Comparison of the vasodilator action of dopamine and dopamine agonists in the renal and coronary beds of the dog.

1 The effects of dopamine and the dopamine receptor agonists, SK&F 38393 and bromocriptine, on renal and coronary blood flow in the anaesthetized dog were examined. Dopamine was found to dilate both vascular beds, whereas SK&F 38393 increased renal blood flow but did not have any dilator activity in the coronary vasculature. Bromocriptine did not cause vasodilatation in either vascular bed. 2 The vasodilator responses to dopamine and SK&F 38393 were significantly reduced by the dopamine receptor antagonists, ergometrine or metoclopramide. 3 It is proposed that the selective action of SK&F 38393 on the renal vasculature suggests that the dopamine receptors of the renal and coronary vascular beds may be of different types.     

Renal hemodynamics in hemorrhagic hypotension: studies on the effects of pre- and postjunctional dopamine receptor agonists

The present study was conducted to determine if selective prejunctional dopamine receptor agonists will be useful in improving renal hemodynamics in acute hemorrhagic shock in anesthetized mongrel dogs. Both bromocriptine and N-n-propyl-N-n-butyl dopamine (PBDA) effectively increased renal blood flow, due to a decrease in renal vascular resistance in intact anesthetized dogs. However, these two agents failed to increase renal blood flow after acute hemorrhage in the innervated or denervated kidneys. Dopamine was effective in increasing renal blood flow in both intact and hemorrhaged animals. However, this action of dopamine in hemorrhaged animals was associated with a significant increase in arterial blood pressure. These data could be explained based on the observations that the reduction in renal blood flow following hemorrhage was primarily due to a decrease in blood pressure as a result of the decrease in cardiac output and was not due to an increase in renal vascular resistance. Because elevation of sympathetic tone appeared to play little role, prejunctional inhibition by bromocriptine and/or PBDA of sympathetic nerve function was ineffective in altering renal vascular resistance. Dopamine was effective in increasing renal blood flow, not because of its pre- or postjunctional actions on dopamine receptors on renal nerves or vasculature, but because of its ability to increase cardiac output and arterial pressure. Based on the experimental model employed in these studies, it is concluded that agents such as PBDA and bromocriptine, which are considered to be selective prejunctional dopamine agonists, may not be clinically useful in improving renal circulation during hemorrhagic shock.     

Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function

The striatum contains a high density of histamine H(3) receptors, but their role in striatal function is poorly understood. Previous studies have demonstrated antagonistic interactions between striatal H(3) and dopamine D(1) receptors at the biochemical level, while contradictory results have been reported about interactions between striatal H(3) and dopamine D(2) receptors. In this study, by using reserpinized mice, we demonstrate the existence of behaviorally significant antagonistic postsynaptic interactions between H(3) and D(1) and also between H(3) and dopamine D(2) receptors. The selective H(3) receptor agonist imetit inhibited, while the H(3) receptor antagonist thioperamide potentiated locomotor activation induced by either the D(1) receptor agonist SKF 38393 or the D(2) receptor agonist quinpirole. High scores of locomotor activity were obtained with H(3) receptor blockade plus D(1) and D(2) receptor co-activation, i.e., when thioperamide was co-administered with both SKF 38393 and quinpirole. Radioligand binding experiments in striatal membrane preparations showed the existence of a strong and selective H(3)-D(2) receptor interaction at the membrane level. In agonist/antagonist competition experiments, stimulation of H(3) receptors with several H(3) receptor agonists significantly decreased the affinity of D(2) receptors for the agonist. This kind of intramembrane receptor-receptor interactions are a common biochemical property of receptor heteromers. In fact, by using Bioluminescence Resonance Energy Transfer techniques in co-transfected HEK-293 cells, H(3) (but not H(4)) receptors were found to form heteromers with D(2) receptors. This study demonstrates an important role of postsynaptic H(3) receptors in the modulation of dopaminergic transmission by means of a negative modulation of D(2) receptor function.     

