Selective DA-1 Receptor Antagonist Research Articles

Vagally mediated effects of brain stem dopamine on gastric tone and phasic contractions of the rat

Dopamine (DA)-containing fibers and neurons are embedded within the brain stem dorsal vagal complex (DVC); we have shown previously that DA modulates the membrane properties of neurons of the dorsal motor nucleus of the vagus (DMV) via DA1 and DA2 receptors. The vagally dependent modulation of gastric tone and phasic contractions, i.e., motility, by DA, however, has not been characterized. With the use of microinjections of DA in the DVC while recording gastric tone and motility, the aims of the present study were 1) assess the gastric effects of brain stem DA application, 2) identify the DA receptor subtype, and, 3) identify the postganglionic pathway(s) activated. Dopamine microinjection in the DVC decreased gastric tone and motility in both corpus and antrum in 29 of 34 rats, and the effects were abolished by ipsilateral vagotomy and fourth ventricular treatment with the selective DA2 receptor antagonist L741,626 but not by application of the selective DA1 receptor antagonist SCH 23390. Systemic administration of the cholinergic antagonist atropine attenuated the inhibition of corpus and antrum tone in response to DA microinjection in the DVC. Conversely, systemic administration of the nitric oxide synthase inhibitor nitro-l-arginine methyl ester did not alter the DA-induced decrease in gastric tone and motility. Our data provide evidence of a dopaminergic modulation of a brain stem vagal neurocircuit that controls gastric tone and motility.NEW & NOTEWORTHY Dopamine administration in the brain stem decreases gastric tone and phasic contractions. The gastric effects of dopamine are mediated via dopamine 2 receptors on neurons of the dorsal motor nucleus of the vagus. The inhibitory effects of dopamine are mediated via inhibition of the postganglionic cholinergic pathway.

The tegmental–accumbal dopaminergic system mediates the anxiolytic effect of acupuncture during ethanol withdrawal

This study investigated the involvement of the mesolimbic dopamine (DA) system in the anxiolytic effects of acupuncture during ethanol withdrawal (EW). Rats were intraperitoneally treated with 3g/kg/day of ethanol for 28 days and experienced 3 days of withdrawal. During EW, the rats were bilaterally treated with acupuncture at acupoints HT7 (Shenmen) or PC6 (Neiguan) or at a non-acupoint (tail) once daily for 1min over 3 days. High-performance liquid chromatographic (HPLC) analysis showed that EW significantly decreased both DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens shell (NaccSh); however, these processes were inhibited by acupuncture at HT7 but not at PC6. Real-time polymerase chain reaction and western blot assays also revealed that acupuncture at HT7 prevented the EW-induced reductions in tyrosine hydroxylase mRNA expression in the ventral tegmental area (VTA) and tyrosine hydroxylase protein expression in the NaccSh. A prior intra-NaccSh infusion of a cocktail of the selective DA1 receptor antagonist SCH23390 and the selective DA2 receptor antagonist eticlopride blocked the anxiolytic effect of acupuncture at HT7 in elevated plus maze tests. In addition, acupuncture at HT7 suppressed EW-induced increased BDNF levels in the VTA. These findings suggest that acupuncture at HT7 improves the VTA–Nacc DAergic function via inhibition of BDNF expression in the VTA, thereby exerting anxiolytic effects during EW.

Bulbocapnine is not a selective DA1 receptor antagonist.

Antagonist activity of bulbocapnine on DA1 versus DA2 dopamine receptors was studied simultaneously in a dog under pentobarbitone anaesthesia and without phenoxybenzamine pretreatment. Fenoldopam (SK&F 82526) injected into the renal artery was the DA1 agonist and dipropyl dopamine or piribedil injected into the femoral artery were the DA2 agonists. Both at 0.5 and 1 mg kg-1 doses intravenous bulbocapnine caused nearly equal inhibition of DA1 and DA2 dopamine receptor-mediated responses. Our results show that under these experimental conditions bulbocapnine is not a selective DA1 dopamine antagonist.

The cardiovascular actions of dopexamine hydrochloride, an agonist at dopamine receptors and beta 2-adrenoceptors in the dog.

