Increase in plasma renin activity evoked by fenoldopam in dogs is directly mediated by dopamine1 receptor stimulation

In anesthetized dogs, a 15-min intravenous (i.v.) infusion of fenoldopam (2.0 micrograms/kg/min) produced a decrease in mean aortic blood pressure (MAP) and an increase in renal blood flow (RBF) and plasma renin activity (PRA). The hypotensive effect attained a maximum within 5 min and then waned by approximately 30% at the end of fenoldopam administration. The development of this "tolerance" phenomenon was prevented by enalapril or saralasin. The hypotension and the increase in PRA were not modified by either propranolol or chlorisondamine but were inhibited by SCH 23390, a DA1 antagonist. Fenoldopam (0.1 microgram/kg/min for 15 min) infused into the left renal artery (i.a.) in intact or ganglion-blocked dogs did not change MAP but increased PRA. This effect was antagonized by SCH 23390. In ganglion-blocked preparations in which an apparently maximal renal vasodilatation had been achieved by an i.a. acetylcholine, i.a. fenoldopam produced an increase in PRA which was again blocked by SCH 23390. In uninephrectomized dogs, blockade of alpha- and beta-adrenoceptors or inhibition of renal baroreceptor and macula densa mechanisms of renin release failed to prevent the fenoldopam-induced increase in PRA. In conclusion, the release of renin by fenoldopam is responsible for the development of tolerance to the hypotensive effects of fenoldopam. Furthermore, because the increase in PRA was blocked by SCH 23390 and occurred in the absence of either operational systemic or intrarenal regulatory mechanisms, we propose that it is mediated by stimulation of specific dopamine (DA1) receptors on the juxtaglomerular (JG) cells.     

Studies on the mechanisms of the development of tolerance to the hypotensive effects of fenoldopam in rats

In pentobarbital-anesthetized rats prepared for hemodynamic measurements with Doppler flow probes, intravenous (i.v.) infusions of fenoldopam (2.5 - 160.0 micrograms/kg/min during 15 min) decreased mean carotid artery blood pressure, total peripheral, hindquarter, renal, and mesenteric vascular resistances and increased renal blood flow strongly. The hypotensive effects attained a maximum within the first 3 min of infusion but waned by greater than 30% at the end of fenoldopam administration. This tolerance was observed for calculated total peripheral and hindquarter vascular resistances and to a lesser extent for mesenteric resistance. However, it was absent on the renal vascular bed. Pretreatment with either enalapril, pepstatine, or bilateral nephrectomy significantly increased the hypotensive response to fenoldopam and attenuated the development of tolerance. In conscious spontaneously hypertensive rats (SHR), enalapril potentiated strongly the small blood pressure-lowering activity of fenoldopam. The fall in blood pressure produced by fenoldopam was specifically blocked by SCH 23390, an antagonist of DA-1 dopamine receptors. In normotensive vasopressin-supported pithed rats given phenoxybenzamine plus propranolol, fenoldopam, like SCH 23390, blocked the vasodepressor effects of i.v. bolus injection of dopamine and fenoldopam. In pithed rats, fenoldopam evoked a pressor response that was significantly reduced by enalapril, SCH 23390, or bilateral nephrectomy. In conclusion, fenoldopam exerts DA-1 agonist and antagonist effects. The latter property, together with the activation of the renin-angiotensin system, appears to be responsible for the development of tolerance to the fenoldopam evoked-hypotension. The lack of a tolerance at the level of the renal vascular bed is possibly due to the existence of a large population of DA-1 receptors in this region.     