Dopamine preferentially stimulates postsynaptic alpha 2-adrenoceptors in the femoral vascular bed, but alpha 1-adrenoceptors in the renal vascular bed of the anaesthetised dog

The decrease in blood flow in response to dopamine (DA) injected intraarterially (i.a.) into the femoral or renal vascular beds was examined in the anaesthetised dog. DA or noradrenaline (NA) were 10 times more potent as vasoconstrictor agents in the femoral than in the renal vasculature. In the femoral bed, the DA induced vasoconstriction was completely resistant to antagonism by prazosin (30-300 micrograms/kg i.v.), but was dose-dependently blocked by the alpha 2-receptor antagonist idazoxan (30-300 micrograms/kg i.v.). In the renal bed the vasoconstrictor effects of DA were resistant to blockade by idazoxan, but were prazosin sensitive indicating that alpha 1-adrenoceptors were involved in this response. The alpha-receptor agonist profile for DA was not modified in the femoral bed after blockade of dilatory D1-receptors with SCH 23390 (0.5 mg/kg i.v. and 0.1 mg/kg per h i.v.). However, this antagonist significantly increased the vasoconstrictor potency for DA in the renal bed. The decrease in femoral blood flow induced by an injection of DA, appears to be mediated by alpha 2-adrenoceptors. In the renal vascular bed where the predominant alpha-adrenoceptor corresponds to the alpha 1-subtype and there are few postsynaptic alpha 2-receptors subserving vasoconstriction, DA can stimulate alpha 1-receptors but this action requires higher doses of agonist than those needed for alpha 2-adrenoceptor stimulation.     

The action of a dopamine (DA1) receptor agonist, fenoldopam in human vasculature in vivo and in vitro.

This study was designed to investigate dopaminergic mechanisms in human vasculature using the selective vascular dopamine receptor agonist fenoldopam in vivo and in vitro. In vivo, forearm blood flow was measured plethysmographically and in vitro isolated rings of human blood vessels from a variety of sites were used for tissue bath studies. Intra-arterial fenoldopam markedly increased forearm blood flow, this effect was antagonised by (R) sulpiride, a vascular dopamine (DA1) antagonist, but not by metoclopramide, a neuronal (DA2) antagonist, or by guanethidine, an adrenergic neurone blocking agent. In vitro, fenoldopam relaxed preconstricted human renal, mesenteric and lumbar arteries, but not saphenous vein in a concentration dependent manner. (RS) sulpiride and SCH 23390 competitively antagonised this effect. These studies demonstrate the presence of a vasodilatory vascular dopamine receptor in man both in vivo and in vitro.     

Identification and characterization of postsynaptic D1- and D2-dopamine receptors in the cardiovascular system

Measuring adenylate cyclase activity (AC) as a biochemical index of dopamine (DA) receptor function, we obtained evidence for the presence in rabbit vasculature of both D1 receptors associated with stimulation of AC and of D2 receptors coupled with AC in an inhibitory way. The cAMP generating system in rabbit mesenteric artery was stimulated by DA and several DA agonists, an effect antagonized by the D1-receptor blocker SCH 23390 and by other neuroleptic drugs. When activation of D1 sites was impeded by SCH 23390, DA, (-)apomorphine, and (-)NPA inhibited cAMP formation. In addition, selective D2 agonists inhibited basal AC activity even when there was no D1-receptor blockade. The relative order of potency of various neuroleptics in antagonizing bromocriptine-induced inhibition of AC confirmed the D2 nature of these binding sites. Inhibition of AC activity elicited by bromocriptine remained unchanged after chemical sympathectomy, suggesting that vascular D2 receptors inhibiting AC activity are located postsynaptically in the arterial wall.     

Renal and iliac vascular effects of dopamine in the anaesthetized rat

Summary The renal and iliac vascular effects of dopamine were compared in pentobarbital anaesthetized rats. Local vascular resistances were calculated from simultaneous measurement of blood pressure, renal and iliac blood flow. Without pretreatment, dopamine increased renal and iliac vascular resistance. After pretreatment with prazosin, dopamine decreased the renal vascular resistance while the iliac vascular resistance was still increased. After a combination of yohimbine and prazosin pretreatment, dopamine lowered both the renal and iliac vascular resistance by 30%. These responses were not modified by the beta-adrenoceptor antagonist, sotalol, or by pretreating the rats with reserpine. The renal but not the iliac vascular response to dopamine was abolished by (+)-butaclamol, a stereoselective dopamine receptor antagonist, and by SCH 23390, the DA₁-selective dopamine receptor antagonist. The decrease in iliac vascular resistance was not modified by indomethacin or the non-selective 5-HT receptor antagonist, metitepin. These results show that after blockade of alpha₁ and alpha₂-adrenoceptors, dopamine induces iliac vasodilation by a postsynaptic mechanism independent of an interaction with beta-adrenoceptors, dopamine or serotonin receptors. They also confirm in the rat in vivo the existence of renal vasodilation mediated by DA₁ dopamine receptors. Send offprint requests to: M. Schmidt at the above address     

Differential modulation of the D1-like- and D2-like dopamine receptor-induced locomotor responses by group II metabotropic glutamate receptors in the rat nucleus accumbens.