The receptor pharmacology of the cardiovascular effects of dopexamine hydrochloride in the anaesthetized dog (given by i.v. infusion of 3 X 10(-9)-10(-7) mol kg-1 min-1) has been analysed by the use of selective receptor antagonists and of ganglionic blockade. The increases in cardiac output, contractility, and rate were antagonized by the beta 2-adrenoceptor antagonist, ICI 118551. Renal blood flow rose secondary to reduction in renal vascular resistance and this was antagonized by SCH 23390, a highly selective DA1-receptor antagonist. Peripheral vasodilation and reduction of blood pressure were mediated by a combination of DA1- and DA2-receptor and beta 2-adrenoceptor stimulation. In a separate group of dogs, the cardiac stimulant effects of dopexamine HCl were partially reflex and were reduced by ganglion block, revealing responses due to stimulation of cardiac beta 2-adrenoceptors. Thus the beta 2-adrenoceptor agonist action of dopexamine HCl is not only partly responsible for afterload reduction but also leads to direct cardiac stimulation. From its cardiovascular profile, dopexamine HCl is likely to be of use in acute treatment of heart failure.

Renal hemodynamics in radiocontrast medium-induced renal dysfunction: A role for dopamine-1 receptors

Radiocontrast medium (RCM) administration induces a transient increase in renal blood flow (RBF), followed by a prolonged vasoconstriction. This vasoconstrictor phase in RBF is accompanied by a decrement in glomerular filtration rate (GFR). Nonselective dopamine (DA) receptor stimulation is known to increase RBF and GFR. Clinical studies, however, fail to demonstrate a renoprotective effect of DA following RCM administration. This lack of renoprotection may relate to nonspecific adrenergic stimulation by DA. The effect of select DA-1 receptor stimulation on renal hemodynamics following RCM administration has not been evaluated. This study tests the hypothesis that selective DA-1 receptor stimulation blunts the declines in RBF and GFR that follow RCM injections, independent of changes in baseline RBF and GFR. Experiments were performed in six anesthetized, volume-depleted dogs. RBF was measured by an electromagnetic flow probe around the renal artery and GFR by inulin clearance. After a 60-minute equilibration period, baseline values of RBF, GFR, and arterial pressure were determined. Two separate intrarenal bolus injections of the ionic RCM Renograffin were then given in the presence of saline infusion. After a 60-minute recovery period, intra-arterial infusions of either the selective DA-1 receptor agonist fenoldopam or the selective DA-1 receptor antagonist Schering 23390 were started in random order, and experiments were repeated. Neither agent significantly altered baseline values of arterial pressure, RBF, or GFR rate. Fenoldopam prevented reductions in GFR (-17 +/- 2 Deltaml/min, control vs. 2 +/- 1 Deltaml/min, fenoldopam, P < 0.001). Conversely, GFR was further reduced in the presence of Schering 23390 (-15 +/- 2 Deltaml/min, control vs. -23 +/- 1 Deltaml/min, Schering 23390, P < 0.05). Similarly, the maximal reduction in RBF was blunted with fenoldopam (-71 +/- 12 Deltaml/min, control vs. -3 +/- 2 Deltaml/min, fenoldopam, P < 0. 01), whereas Schering 23390 potentiated maximal RBF reductions following the RCM injection (-85 +/- 11 Deltaml/min, control vs. -119 +/- 14 Deltaml/min, Schering 23390, P < 0.05). The duration of recovery from vasoconstriction was also prolonged in the presence of Schering 23390 (342 +/- 35 seconds, control vs. 762 +/- 56 seconds, Schering 23390, P < 0.0001). We conclude that selective DA-1 receptor stimulation protects against RCM-mediated decrements in renal hemodynamics, independent of changes in baseline GFR and RBF. Clinical trials are required to examine whether selective DA-1 receptor stimulation may have a role in prophylaxis against nephropathy development in high-risk patients undergoing procedures that require RCM.

Dopamine is taken up from the circulation by, and released from, local noradrenergic varicose axon terminals in zona glomerulosa of the rat: a neurochemical and immunocytochemical study.