DA-1 RECEPTORS MEDIATE RENAL EFFECTS OF THE DOPAMINE PRODRUG, GLUDOPA, IN CONSCIOUS RABBITS

1. Eight male rabbits were implanted with Doppler flow probes around the lower abdominal aorta and left renal artery. A 2 week recovery period was allowed prior to the experiment. 2. Normal saline, gludopa at 25 micrograms/kg per min and at 100 micrograms/kg per min were each infused i.v. for 60 min. One week later the same protocol was administered to four of these animals in addition to DA-1 antagonist SCH 23390 (0.3 mg/kg i.v.) before gludopa infusion. 3. Gludopa elicited significant increases in urine flow, urinary sodium excretion and renal blood flow, and decreased renal vascular resistance. These changes were abolished by the DA-1 antagonist. Blood pressure, heart rate and hindlimb blood flow remained unchanged. 4. Urine dopamine excretion was increased 1200-fold and 7800-fold after gludopa administration at 25 micrograms/kg per min and 100 micrograms/kg per min, respectively, while plasma dopamine concentration and plasma renin activity (PRA) were not significantly altered. However, PRA was elevated by gludopa with DA-1 antagonism. 5. The renal vasodilation, natriuresis and diuresis produced by gludopa in conscious rabbits appears to be mediated by locally generated dopamine via DA-1 receptors.     

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.     

The pharmacology of pramipexole in the spontaneously hypertensive rat.

Pramipexole (SND-919) administration to spontaneously hypertensive rats resulted in a biphasic response with lower doses (1-30 micrograms/kg) causing a hypotensive response and higher doses (100-1000 micrograms/kg) increasing blood pressure. S-Sulpiride (1 mg/kg i.v.) and domperidone (100 micrograms/kg i.v.) but not SCH 23390(1 microgram/kg per min i.a.), prazosin (0.1 mg/kg i.v.) or rauwolscine (1 mg/kg i.v.) blocked the depressor effect, whereas rauwolscine but not S-sulpiride, SCH 23390 or prazosin blocked the pressor effects. The data indicate that pramipexole stimulates presynaptic DA2 receptors at low doses and postsynaptic alpha 2-receptors at high doses.     

Stimulation of dopamine D-2 but not D-1 receptors reduces immobility time of rats in the forced swimming test: implication for antidepressant activity

The involvement of dopamine D-1 and D-2 receptor mechanisms was investigated in the forced swimming test with rats. d,1-Sulpiride, a D-2 receptor antagonist, reported to reduce desipramine-induced anti-immobility, did not alter the brain levels of desipramine. In addition, the anti-immobility effect of desipramine was not antagonized by SCH 23390, a D-1 receptor antagonist. Amineptine (20 mg/kg i.p., 60 min before testing), a dopamine uptake blocker, and LY171555 (0.2 mg/kg i.p., 60 min before testing), a dopaminergic D-2 stimulant reduced immobility time in the forced swimming test, but benserazide + 1-DOPA (200 mg/kg p.o., 45 min before testing), which increases dopamine release, or SKF 38393A (20 mg/kg s.c., 60 min before testing), a D-1 agent, did not. The anti-immobility effect but not the stereotypy was increased following chronic (21 days) LY171555 (0.1 and 0.2 mg/kg i.p.) treatment. The effect of acute or repeated (7 days) LY171555 (0.2 mg/kg i.p.) treatment was antagonized by 1-sulpiride (50 mg/kg i.p., 90 min before testing), a D-2 receptor antagonist. Neither SKF 38393A (20 mg/kg s.c., 60 min before testing) nor SCH 23390 (0.05 mg/kg s.c., 30 min before testing) modified the acute anti-immobility effect of LY171555 (0.2 mg/kg i.p.) SCH 23390 (0.025 and 0.05 mg/kg) increased the immobility time at doses which decreased motor activity. The increase in immobility time brought about by SCH 23390 was not antagonized by SKF 38393A (20 mg/kg). The findings indicate that activation of dopamine D-2 receptors could reduce immobility time.     