There is strong evidence for the existence of functional interactions between metabotropic glutamate receptors and dopamine transmission in the nucleus accumbens. In the present study, we investigated the interactions between group II mGlu receptors and D1-like- and D2-like receptors in the rat nucleus accumbens. Administration of the selective group II metabotropic glutamate receptor agonist APDC, which had no effect when injected alone, potentiated the locomotor response produced by the selective D1-like receptor agonist SKF 38393 but had no effect on those induced by the selective D2-like receptor agonist quinpirole (also known as LY 171555)--a compound believed to act only at D2-like presynaptic receptors when injected alone--or co-administration of SKF 38393+quinpirole--a pharmacological condition thought to stimulate both D1-like receptors and presynaptic and postsynaptic D2-like receptors. In contrast, the selective group II mGlu receptor antagonist LY 341495, which induced an increase in basal locomotor activity, showed no effect on the SKF 38393-induced locomotor response, but abolished that produced by quinpirole or SKF 38393+quinpirole. The present findings demonstrate that stimulation of group II mGlu receptors has a cooperative and potentiating action on the locomotor response induced by D1-like receptor activation, whereas blockade of group II mGlu receptors has an antagonist action on the locomotor responses induced by activation of D2-like receptors. Although these data are consistent from a pharmacological point of view, as the effects of the group II mGlu receptor antagonist LY 341495 were blocked by the group II mGlu receptor agonist APDC and conversely, the subtle neurochemical crosstalks underlying such a differential effect of group II mGlu receptors on D1-like- and D2-like DA receptors remain to be elucidated.     

Effects of stimulation of putative dopamine autoreceptors on electroencephalographic power spectrum in comparison with effects produced by blockade of postsynaptic dopamine receptors in rats

Alterations in cortical EEG activity in male rats produced by putative agonists at dopamine (DA) autoreceptors and by antagonists at postsynaptic DA receptors were compared in order to study, whether an impairment in dopaminergic neurotransmission via two different mechanisms might result in similar or different effects. Simultaneously to the EEG recordings, gross behaviour was observed. Putative agonists at DA autoreceptors (apomorphine 0.05 mg/kg, quinpirole 0.05 mg/kg, or talipexole 0.02 mg/kg s.c.) produced increases in the power iin all of the frequency bands, except beta-2, with the most pronounced increase in the delta band. These EEG alterations were accompanied by hypokinesia, ptosis and yawning. In contrast, antagonists at DA receptors (haloperidol 0.1 mg/kg i.p., D₂ blocker) or SCH 23390 (0.2 mg/kg i.p., D₁ blocker) led to little increases in the delta band, but more pronounced increases in the alpha-2 band. Behavioural signs were hypokinesia, but little ptosis and yawning. The combination of both blockers produced, in addition, strong increases in the delta band and behavioural signs of ptosis and yawning. These results suggest that activation of putative dopamine autoreceptors produced EEG patterns and behavioural patterns different from those produced by blockade of either D₁ or D₂ postsynaptic dopamine receptors. In contrast, the effects following a stimulation of putative DA autoreceptors, which are expected to decrease the release of the agonist and its action at postsynaptic D₁ and D₂ receptors, were very similar to those found after a combined blockade of both types of postsynaptic dopamine receptors.     

Effects of chronic SCH 23390 treatment on dopamine autoreceptor function in rat brain

The effects of chronic treatment with SCH 23390 (0.5 mg/kg per day, 18 days), a selective (DA) D-1 receptor antagonist, on dopamine autoreceptor function in rats were investigated. The decrease of DA metabolism in mesolimbic and nigrostriatal systems and inhibition of spontaneous explorative locomotor activity by low doses of the selective D-2 receptor agonist, quinpirole, were used as behavioral and biochemical indices of DA autoreceptor function. The DA metabolism decreasing effect of quinpirole (20 and 50 micrograms/kg) in mesolimbic or nigrostriatal DA systems was similar in SCH 23390- and vehicle-treated rats. Two-way analysis of variance showed that rats treated chronically with SCH 23390 were significantly more active than vehicle-treated rats. However, there were no statistically significant differences in the quinpirole-induced hypomotility response between these groups. These results indicate that chronic D-1 blockade, unlike classical antipsychotic drugs, does not modulate the biochemical and behavioral indices of DA autoreceptor activation, suggesting a lack of interaction between DA autoreceptors and D-1 receptors in the central nervous system.     

