of' D A a receptors associated with renal cortical tubules and DA 2 receptors of unknown function located in the glomerulus (Felder et al., 1984). Although the dopamine-induced increase in renal blood flow and sodium excretion has been attributed to the action of dopamine on DA 1 receptors (Frederickson et al., 1985), the subtype of dopamine receptor present on renal resistance vessels has not been directly examined. Recently, a number of selective dopamine receptor agonists and antagonists have become available. Therefore, the purpose of the present study was to identify the dopamine receptor subtype present on renal afferent and efferent arterioles using the selective DA 1 receptor agonists fenoldopam and S K & F R-87516 (Ohlstein et al., 1984), and the selective D A 1 receptor antagonist 0014-2999/86/$03.50 © 1986 Elsevier Science Publishers B.V.
Efferent arteriole
Fenoldopam
S K & F R-83566 (Berkowitz et al., 1984; Ohlstein et al., 1985).
2. Materials and methods Afferent and efferent arterioles were dissected and mounted on micropipettes as previously described in detail (Edwards, 1983). Briefly, a single arteriole was dissected from kidney slices obtained from male New Zealand White rabbits (1.5-2.5 kg). The arteriole was transferred to a temperature controlled chamber mounted on the stage of an inverted microscope. One end of the arteriole was cannulated with glass micropipettes while the other end of the arteriole was occluded. Intraluminal pressure was set a t 70 mm Hg for afferent arterioles and at 20 mm Hg for efferent arterioles. The image of the arteriole was displayed on a video screen at a final magnification of 1440 x and changes in lumen diameter in response to the experimental compounds were measured. The average control lumen diameter of the arterioles used in this study was 23.4 + 0.4/~m
168
for afferent arterioles ( + S.E., n = 16), and 10.9 + 0.8 # m (n = 18) for efferent arterioles. The arteriole was continuously superfused at 0.5 m l / m i n with a modified Krebs-Ringer bicarbonate buffer (pH 7.4) equilibrated with 95% 02-5% CO 2 consisting of (in mM): NaC1 120, N a H C O 3 25, KCI 4.7, NaH2PO 4 1.2, MgSO 4 1.2, CaCI 2 2.0, glucose 5.0, pyruvate 2.0, calcium-disodium EDTA 0.027 and 1 /~M propranolol. The perfusate was identical to the bath solution except that it contained 10 g/1 of dialyzed bovine serum albumin (Fraction V, Sigma Chem. Co., St. Louis, MO). All experiments were performed at 37 + 0.5°C. Concentration-response curves to fenoldopam, S K & F R-87516 and dopamine were obtained in arterioles contracted with 3 × 10 - 7 M norepinephrine (NE) or 10 10 M angiotensin II (All). After the contraction to N E or AII had stabilized (1 min), the chamber was rapidly flushed (20 s) with 4 ml of solution containing N E or All and progressively higher concentrations of the agonists. Lumen diameter was measured at each agonist concentration after the response had stabilized. The responses of the arterioles to the dopamine agonists were expressed as the percent relaxation of NE- or AII-induced contraction. In experiments with the DA 1 receptor antagonist, S K & F R-83566, control concentration-response curves to fenoldopam were obtained as described above. The arteriole was then exposed to the antagonist (10 -7 M) for 30 min, and the concentration-response curve to fenoldopam was repeated. The following compounds were used: 1-norepinephrine hydrochloride, dopamine hydrochloride, dl-propranolol and angiotensin II (Sigma Chem. Co., St. Louis, MO); fenoldopam (6chloro-7,8-dihydroxy-l-(p-hydroxyphenyl(-2,3,4,5tetrahydro-(1H)-3-benzazepine), S K & F R-87516 (6- floro-7,8-dihydroxy-1-(p-hydroxyphenyl)2,3,4,5tetrahydro-(1H)-3-benzazepine) and S K & F R83566 (7-bromo-8-hydroxy-3-methyl-l-phenyl2,3,4,5-tetrahydro-(1H)-3-benzazepine) (Smith Kline and French Labs., Philadelphia, PA). The data are expressed as means + S.E. The concentration of agonists needed to produce 50% of the maximal relaxation (EDs0) was determined
for each arteriole from the linear portion of the concentration-response curve and expressed as the - l o g EDs0 for statistical analysis. Dissociation constants (KB) were determined at a single concentration of antagonist by the dose-ratio method (Furchgott, 1972). Data were compared with Student's t-test or analysis of variance as appropriate. A P value of 0.05 was considered to be statistically significant.