The effect of supramaximal electric field stimulation on [3H]dopamine (DA) release by rat adrenal capsule-glomerulosa preparations was studied using a micro-volume perfusion system. When the tissues were preloaded with [3H]DA, a considerable amount of [3H]DA and [3H]noradrenaline (NA) were released in response to field stimuli. Reserpinization, calcium removal or tetrodotoxin blocking of Na+ influx all completely inhibited the stimulation-evoked release of DA/NA, indicating that the radioactivity released is of neuronal and vesicular origin. In the adrenal cortex, a substantial proportion of tyrosine hydroxylase and dopamine-beta-hydroxylase immunoreactive nerve fibres and varicosities were observed around the zona glomerulosa. DA-containing nerves were not seen in the adrenal cortex; however, the same immunocytochemical procedures clearly demonstrated dopaminergic nerve cells and fibres in the substantia nigra and the striatum respectively, and cells of the adrenal medulla. Like the NA release from noradrenergic varicosities in the zona glomerulosa, the DA release from noradrenergic endings is not subject to negative feedback modulation through DA2 receptors since apomorphine, a DA2-receptor agonist, and sulpiride, a selective DA2-receptor antagonist, failed to affect the release. After in-vivo i.v. administration of [3H]DA, the glomerulosa content of DA and NA and the in-vitro release of [3H]DA and [3H]NA of zona glomerulosa both increased, indicating that the local varicose axon terminals were able to accumulate DA from the circulation, convert it into NA and release it in response to neural activity. This local arrangement of noradrenergic axon terminals, able to take up DA from the circulation and release it or convert it into NA, provides the possibility of a fine tuning of local circulation and aldosterone synthesis in the zona glomerulosa.

Dopamine receptor-mediated activation of phospholipase C is associated with natriuresis during high salt intake.

Activation of phospholipase C (PLC) is considered to be one of the cellular signaling events involved in dopamine (DA)-mediated natriuresis. In the present study we have examined the role of renal cortical PLC in contributing to the increase in urinary sodium excretion during high sodium intake and its relationship with intrarenal DA synthesis. Rats were given either 1% NaCl (high sodium intake) or tap water (normal sodium intake) to drink for 24 h, and urine was collected over this time period. PLC activity in the renal cortex from these rats was measured by prelabeling cortical slices with myo-[2-3H]inositol and was expressed as fractional release (FR) of inositol (mono-, bis-, and tris-) phosphates. Acute increase in sodium intake produced 93 +/- 8% increase over control in urinary DA excretion. These changes were accompanied by significant increases (30 +/- 8%) in basal FR of inositol phosphates and 243 +/- 40 and 76 +/- 14% increases in urinary sodium and water excretion, respectively. The elevated basal PLC activity in rats with high sodium intake was significantly reduced in the presence of Sch 23390, a selective DA-1 receptor antagonist. Exogenously added DA (3 mM) also produced significant increases in PLC activity, although the magnitudes of increases were different in rats with high (37 +/- 8%) and normal (66 +/- 9%) sodium intake. However, Sch 23390 alone or carbidopa pretreatment did not affect the basal PLC activity in rats maintained on normal sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation of renal dopamine production during acute volume expansion requires the presence of intact vagi but not renal nerves.

We have previously reported that acute volume expansion (VE) with isotonic saline stimulates the production of renal dopamine (DA) which in turn contributes to the accompanying diuresis and natriuresis via activation of renal tubular DA-1 receptors. The purpose of the present study was to determine whether the presence of vagi and/or renal nerves is essential in order to activate the renal dopaminergic system during acute VE. Acute VE (6% body weight) with isotonic saline was performed in two groups of anesthetized rats, one of which served as sham control whereas the other was subjected to bilateral cervical vagotomy. The diuretic and natriuretic responses to acute VE did not differ between the sham control and vagotomized groups. However, urinary DA excretion (UDAV) was significantly increased in the sham control but not vagotomized group. Pretreatment with SCH 23390, a selective DA-1 receptor antagonist led to significant attenuation of the diuretic and natriuretic response to acute VE in the sham control but not vagotomized group. In another group of animals, the diuretic and natriuretic response to acute VE was studied in rats subjected to acute unilateral renal denervation. Basal UDAV was not significantly different between the denervated (DNX) kidney and the contralateral innervated (INX) kidney. Acute VE evoked diuresis and natriuresis in both kidneys, the response in the DNX kidney being significantly greater when compared to that in the INX kidney. UDAV increased significantly and to similar levels in both kidneys. Pretreatment with SCH 23390 led to attenuation of the diuretic and natriuretic response to acute VE in the DNX but not INX kidney. After DA-1 receptor blockade, the residual renal response to volume expansion in the DNX kidney did not differ significantly from that in the INX kidney. The results of this study suggest that 1) afferent vagal pathways appear to mediate the VE induced stimulation of renal DA production; 2) the increase in UDAV during acute VE occurs primarily through a mechanism which is independent of renal noradrenergic and putative dopaminergic nerves.