Do renal tubular dopamine receptors mediate dopamine-induced diuresis in the anesthetized cat?

The aim of this study was to investigate whether the pentobarbitone anesthetized cat is a suitable preparation in which to characterize renal tubular dopamine receptors. Intravenous infusion of dopamine (10-100 micrograms/kg/min) resulted in a dose-related increase in mean blood pressure (MBP), urine output, sodium excretion (UNaV), and fractional sodium excretion (FENa). This diuretic effect occurred despite little change in glomerular filtration rate, suggesting that it is a consequence of decreased tubular reabsorption. Dopamine (10-100 micrograms/kg/min, i.v.) also induced marked dose-related falls in renal vascular conductance; however, renal blood flow was not significantly reduced. The increases in MBP, urine output, UNaV, and FENa induced by dopamine (10-100 micrograms/kg/min, i.v.), were unaffected by pretreatment of cats with either the selective dopamine DA1 or DA2 receptor antagonists, SCH 23390 (30 micrograms/kg, i.v.), or domperidone (100 micrograms/kg, i.v.) respectively. In contrast, pretreatment of cats with the nonselective alpha-adrenoceptor antagonist, phentolamine (1 mg/kg, i.v.) prevented dopamine-induced increases in urine output and MBP. Infusion of the selective dopamine DA1 receptor agonist fenoldopam (0.01-10 micrograms/kg/min) into the left renal artery failed to increase left renal vascular conductance, or left kidney urine output, UNaV, or FENa. In conclusion, this study provides no evidence for the involvement of renal tubular dopamine receptors in dopamine-induced diuresis in anesthetized cats. Rather, the diuretic effect appears to be linked to stimulation of alpha-adrenoceptors.     

Dopamine D-2 receptor agonist-induced behavioural depression: critical dependence upon postsynaptic dopamine D-1 function

Summary The dopamine (DA) D-2 receptor agonists quinpirole (threshold dose, 0.01 mg/kg IP), pergolide (0.025 mg/kg), B-HT 920 (0.003 mg/kg) and (–)-3-PPP (4 mg/kg) produced dose-dependent locomotor depression (immobility) in mice as assessed by a subjective scoring system, with the immobility being characterized by a frozen posture. The animals were still but had their eyes open. The immobility was accompanied by reductions in sniffing, rearing and grooming. The depression (and the associated reduction in the various behaviours) produced by quinpirole (0.1 mg/kg), pergolide (0.1 mg/kg) and B-HT 920 (0.1 mg/kg) was substantially (but not always completely) reversed by the selective D-1 receptor agonist SKF38393 (up to 12 mg/kg) and the non-selective D-1 receptor agonist CY208243 (up to 3 mg/kg). The immobility induced by (–)-3-PPP (16 mg/kg) was also reversed by CY208243 and SKF38393, but the reversal was due to an increase in grooming behaviour in mice challenged with the D-1 receptor agonists, whether or not the animals had also received (–)-3-PPP. There was no reversal of the depression of rearing or sniffing. In contrast, CY208243 and SKF38393 also antagonized the immobility induced by B-HT 920, but the reversal was accompanied by at least partial reversals of the depression of sniffing, rearing and grooming. The reversal of quinpirole-induced immobility by SKF38393 and CY208243 was antagonized by SCH23390 (0.1 mg/kg). The selective D-2 receptor antagonist raclopride (0.025 to 0.4 mg/kg) could not reverse quinpirole-induced immobility. High doses of either raclopride (0.4 mg/kg) or SCH23390 (> 0.1 mg/kg) significantly increased immobility. Although raclopride itself (0.2 mg/kg) produced a substantial increase in DOPAC and homovanillic acid (HVA) levels in the striatum, it did not antagonize the autoreceptor mediated effects of quinpirole (0.1 mg/kg) in reducing the striatal dihydroxyphenylacetic acid (DOPAC) to DA ratio. However, the same dose of raclopride was partly effective in reducing the effects of lower doses of quinpirole (0.01 and 0.03 mg/kg) on the striatal DOPAC to DA ratio. Raclopride (0.2 mg/kg) also partially but significantly reduced the locomotor stimulant effects of d-amphetamine in reserpinized mice. Biochemical analyses in the striata indicated that CY208243 slightly retarded DA turnover (as assessed by the DOPAC/DA ratio). SKF38393 itself also slightly reduced DA turnover. In automated activity cages, using mice depleted of DA with reserpine and a-methyltyrosine, all the D-2 receptor agonists tested, in combination with SKF38393, produced an increase in activity. It is concluded that the depression induced by D-2 receptor agonists is due substantially to a deprivation of DA at postsynaptic D-1 receptors and that, at the doses tested, the D-2 receptor agonists were able to exert measurable stimulation of the postsynaptic receptors. The ability of D-1 receptor agonists to reverse the D-2-mediated depression is due to the stimulation of the postsynaptic D-1 receptors with the injected D-1 receptor agonist (replacing the endogenous transmitter) and the stimulation of the postsynaptic D-2 receptors by the injected D-2 receptor agonist.     