3. Results
In both afferent and efferent arterioles, the selective DA 1 receptor agonists, fenoldopam and S K & F R-87516, produced concentration-dependent relaxations of NE-induced tone with potencies similar to that of dopamine (fig. 1). In afferent arterioles the EDs0 values (mean and 95% confidence limits) for relaxaiton for fenoldopam, S K & F R-87516 and dopamine were 0.14 /~M (0.09___ 0.3), 0.19 /~M (0.02-1.8) and 0.24 FM (0.01-5.3) respectively. In efferent arterioles the A. A f f e r e n t
Arteriole
B. E f f e r e n t
Arteriole
100 80 60 4O Z
20
9 0 100 uJ o:
80 6C 40 2(3
AGONIST (Log M}
Fig. 1. Comparison of the relaxation produced by dopamine
(A), fenoldopam (O) and SK&F R-87516 (©) in norepinephrine-contracted arterioles. Fenoldopam was also examined in angiotensin II-contracted efferent arterioles (zx). Each point is the mean_+S.E. of 5-12 arterioles.
169
loolA.
Afferent Arteriole • QONTROL
80 6O 40
Z
_o
20
0 B. E f f e r e n t A r t e r i o l e LU E ~R
100
• CONTROL
8O 6O 4O 2O
-9
-8
-7
FENOLDOP AM
-6
-5
(Log
-4 M)
Fig. 2. Effect of the selectiveDA1 receptor antagonist, SK&F R-83566, on the response to fenoldopam in norepinephrinecontracted afferent (A) and efferent (B) arterioles. The concentration of SK&F R-83566 w a s 1 0 - 7 M. Each point is the mean + S.E. of 6 afferent and 5 efferent arterioles.
EDs0 values were 0.15 /~M (0.09-0.2), 0.23 /~M (0.1-0.5) and 0.35 /~M (0.2-0.7) for fenoldopam, S K & F R-87516 and dopamine. Fenoldopam also caused relaxation of AII-mediated contractions in efferent arterioles yielding an EDs0 of 0.05 /xM (0.01-0.25). The selective DA~ receptor antagonist, S K & F R-83566, at 10 -v M produced a parallel rightward shift in the concentration-response curve to fenoldopam in both the afferent and efferent arteriole without affecting the contractile response to N E (fig. 2). K B values (means and 95% confidence limits) for S K & F R-83566 were 10.5 nM (5.5-19.8) for the afferent arteriole and 8.3 nM (2.6-26.8) for the efferent arteriole, values not significantly different from each other.
4. Discussion
Dopamine has multiple effects on the kidney including vasodilation, natriuresis (Frederickson
et al., 1985), and inhibition of NA release from renal sympathetic nerves (Bass and Robie, 1984). Current evidence suggests that both the vasodilatory and natriuretic effects of dopamine are due to DA 1 receptor activation (Frederickson et al., 1985), while the presynaptic actions are mediated by DA 2 receptors (Goldberg and Rajfer, 1985). However, because of the diverse renal effects of dopamine and, until recently, the lack of selective dopamine receptor agonists and antagonists, it has been difficult to ascertain the location and subtypes of renal DA receptors. Furthermore, in the intact kidney, the factors responsible for changes in blood flow are sometimes difficult to interpret because of the accompanying changes in systemic hemodynamics. Therefore, in the present study the characteristics of renal vascular dopamine receptors were studied directly in the afferent and efferent arterioles, the major sites of resistance to blood flow in the kidney. It has previously been demonstrated that dopamine produces a concentration-dependent relaxation of renal arterioles in vitro that is antagonized by metoclopramide (Edwards, 1985). The present study provides direct evidence that this dopamine-induced relaxation of renal arterioles is due to activation of DA1 receptors. This conclusion is based on the observations that the selective DA t receptor agonists, fenoldopam and S K & F R-87516, produced a concentrationdependent relaxation of NE- and AII-induced tone and that the selective DA 1 receptor antagonist, S K & F R-83566, caused a parallel rightward shift in the concentration-response curve to fenoldopam. Because of the technical difficulty of these experiments, only one concentration of antagonist was used. However, the K B values obtained with S K & F R-83566 are similar to those reported for inhibition of fenoldopam-induced relaxation in the splenic artery (73 nM) and the isolated perfused mesenteric-ileal vascular bed (20 nM) (Berkowitz et al., 1984). A recent study has shown that fenoldopam possesses a moderate degree of a2-adrenoceptor antagonist activity in vitro (Ohlstein et al., 1985). However, it is unlikely that the effects of fenoldopam observed in the present study were due to c~2-adrenoceptor blockage. First, fenoldo-