Effect of fenoldopam prodrug, SK&amp;F R-105058, on renal function in rats

Recent development of and studies on fenoldopam prodrugs have shown their prolonged hemodynamic effects. This study was carried out in order to examine the effect of a fenoldopam prodrug on renal function in rats. In the present study we administered SK&F R-105058, the 4′,7,8-tris-N-ethyl carbamate ester of R-fenoldopam, at a dose of 30 μg/kg/min intravenously to the anesthetized rats. This prodrug produced long-lasting increases in water and sodium excretion after termination of the 30-min drug infusion with minimum changes in hemodynamic parameters. The diuresis and natriuresis were attenuated in the presence of a selective DA1 receptor antagonist SCH 23390. Therefore, it is suggested that production of fenoldopam from its precursor drug SK&F R-105058 caused these prolonged renal effects, which were mediated via the activation of DA1 receptors located on renal tubules. © 1992 Wiley-Liss, Inc.

Dietary salt and blood pressure

We have previously shown that the association between salt intake and blood pressure is large and of substantial public health importance. Analysis of the average blood pressure and average sodium intake in different communities yielded estimates of the decrease in blood pressure for a given reduction in dietary sodium according to age and blood pressure centile that successfully predicted both the association between sodium and blood pressure in observational studies and the reduction in blood pressure obtained in trials of dietary salt reduction. Here we consider the validity of criticisms of the appraisal. The fact that the observed blood pressure reductions in individual trials closely mirrored predicted values for individuals trials that varied widely (from 2.6 to 25.2 mmHg systolic according to age, existing blood pressure and the extent of salt restriction) renders bias implausible since it would be too great a coincidence for a source of error to reproduce such close matching. If the analysis is restricted to trials that avoided possible bias because (1) the high- and low-salt diets were otherwise identical, (2) the order of the diet avoided regression to the mean or (3) the trials were double-blind with diets that were otherwise identical and the order was random, the matching between observed and predicted blood pressure reductions is equally close. Our results are consistent with the Intersalt study. A reduction in dietary salt could be a simple change, yet the reduction in mortality would be large.

Dopamine receptors mediating inhibition of the cyclic adenosine monophosphate generating system in the rat renal cortex

1. In vitro addition of dopamine (DA) or of DA-1 receptor agonists increases 3'- 5'-cyclic adenosine monophosphate (cAMP) levels through the stimulation of DA-1 receptors. 2. Although receptor binding studies suggest the existence of DA-2 receptors in the renal cortex, the presence of DA receptors negatively coupled to cAMP generation (DA-2 effect) has not been so far characterized. 3. In this study we have shown that the addition of DA plus the selective DA-1 receptor antagonist SCH 23390 to membrane fractions of rat renal cortex decreased cAMP concentration below basal levels. 4. DA-2 receptor responses were also elicited with the DA-2 receptor agonists bromocriptine and quinpirole in the absence of SCH 23390. These inhibitory effects on cAMP generation were abolished by the DA-2 receptor antagonist 1-sulpiride. 5. The above findings are indicative of the existence in the rat renal cortex of DA-2 receptors showing an effect upon cAMP generation similar to that found in the brain and in several peripheral tissues.