Role of the renin-angiotensin system in the compensation of quinpirole-induced blood pressure decrease

The dopamine D(2)-like receptor agonist quinpirole has been reported to lower blood pressure. This effect appears to be mediated via activation of presynaptic D(2)-like receptors inhibiting the stimulated neural norepinephrine release. The aim of the present study was to investigate the role of renal nerves and the renin-angiotensin system (RAS) in the blood pressure lowering effect of quinpirole. Therefore, clearance experiments using different doses of quinpirole (0.3 to 100 microg/kg/min) were performed in thiopental-anesthetized rats with intact kidneys (INN) or 5 to 7 days after bilateral renal denervation (DNX). The functional involvement of the RAS in the blood pressure lowering effect of quinpirole was determined in rats pretreated with a subpressor dose of angiotensin II (10 microg/kg/min) or in rats pretreated with the angiotensin II (AT(1)) receptor antagonist losartan, in a subdepressor dose (10 microg/kg/min). Quinpirole dose-dependently decreased mean arterial blood pressure (MAP) by up to 29%. This blood pressure lowering effect of quinpirole was observed at lower doses in DNX rats when compared with INN animals (ED(50): 0.98 microg/kg/min in DNX vs. 6.02 microg/kg/min in INN animals). Quinpirole in a dose of 3 microg/kg/min, which did not affect MAP in vehicle treated INN rats, significantly reduced MAP in rats with losartan pretreatment. In DNX rats pretreated with angiotensin II the MAP-response to the infusion of 3 microg/kg/min quinpirole was clearly attenuated in comparison with untreated DNX animals. Our data show that stimulation of dopamine D(2)-like receptors dose-dependently decreased blood pressure, which was potentiated by both interruption of the renal innervation and AT(1) receptor blockade, while exogenous ANG II restored the enhancement of the blood pressure response to quinpirole. We conclude that the increased vasodilatory effect of quinpirole after renal denervation might depend on a decreased activity of the RAS.     

SCH 23390, a selective dopamine D1 antagonist, activates dopamine neurons but fails to prevent their inhibition by apomorphine

SCH 23390, a rather selective D1 receptor blocker, activates the firing rate of dopamine (DA) neurons in the substantia nigra (SN-DA neurons) in rats, similarly to haloperidol (a D1-D2 receptor antagonist) and sulpiride (a selective D2 receptor blocker). These neuroleptics produce no additional increase over the maximal activation produced by SCH 23390. Unlike haloperidol or sulpiride, SCH 23390 fails to prevent the inhibition by apomorphine of SN-DA neurons, a DA autoreceptor-mediated effect. It is suggested that the doses of SCH 23390 that stimulate DA neurons block D2 in addition to D1 receptors, or that D1 blockade results in the functional inactivation of a specific population of D2 receptors as well. The failure of SCH 23390 to block the apomorphine effect indicates that DA autoreceptors can be pharmacologically differentiated form postsynaptic DA receptors.     