170 p a m relaxed b o t h N E - a n d A I I - i n d u c e d tone. Secondly, these arterioles a p p e a r to lack a 2 - a d r e n o c e p t o r s as d e m o n s t r a t e d b y the lack of effect of the selective a 2 - a d r e n o c e p t o r agonist, B - H T 933, a n d the i n a b i l i t y of rauwolscine to a n t a g o n i z e N E - m e d i a t e d c o n t r a c t i o n s ( u n p u b l i s h e d observations). G l o m e r u l a r c a p i l l a r y pressure, a n d therefore g l o m e r u l a r filtration rate, is in large p a r t det e r m i n e d b y the relative resistances of the afferent a n d efferent arterioles. A s shown in the p r e s e n t study, the sensitivity of the afferent a n d efferent arterioles to d o p a m i n e a n d the D A 1 r e c e p t o r agonists was similar. Therefore, in the intact kidney, s t i m u l a t i o n of vascular DA1 receptors s h o u l d increase renal b l o o d flow w i t h o u t significantly altering g l o m e r u l a r filtration rate if the afferent a n d efferent arterioles in vivo possess similar degrees of tone. This has, in fact, recently been shown b y F r e d e r i c k s o n et al. (1985) in experim e n t s in which renal arterial infusion of d o p a m i n e in a - and / 3 - a d r e n o c e p t o r - b l o c k e d dogs increased renal b l o o d flow b y 52% w i t h o u t affecting glomerular filtration rate. In s u m m a r y , the results of the present s t u d y have identified the D A receptors present on renal arterioles as b e l o n g i n g to the DA1 subtype. A l t h o u g h a p h y s i o l o g i c role for d o p a m i n e in regulating renal h e m o d y n a m i c s has n o t been clearly d e m onstrated, these results show that d o p a m i n e a n d DA~ r e c e p t o r agonists p r o d u c e r e l a x a t i o n of b o t h the pre- a n d p o s t - g l o m e r u l a r microvasculature.
Acknowledgements The author wishes to thank Drs. R. Ruffolo and L. Kinter for their helpful discussion, and Ms. Sue Tirri for her expert secreterial assistance.
References Bass, A.S. and N.W. Robie, 1984, Stereoselectivity of S- and R-sulpiride for pre- and post-synaptic dopamine receptors in the canine kidney, J. Pharmacol. Exp. Ther. 229, 67. Berkowitz, B.A. and E.H. Ohlstein, 1984, Cardiovascular doparnine receptors: Recent advances in agonists and antagonists of the DAa-receptor, J. Cardiovasc. Pharmacol. 6, $559. Edwards, R.M., 1983, Segmental effects of norepinephrine and angiotensin II on isolated renal microvessels, Am. J. Physiol. 224, F526. Edwards, R.M., 1985, Response of isolated renal arterioles to acetylcholine, dopamine and bradykinin, Am. J. Physiol. 248, F183. Felder, R.A., M. Blecher, G.M. Eisner and P.A. Jose, 1984, Cortical tubular and glomerular dopamine receptors in the rat kidney, Am. J. Physiol. 246, F557. Frederickson, E.D., T. Bradley and L.I. Goldberg, 1985, Blockade of renal effects of dopamine in the dog by the DA 1 antagonist SCH 23390, Am. J. Physiol. 249, F236. Furchgott, R.F., 1972, The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory, in: Catecholamines, eds. H. Blaschko and E. Muscholl (Springer-Verlag, Berlin) p. 283. Goldberg, L.I. and S.I. Rajfer, 1985, Dopamine receptors: application in clinical cardiology, Circulation 72, 245. Ohlstein, E.H., B. Zapko-Potapovich and B.A. Berkowitz, 1984, Studies on vascular dopamine receptors with the dopamine receptor agonist: SK&F 82526, J. Pharmacol. Exp. Ther. 229, 433. Ohlstein, E.H., B. Zapko-Potapovich and B.A. Berkowitz, 1985, The DA 1 receptor agonist fenoldopam (SK&F 82526) is also an a2-adrenoceptor antagonist, European J. Pharmacol. 118, 321.