Involvement of Endogenous Dopamine and Da-1 Receptors in the Renal Effects of Atrial Natriuretic Factor in Rats

The precise mechanism of the diuretic and natriuretic effects of Atrial Natriuretic Factor (ANF) is still unclear. The present study was undertaken with the aim of elucidating the mechanism of interaction between ANF, dopamine (DA) and DA receptors in the renal effects of ANF in rats. In pentobarbital anesthetized rats, ANF infusion (10 micrograms/kg/hour) produced marked diuresis and natriuresis which was accompanied by significant hypotension, bradycardia and also a modest increase in glomerular filtration rate. However, there was no accompanying increase in urinary DA excretion during ANF infusion. Pretreatment with SCH 23390, a selective DA-1 receptor antagonist caused significant attenuation of the diuretic and natriuretic effects of ANF whereas the hemodynamic changes produced by ANF were still evident in SCH 23390 treated animals. Plasma ANF levels were elevated to the same magnitude in both the control and SCH 23390 treated groups. Pretreatment with carbidopa, a dopa decarboxylase inhibitor also significantly blunted the diuretic and natriuretic effects of ANF. The antagonism of the ANF-induced diuresis and natriuresis by SCH 23390 and carbidopa was comparable in magnitude. These results suggest that endogenous DA, via activation of DA-1 receptors plays a permissive role in the renal effects of ANF, perhaps by enhancing tubular responsiveness to ANF. However, there does not appear to be a stimulatory effect of ANF on renal DA production or release.

Renal dopamine and tubular DA‐1 receptors in the regulation of sodium excretion

1. We have performed studies in rats with selective DA-1 receptor agonists fenoldopam and dopexamine which show that activation of tubular DA-1 receptors by these agents results in natriuresis and diuresis. 2. In pentobarbital-anaesthetized rats, an acute increase in sodium intake produced by volume expansion (5% body weight) with isotonic sodium chloride led to pronounced increases in sodium and water excretion. These natriuretic and diuretic responses were accompanied by significant increases in urinary dopamine excretion and could be attenuated by the selective DA-1 receptor antagonist, SCH 23390. 3. Intravenous infusion of atrial natriuretic factor produced hypotension, bradycardia and an increase in sodium and water excretion. The natriuretic and diuretic response to the peptide was not accompanied by any changes in urinary dopamine excretion but it was attenuated by SCH 23390 and the dopa decarboxylate inhibitor, carbidopa. 4. These results show that renal tubular DA-1 receptors can be activated by selective agonists, which subsequently leads to natriuresis and diuresis. During acute volume expansion, there is an increased production of renal dopamine, which contributes to the natriuretic response via activation of tubular DA-1 receptors. Finally, we discovered that endogenous dopamine plays a permissive role in the full expression of the renal effects of the atrial natriuretic factor.

Demonstration of dopamine DA-1 receptor sites in rat juxtaglomerular cells by light microscope autoradiography

The binding of the selective DA-1 receptor antagonist [3H]-SCH 23390 in sections of rat kidney was studied using combined in vitro biochemical radio-receptor assay and autoradiography. [3H]-SCH 23390 was bound to sections of rat kidney in a manner consistent with the labeling of DA-1 receptors with a dissociation constant value of 4.2 nmol/l and a Bmax value of 180.6 fmol/mg protein. Light microscope autoradiography revealed a dense accumulation of silver grains in juxtaglomerular cells and in proximal convoluted tubule cells. These findings suggest that the stimulation of renin release elicited by dopamine and DA-1 receptor agonists may be mediated by the activation of DA-1 receptors located on juxtaglomerular cells.

Peripheral vascular and neuronal effects of dopamine receptor agonists. A comparison with receptor binding studies in rat striatum

A series of dopamine (DA)-receptor agonists was tested in vitro on vascular DA1- and neuronal DA2-receptors and the activity observed was compared to their ability to compete with [3H]-SCH23390 and [3H]-domperidone binding to rat striatal membranes. In rabbit splenic artery, where the presence of the DA1-receptor is established, DA and related agonists produced a complete concentration-dependent relaxation of the thromboxane A2-mimetic U46619-induced tone in IBMX (3-isobutyl-1-methylxanthine) treated preparations. The DA vasorelaxant effect proved to be mediated by DA1-receptors, being inhibited by the selective DA1-receptor antagonist SCH23390. Fenoldopam proved to be the most potent agonist in the rabbit splenic artery consistent with the result obtained in the D1-receptor binding assay. Epinine was about 5 times more potent than DA and only 3 times less active than fenoldopam on DA1-receptors although the D1-receptor binding study did not reveal major differences from DA. An opposite profile was observed with N,N-di-n-propyl dopamine (DPDA) showing a functional potency lower than that expected from the binding assay. In cat right atrium, DA and related agonists caused concentration-dependent inhibition of the tachycardia induced by electrical stimulation. The DA effects proved to be mediated by presynaptic DA2-receptor activation, being inhibited by the selective DA2-receptor antagonist domperidone. The DA2-receptor agonist 6-(di-n-propylamino)-5,6,7,8-tetrahydro-1,2-naphthalenediol (DP-5,6-ADTN) was the most potent compound both in the cat atrium and in the binding assay. Epinine was 2 times more potent than DA on DA2-receptors but it showed no differences in the D2-receptor binding assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal Dopamine and Sodium Excretion