Preclinical and clinical studies on the cardiovascular and renal effects of fenoldopam: A DA-1 receptor agonist

Recent research in the area of peripheral dopamine (DA) receptors has led to the identification of two distinct subtypes of DA receptors, activation of which results in marked changes in the cardiovascular and renal function consisting of hypotension, bradycardia, diuresis, and natriluresis. Peripheral DA receptors mediating these effects are subdivided into DA-1 and DA-2 subtypes. The development of selective DA-1 and DA-2 receptor agonists and antagonists has made it possible to furhter characterize DA receptors located at various sites within the cardiovascular system. It is now established that activation of DA-1 receptors located on blood vessel produces vasodilation, whereas stimulation of DA-2 receptors on postganglionic sympathetic nerves results in the inhibition of norepinephrine release. The renal effects of DA receptor agonists either involve activation of specific DA receptors at various sites in the kidney and/or result from renal hemodynamic changes produced by these compounds. The concept of developing selective DA receptor agonists as therapeutic agents in the treatment of cardiovascular disorders has been proposed by several investigators. Fenoldopam (SK&F 82526) represents one of these new orally active DA receptor agonists developed for potential use in the treatment of hypertension and ischemic renal disease. In animal experiments fenoldopam was shown to produce hypotension and increase renal blood flow. It produced natriuresis and diuresis, and these effects were due to the activation of DA-1 receptors. Recent clinical studies show that fenoldopam decreases blood pressure and renal vascular resistance and causes diuresis and natriuresis in hypertensive patients. The antihypertensive action of fenoldopam is mediated by a decrease in total peripheral resistance. There are increases in heart rate and plasma renin activity in hypertensive patients. Fenoldopam also improves left ventricular performance in patients suffering from congestive heart failure. These initial studies with fenoldopam show that peripheral DA-1 receptor stimulation may represent an effective approach in the treatment of cardiovascular diseases. Future research in this area should be aimed toward developing DA-1 receptor agonists that have longer duration of action and do not evoke renin release, while maintaining the beneficial effects on the kidney.     

Interaction of A2A adenosine and D2 dopamine receptors modulates corticostriatal glutamatergic transmission

Adenosine and dopamine (DA) strongly modulate the neuronal activity in the striatum by pre- and postsynaptic mechanisms. As several behavioral and molecular studies indicate a functional antagonism between A2A adenosine and D2 DA receptors, compounds that are able to block A2A receptors are of particular interest as antiparkinsonian agents. To study the interaction of A2A and D2 receptors in the striatum, we performed intracellular recordings with sharp microelectrodes and whole-cell patch clamp recordings from spiny neurons in rat corticostriatal slices. The amplitude of the evoked excitatory postsynaptic potentials (EPSPs), as well as the frequency and the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), were affected neither by the A2A receptor antagonists ST1535 and ZM241385, nor by the D2 receptor agonist quinpirole when applied in isolation. However, co-application of quinpirole and ST1535 or ZM241385 significantly reduced the EPSPs amplitude. This inhibitory effect was associated with an increased paired-pulse facilitation suggesting a presynaptic mechanism of action. Accordingly, whole-cell recordings showed that the concomitant activation of D2 receptors and the antagonism of A2A receptors decreased the frequency of sEPSCs without affecting their amplitude. These results suggest that A2A and D2 receptors converge in the control of corticostriatal glutamatergic transmission by exerting an opposite function.     

Differential induction of adenylyl cyclase supersensitivity by antiparkinson drugs acting as agonists at dopamine D1/D2/D3 receptors vs D2/D3 receptors only: parallel observations from co-transfected human and native cerebral receptors

Though there is evidence that sustained exposure of dopamine (DA) receptors to agonists can elicit a supersensitivity of adenylyl cyclase (AC), little is known about the pharmacological characteristics of this phenomenon, and possible interrelationships amongst DA receptor subtypes have not been examined. In cells co-transfected with D(1) plus D(2), or D(1) plus D(3), receptors, which are known to physically and functionally interact, long-term exposure to quinpirole, pramipexole and ropinirole (which possess negligible affinities for D(1) sites) elicited supersensitivity of D(1) receptor-activated AC. By contrast, D(2)/D(3) receptor agonists that also act as D(1) receptor agonists, bromocriptine, lisuride, cabergoline, apomorphine and DA itself, did not elicit supersensitivity. Interestingly, AC supersensitivity was also observed in the nucleus accumbens of mice pretreated with twice-daily pramipexole and quinpirole, whereas no change was seen either with lisuride or with the DA precursor, L-DOPA. Thus, AC supersensitivity is elicited by the sustained exposure of cloned human and native mouse populations of dopaminergic receptors, to D(2)/D(3) but not D(1)/D(2)/D(3) agonists. These observations may be related to the exacerbation of gambling in Parkinson's disease that is provoked by antiparkinson agents acting as selective D(2)/D(3) receptor agonists, notably pramipexole.     