167
Elsevier
Short communication C O M P A R I S O N OF T H E EFFECTS OF F E N O L D O P A M , S K & F R-87516 A N D D O P A M I N E O N RENAL ARTERIOLES IN VITRO RICHARD M; EDWARDS Department of Pharmacology, Smith Kline and French Laboratories, L-521, 709 Swedeland Road, Swedeland, PA 19479, U.S.A.
Received 12 May 1986, accepted 20 May 1986
R.M. EDWARDS, Comparison of the effects of fenoldopam, S K & F R-87516 and dopamine on renal arterioles in vitro, European J. Pharmacol. 126 (1986) 167-170. The ability of the selective DA 1 agonists fenoldopam and SK&F R-87516 to relax norepinephrine-contracted afferent and efferent arterioles isolated from rabbit kidney was compared. In both arterioles, fenoldopam and SK&F R-87516 produced a concentration-dependent relaxation with a potency similar to that of dopamine. Fenoldopam also relaxed efferent arterioles contracted with angiotensin II. The selective DA 1 receptor antagonist, SK&F R-83566, caused parallel displacements in the concentration-response curves to SK&F 82526, corresponding to dissociation constants of 10.5 and 8.3 nM for afferent and efferent arterioles, respectively. The results provide direct evidence that the dopamine receptor present on renal resistance vessels is of the DA 1 subtype. Dopamine receptor
Renal vasculature
Afferent arteriole
1. Introduction Recent studies have demonstrated that the kidney contains dopamine receptors of both the DA 1 and DA 2 subtypes (Felder et al., 1984; Frederickson et al., 1985). Ligand binding studies have shown the presence of' D A a receptors associated with renal cortical tubules and DA 2 receptors of unknown function located in the glomerulus (Felder et al., 1984). Although the dopamine-induced increase in renal blood flow and sodium excretion has been attributed to the action of dopamine on DA 1 receptors (Frederickson et al., 1985), the subtype of dopamine receptor present on renal resistance vessels has not been directly examined. Recently, a number of selective dopamine receptor agonists and antagonists have become available. Therefore, the purpose of the present study was to identify the dopamine receptor subtype present on renal afferent and efferent arterioles using the selective DA 1 receptor agonists fenoldopam and S K & F R-87516 (Ohlstein et al., 1984), and the selective D A 1 receptor antagonist 0014-2999/86/$03.50 © 1986 Elsevier Science Publishers B.V.
Efferent arteriole
Fenoldopam
S K & F R-83566 (Berkowitz et al., 1984; Ohlstein et al., 1985).
2. Materials and methods Afferent and efferent arterioles were dissected and mounted on micropipettes as previously described in detail (Edwards, 1983). Briefly, a single arteriole was dissected from kidney slices obtained from male New Zealand White rabbits (1.5-2.5 kg). The arteriole was transferred to a temperature controlled chamber mounted on the stage of an inverted microscope. One end of the arteriole was cannulated with glass micropipettes while the other end of the arteriole was occluded. Intraluminal pressure was set a t 70 mm Hg for afferent arterioles and at 20 mm Hg for efferent arterioles. The image of the arteriole was displayed on a video screen at a final magnification of 1440 x and changes in lumen diameter in response to the experimental compounds were measured. The average control lumen diameter of the arterioles used in this study was 23.4 + 0.4/~m
168
for afferent arterioles ( + S.E., n = 16), and 10.9 + 0.8 # m (n = 18) for efferent arterioles. The arteriole was continuously superfused at 0.5 m l / m i n with a modified Krebs-Ringer bicarbonate buffer (pH 7.4) equilibrated with 95% 02-5% CO 2 consisting of (in mM): NaC1 120, N a H C O 3 25, KCI 4.7, NaH2PO 4 1.2, MgSO 4 1.2, CaCI 2 2.0, glucose 5.0, pyruvate 2.0, calcium-disodium EDTA 0.027 and 1 /~M propranolol. The perfusate was identical to the bath solution except that it contained 10 g/1 of dialyzed bovine serum albumin (Fraction V, Sigma Chem. Co., St. Louis, MO). All experiments were performed at 37 + 