In the present study, we examined the renal effects of a low dose of fenoldopam in pentobarbital anesthetized rats in an attempt to unmask a direct tubular DA-1 receptor mediated diuresis and natriuresis. We also performed experiments to determine the possible contribution of renal dopamine (DA) and DA receptors in the natriuretic response to acute sodium loading. Fenoldopam (0.5 microgram/kg/min) produced significant increases in urine output (UV) and urinary sodium excretion (UNaV) without altering mean blood pressure (MBP), renal blood flow (RBF) or heart rate (HR), suggesting a direct tubular site of action. This renal response to fenoldopam was completely abolished in the presence of the selective DA-1 receptor antagonist, SCH 23390. Isotonic NaCl loading (5% body weight for 1 h) enhanced urinary DA excretion (UDA V) which correlated significantly with the increase in UNa V. Pretreatment with selective DA-1 receptor antagonist SCH 23390 resulted in significant attenuation of the increase in UNa V whereas the increase in UDA V was unaltered. Pretreatment with selective DA-2 receptor antagonist domperidone did not alter the increase in UNa V during isotonic NaCl loading. These results suggest that renal tubules are endowed with DA-1 receptors activation which results in diuresis and natriuresis. Furthermore, activation of these DA-1 receptors but not DA-2 receptors by endogenous DA contributes to the natriuretic response to isotonic saline loading.

Prejunctional adrenoceptor activity of N-0437: a relatively selective DA 2 dopamine receptor agonist

Prejunctional adrenoceptor activity of N-0437, 2[N-n-propyl-N-2-(thienylethyl-amino)-5-hydroxytetralin], was investigated by means of the cat nictitating membrane (CNM) preparation. Intra-arterial (i.a.) administration of N-0437 produced a dose-related inhibition (ED50 = 14 micrograms) of the CNM contractions elicited by electrical stimulation of pre- and postganglionic sympathetic nerves of the superior cervical ganglion. Pretreatment with domperidone i.a., a relatively selective DA2 receptor antagonist, markedly attenuated the CNM response to racemic N-0437 (ED50 = 6.7 x 10(2) micrograms). However, pretreatment with rauwolscine i.a., a relatively selective alpha 2-receptor antagonist, did not alter the CNM responses to racemic N-0437. Evaluation of the (R)-(+) and (S)-(-) enantiomers showed that only the (S)-(-) enantiomer was active in suppressing the contractions in the CNM preparation. These results demonstrate that N-0437 is a potent agonist for prejunctional DA2 dopamine receptors on peripheral sympathetic nerves in the CNM and that these peripheral DA2 receptors appear to be enantioselective.

Role of kidney dopamine in the natriuretic response to volume expansion in rats.

It has been postulated that endogenously produced dopamine (DA) may play a role in the regulation of renal sodium excretion. In the present study, experiments were designed to test the hypothesis that acute volume expansion with isotonic sodium chloride stimulates the production of DA within the kidney, which in turn acts on specific DA1 receptors to promote sodium excretion. In pentobarbital-anesthetized rats, acute volume expansion over a period of 1 hour evoked a pronounced increase in urine output and urinary sodium excretion. These diuretic and natriuretic effects were not accompanied by any significant changes in blood pressure or heart rate. However, there was a significant elevation in central venous pressure and a transient rise in glomerular filtration rate. The natriuretic and diuretic response was accompanied by a significant increase in urinary DA excretion, and this effect was clearly dissociated from the rise in glomerular filtration rate. In a separate group of rats, the effects of acute volume expansion were studied in the presence of selective DA1 receptor antagonist SCH-23390 (50 micrograms/kg i.v. bolus; 10 micrograms/kg/min). During DA1 receptor blockade, there was a marked attenuation in the diuretic and natriuretic response throughout the period of volume expansion, when compared with that in the control group. The changes in central venous pressure and glomerular filtration rate were identical in the two groups. In another group of rats, the renal effects of exogenously administered DA were studied. DA (0.5 micrograms/kg/min) produced significant increases in urine output and urinary sodium excretion, without causing any alterations in blood pressure or glomerular filtration rate, suggesting a tubular site of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurogenic vasodilatation produced by fenoldopam in the rat hindquarters vascular bed