Agonistic actions of DPI (2-(3,4-dihydroxyphenylimino)-imidazolidine) on alpha-adrenoceptors and dopamine receptors

Some of the pharmacological actions of 2-(3,4-dihydroxyphenylimino)-imidazolidine (DPI) were studied in vivo and vitro. DPI (1 nM-100 micro M) had a similar affinity but a lower intrinsic activity on alpha-adrenoceptors in rabbit aortic strips to noradrenaline (1 nM-10 micro M). DPI did not affect the uptake of [3H]noradrenaline in guinea-pig isolated atria. The effects of DPI on dopamine receptors were examined in the dog coronary and renal vasculature and in the rat isolated, perfused kidney. In the dog coronary vasculature DPI (0.005-10 micrograms, i.a.), like dopamine (5-50 micrograms, i.a.), caused an increase in coronary blood flow which was antagonized by the dopamine receptor antagonist, ergometrine. In the renal vasculature of both the rat and the dog, dopamine (5-50 micrograms, i.a.) caused vasodilatation but there was no evidence of an effect of DPI on dopamine receptors. It appears that DPI is a selective agonist for dopamine receptors in the coronary vasculature.     

A novel orally active dopamine (DA) prodrug TA-870. IV. Renal vasodilatory and negative chronotropic effects in anesthetized dogs: influence of DA1 and DA2 dopamine receptor selective antagonists.

We investigated the involvement of the activations of dopamine (DA) receptors DA1 and DA2 in the effects of a novel DA prodrug TA-870 in anesthetized dogs and compared the effects with those of DA. Intravenous (i.v.) administration of TA-870 in anesthetized dogs produced a dose-dependent increase in free DA in blood and caused a decrease in renal vascular resistance (RVR) and an increase in renal blood flow (RBF). It also produced a bradycardia at high doses. In phenoxybenzamine-treated anesthetized dogs, the renal vasodilatory action of intrarenally administered TA-870 was less than or equal to that of i.v. TA-870, whereas that of intrarenally administered DA was greater than that of i.v. DA. The renal vasodilatory effects of TA-870 and DA were almost completely inhibited by the DA1 selective antagonist SCH-23390 but were not affected by the DA2 selective antagonist domperidone. In bilaterally vagotomized dogs, both TA-870 and DA at high doses partially reduced the positive chronotropic responses to the right postganglionic cardioaccelerator nerve stimulation; this effect was abolished after treatment with domperidone. In isolated guinea pig right atria, unchanged TA-870 and deethoxycarbonyl metabolite of TA-870, the intermediate from TA-870 to DA, did not affect the spontaneous atrial rate even at high concentrations, whereas DA produced a concentration-dependent increase in the rate. In addition, neither compound showed antagonistic action to the positive chronotropic effect of DA, which was competitively inhibited by propranolol. We conclude that the renal vasodilatory effect of TA-870 results simply from the activation of DA1 receptors by DA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sulpiride antagonizes the biphasic locomotor effects of quinpirole in weanling rats

Low doses of dopamine (DA) agonists such as the D₂ receptor subfamily agonist quinpirole are thought to stimulate DA autoreceptors selectively, thereby inhibiting locomotor activity. High doses of quinpirole initially suppress and later activate locomotion during a single test session; the activation is presumably due to stimulation of postsynaptic receptors. The aim of this study was to investigate whether pretreatment with a selective DA D₂ receptor antagonist, sulpiride, could block the putative autoreceptor-mediated inhibition at a lower dose than was required to block the postsynaptically mediated activation. Male and female 30-day-old rats were injected SC with one of eight doses of sulpiride (0.313–40 mg/kg) or the vehicle. Sixty minutes later, rats were injected SC with 0.2 mg/kg quinpirole or the vehicle. Five minutes after the second injection, rats were placed in automated activity monitors which recorded locomotor behavior for 60 min at 5-min intervals. Quinpirole at this dose first suppressed and later increased locomotor activity. Sulpiride pretreatment dose-dependently reversed both the early inhibition and later activation of quinpirole-induced locomotion. However, sulpiride did not block the quinpirole-induced early suppression at a lower dose than was required to block the later activation. Thus, there was no evidence that the locomotor suppression elicited by quinpirole is mediated by a more sensitive subset of DA receptors.