0.5°C. Concentration-response curves to fenoldopam, S K & F R-87516 and dopamine were obtained in arterioles contracted with 3 × 10 - 7 M norepinephrine (NE) or 10 10 M angiotensin II (All). After the contraction to N E or AII had stabilized (1 min), the chamber was rapidly flushed (20 s) with 4 ml of solution containing N E or All and progressively higher concentrations of the agonists. Lumen diameter was measured at each agonist concentration after the response had stabilized. The responses of the arterioles to the dopamine agonists were expressed as the percent relaxation of NE- or AII-induced contraction. In experiments with the DA 1 receptor antagonist, S K & F R-83566, control concentration-response curves to fenoldopam were obtained as described above. The arteriole was then exposed to the antagonist (10 -7 M) for 30 min, and the concentration-response curve to fenoldopam was repeated. The following compounds were used: 1-norepinephrine hydrochloride, dopamine hydrochloride, dl-propranolol and angiotensin II (Sigma Chem. Co., St. Louis, MO); fenoldopam (6chloro-7,8-dihydroxy-l-(p-hydroxyphenyl(-2,3,4,5tetrahydro-(1H)-3-benzazepine), S K & F R-87516 (6- floro-7,8-dihydroxy-1-(p-hydroxyphenyl)2,3,4,5tetrahydro-(1H)-3-benzazepine) and S K & F R83566 (7-bromo-8-hydroxy-3-methyl-l-phenyl2,3,4,5-tetrahydro-(1H)-3-benzazepine) (Smith Kline and French Labs., Philadelphia, PA). The data are expressed as means + S.E. The concentration of agonists needed to produce 50% of the maximal relaxation (EDs0) was determined
for each arteriole from the linear portion of the concentration-response curve and expressed as the - l o g EDs0 for statistical analysis. Dissociation constants (KB) were determined at a single concentration of antagonist by the dose-ratio method (Furchgott, 1972). Data were compared with Student's t-test or analysis of variance as appropriate. A P value of 0.05 was considered to be statistically significant.
3. Results
In both afferent and efferent arterioles, the selective DA 1 receptor agonists, fenoldopam and S K & F R-87516, produced concentration-dependent relaxations of NE-induced tone with potencies similar to that of dopamine (fig. 1). In afferent arterioles the EDs0 values (mean and 95% confidence limits) for relaxaiton for fenoldopam, S K & F R-87516 and dopamine were 0.14 /~M (0.09___ 0.3), 0.19 /~M (0.02-1.8) and 0.24 FM (0.01-5.3) respectively. In efferent arterioles the A. A f f e r e n t
Arteriole
B. E f f e r e n t
Arteriole
100 80 60 4O Z
20
9 0 100 uJ o:
80 6C 40 2(3
AGONIST (Log M}
Fig. 1. Comparison of the relaxation produced by dopamine
(A), fenoldopam (O) and SK&F R-87516 (©) in norepinephrine-contracted arterioles. Fenoldopam was also examined in angiotensin II-contracted efferent arterioles (zx). Each point is the mean_+S.E. of 5-12 arterioles.
169
loolA.
Afferent Arteriole • QONTROL
80 6O 40
Z
_o
20
0 B. E f f e r e n t A r t e r i o l e LU E ~R
100
• CONTROL
8O 6O 4O 2O
-9
-8
-7
FENOLDOP AM
-6
-5
(Log
-4 M)
Fig. 2. Effect of the selectiveDA1 receptor antagonist, SK&F R-83566, on the response to fenoldopam in norepinephrinecontracted afferent (A) and efferent (B) arterioles. The concentration of SK&F R-83566 w a s 1 0 - 7 M. Each point is the mean + S.E. of 6 afferent and 5 efferent arterioles.
EDs0 values were 0.15 /~M (0.09-0.2), 0.23 /~M (0.1-0.5) and 0.35 /~M (0.2-0.7) for fenoldopam, S K & F R-87516 and dopamine. Fenoldopam also caused relaxation of AII-mediated contractions in efferent arterioles yielding an EDs0 of 0.05 /xM (0.01-0.25). The selective DA~ receptor antagonist, S K & F R-83566, at 10 -v M produced a parallel rightward shift in the concentration-response curve to fenoldopam in both the afferent and efferent arteriole without affecting the contractile response to N E (fig. 2). K B values (means and 95% confidence limits) for S K & F R-83566 were 10.5 nM (5.5-19.8) for the afferent arteriole and 8.3 nM (2.6-26.8) for the efferent arteriole, values not significantly different from each other.