1 The effects of local administration of the selective DA1-receptor agonist fenoldopam into the isolated autoperfused rat hindquarters were studied in order to investigate the site of action of fenoldopam in this vascular bed. 2 Bolus injections of fenoldopam produced reductions in perfusion pressure in the preconstricted, constant flow perfused rat hindquarters vascular bed. 3 The vasodilator effect of fenoldopam was abolished by sectioning of the lumbar sympathetic nerves and by pretreatment with the ganglion-blocker hexamethonium or the alpha-adrenoreceptor antagonists phentolamine and prazosin. At the same concentration, local infusion of fenoldopam had no effect on vasoconstrictor responses to locally administered noradrenaline and phenylephrine. 4 The vasodilator effect of fenoldopam was antagonized by the non-selective dopamine receptor antagonist RS-sulpiride and by the selective DA1-receptor antagonist SCH 23390, but not by the selective DA2-receptor antagonist domperidone. 5 These results provide no evidence for the presence of postsynaptic DA1-receptors in the rat hindquarters vascular bed; they show that fenoldopam induces neurogenic vasodilatation in this vascular bed, probably via stimulation of ganglionic DA1-receptors.

Influence of the dopamine receptor agonists fenoldopam and quinpirole in the rat superior mesenteric vascular bed.

The effect of local administration of the dopamine 2 (DA2)-receptor agonist quinpirole and of the DA1-receptor agonist fenoldopam was studied in the in situ, constant flow autoperfused, superior mesenteric vascular bed of the rat. Local infusion of quinpirole (30 micrograms kg-1 min-1 for 5 min) had no effect on baseline perfusion pressure; it reduced the pressor responses to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial sympathetic nerves to 45.6 +/- 2.1% of its original value but did not modify similar pressor responses produced by locally administered noradrenaline. The inhibitory effect of quinpirole was antagonized by the selective DA2-receptor antagonist domperidone (10 micrograms kg-1) but not by the selective DA1-receptor antagonist SCH 23390 (50 micrograms kg-1). Local infusion of fenoldopam (30 micrograms kg-1 min-1 for 5 min) reduced baseline perfusion pressure to 89.9 +/- 1.9%, increased the pressor response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial nerves to 134.7 +/- 14.0%, but reduced the pressor response to locally administered noradrenaline to 37.2 +/- 8.2%. Similar pressor responses induced by the selective alpha 1-adrenoceptor agonist phenylephrine were also reduced by fenoldopam (to 38.4 +/- 6.4%), but responses to locally administered angiotensin II were not modified. Pretreatment with SCH 23390 (50 micrograms kg-1) antagonized the effect of fenoldopam on baseline perfusion pressure, but had no influence on the effect of fenoldopam on responses to electrical stimulation or to noradrenaline. Pretreatment with the selective alpha 2-adrenoceptor antagonist rauwolscine (100 micrograms kg-1) had no effect on the reduction in baseline perfusion pressure induced by fenoldopam nor on its inhibitory effect on the response to noradrenaline, but it antagonized the stimulatory effect of fenoldopam on the response to electrical stimulation. 7 The results show that quinpirole inhibits neurogenic vasoconstriction in the rat superior mesenteric vascular bed through stimulation of presynaptic DA2-receptors while fenoldopam stimulates postsynaptic vasodilatory DA,-receptors. In addition, our results suggest that the inhibitory effect of fenoldopam on the vasoconstrictor response to noradrenaline may be due to an antagonistic action at postsynaptic alpha-adrenoceptors, while its potentiating effect on neurogenic vasoconstriction is due to blockade of presynaptic alpha 2-adrenoceptors.