4. Discussion
Dopamine has multiple effects on the kidney including vasodilation, natriuresis (Frederickson
et al., 1985), and inhibition of NA release from renal sympathetic nerves (Bass and Robie, 1984). Current evidence suggests that both the vasodilatory and natriuretic effects of dopamine are due to DA 1 receptor activation (Frederickson et al., 1985), while the presynaptic actions are mediated by DA 2 receptors (Goldberg and Rajfer, 1985). However, because of the diverse renal effects of dopamine and, until recently, the lack of selective dopamine receptor agonists and antagonists, it has been difficult to ascertain the location and subtypes of renal DA receptors. Furthermore, in the intact kidney, the factors responsible for changes in blood flow are sometimes difficult to interpret because of the accompanying changes in systemic hemodynamics. Therefore, in the present study the characteristics of renal vascular dopamine receptors were studied directly in the afferent and efferent arterioles, the major sites of resistance to blood flow in the kidney. It has previously been demonstrated that dopamine produces a concentration-dependent relaxation of renal arterioles in vitro that is antagonized by metoclopramide (Edwards, 1985). The present study provides direct evidence that this dopamine-induced relaxation of renal arterioles is due to activation of DA1 receptors. This conclusion is based on the observations that the selective DA t receptor agonists, fenoldopam and S K & F R-87516, produced a concentrationdependent relaxation of NE- and AII-induced tone and that the selective DA 1 receptor antagonist, S K & F R-83566, caused a parallel rightward shift in the concentration-response curve to fenoldopam. Because of the technical difficulty of these experiments, only one concentration of antagonist was used. However, the K B values obtained with S K & F R-83566 are similar to those reported for inhibition of fenoldopam-induced relaxation in the splenic artery (73 nM) and the isolated perfused mesenteric-ileal vascular bed (20 nM) (Berkowitz et al., 1984). A recent study has shown that fenoldopam possesses a moderate degree of a2-adrenoceptor antagonist activity in vitro (Ohlstein et al., 1985). However, it is unlikely that the effects of fenoldopam observed in the present study were due to c~2-adrenoceptor blockage. First, fenoldo-
170 p a m relaxed b o t h N E - a n d A I I - i n d u c e d tone. Secondly, these arterioles a p p e a r to lack a 2 - a d r e n o c e p t o r s as d e m o n s t r a t e d b y the lack of effect of the selective a 2 - a d r e n o c e p t o r agonist, B - H T 933, a n d the i n a b i l i t y of rauwolscine to a n t a g o n i z e N E - m e d i a t e d c o n t r a c t i o n s ( u n p u b l i s h e d observations). G l o m e r u l a r c a p i l l a r y pressure, a n d therefore g l o m e r u l a r filtration rate, is in large p a r t det e r m i n e d b y the relative resistances of the afferent a n d efferent arterioles. A s shown in the p r e s e n t study, the sensitivity of the afferent a n d efferent arterioles to d o p a m i n e a n d the D A 1 r e c e p t o r agonists was similar. Therefore, in the intact kidney, s t i m u l a t i o n of vascular DA1 receptors s h o u l d increase renal b l o o d flow w i t h o u t significantly altering g l o m e r u l a r filtration rate if the afferent a n d efferent arterioles in vivo possess similar degrees of tone. This has, in fact, recently been shown b y F r e d e r i c k s o n et al. (1985) in experim e n t s in which renal arterial infusion of d o p a m i n e in a - and / 3 - a d r e n o c e p t o r - b l o c k e d dogs increased renal b l o o d flow b y 52% w i t h o u t affecting glomerular filtration rate. In s u m m a r y , the results of the present s t u d y have identified the D A receptors present on renal arterioles as b e l o n g i n g to the DA1 subtype. A l t h o u g h a p h y s i o l o g i c role for d o p a m i n e in regulating renal h e m o d y n a m i c s has n o t been clearly d e m onstrated, these results show that d o p a m i n e a n d DA~ r e c e p t o r agonists p r o d u c e r e l a x a t i o n of b o t h the pre- a n d p o s t - g l o m e r u l a r microvasculature.
Acknowledgements The author wishes to thank Drs. R. Ruffolo and L. Kinter for their helpful discussion, and Ms. Sue Tirri for her expert secreterial assistance.
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