Dopamine receptors in the stellate ganglion of the dog

Effects of fenoldopam, a selective DA1 dopamine receptor agonist, and dipropyl dopamine and propylphenethyl dopamine, preferential DA2 dopamine receptor agonists, on ganglion transmission were studied in pentobarbital-anesthetized, open-chest dogs. Tachycardia induced by electrical stimulation (supramaximal voltage, 0.5 ms duration, 1-2 Hz) of the preganglionic cardio-accelerator nerves was monitored as a measure of ganglionic transmission. Drugs were injected into the costocervical artery (i.a.) close to the arterial supply of the ganglion. Doses required to produce 30-40% inhibition of ganglionic transmission by the i.a. route were 2-8 micrograms for dipropyl dopamine, 4-16 micrograms for propylphenethyl dopamine, and 100 micrograms for fenoldopam. At these doses none of the agonists affected tachycardia induced by electrical stimulation of the postganglionic nerve. Domperidone (5 micrograms/kg i.v.), a selective DA2 dopamine receptor antagonist, markedly antagonized the effects of dipropyl dopamine and propylphenethyl dopamine, but had only minor (and statistically insignificant) effects on the inhibitory effect of fenoldopam. SCH 23390 (5 micrograms/kg i.v.), a selective and potent DA1 antagonist, failed to modify the effects of any of the agonists. In a separate series, infusion of fenoldopam, 20 micrograms/kg per min i.v. for 5-7 min, facilitated postganglionic nerve stimulation and blocked the inhibitory effect of UK 14,304, an alpha 2-adrenoceptor agonist, on the postganglionic nerve. These results confirm and support the presence of DA2 but do not support the presence of the prototypal DA1 dopamine receptor in the mammalian ganglia. Furthermore, the alpha 2-adrenoceptor blocking property of fenoldopam points to the complication of using i.v. administration for studying its ganglionic actions while monitoring the target tissue effects in response to preganglionic nerve stimulation.     

Evidence of the involvement of D1 dopamine receptors in PCP-induced stereotypy and ataxia in rabbits

A behavioural study on the effects of D1 and D2 dopamine receptor antagonists (SCH 23390 and sulpiride respectively) and of an A1 adenosine receptor agonist (N6-L-phenylisopropyladenosine, L-PIA) against phencyclidine (PCP)-induced effects was assessed in adult male rabbits. SCH 23390 (0.003-0.01 mg/kg i.v.) and sulpiride (12.5 mg/kg i.v.) were able to significantly prevent PCP-induced stereotypy. Ataxia was reduced by SCH 23390 (0.003 mg/kg i.v.), while it was potentiated by sulpiride (12.5 mg/kg i.v.). Given alone at 12.5 mg/kg, sulpiride induced some EEG and behavioural effects in rabbits, while SCH 23390 (0.003 and 0.01 mg/kg) did not. L-PIA prevented both PCP-induced stereotypy and ataxia at the dose (0.1 mg/kg i.v.) devoid of behavioural or EEG effects by itself. Our results suggest that D1 dopamine receptors might play a more important role than D2 receptors in the expression of PCP-induced behaviour. They also propose that A1 adenosine receptors might be involved (e.g. via an influence on the dopamine release) in the behavioural effects of PCP.     

The benzazepine SCH 23390 increases plasma levels of cortisol in the conscious dog

Summary The effect of neuroleptics on the hypothalamopituitary-adrenal system has been early recognized, but never adequately related to antipsychotic or side effects produced by dopamine antagonists. We are now presenting results showing that the newly characterized dopamine D-1 receptor antagonist, SCH 23390 (0.1 mg/kg i.v.) as well as the mainly dopamine D-2 receptor antagonists, haloperidol (0.1 mg/kg i.v.) and chlorpromazine (1 mg/kg i.v.), produced an increase of cortisol levels (108, 144 and 226% respectively, 20 min after the injection) determined by radioimmunoassay in blood samples collected from superficial veins of the legs of conscious dogs. The 5-HT₂ receptor antagonist, cyproheptadine (0.2 mg/kg i.v.), did not modify the cortisol levels. These results suggest that cortisol increase is an effect common to neuroleptic compounds, independently of their relative antagonistic action at dopamine D-1 or D-2 receptors.     

SCH 23390--a selective dopamine D-1 receptor antagonist with putative 5-HT1 receptor agonistic activity

The selective dopamine D-1 receptor antagonist SCH 23390 has been tested in vitro in the rat fundus model and in vivo in the electrically stimulated flexor reflex model. In the fundus model, SCH 23390 showed a potent agonistic activity compared to that of different 5-HT receptor agonists. Pindolol, 1-propranolol and pirenperone showed no or only weak inhibition of the SCH 23390-induced contractions in the fundus strip whereas methysergide was a potent inhibitor. The 5-HT3 receptor antagonist ICS 205-930 did not induce an inhibitory effect. In the electrically stimulated flexor reflex model in pithed rats, SCH 23390 induced a marked increase of the reflex. This increase was slightly inhibited by a mixed dopamine (DA) D-1/D-2 antagonist cis(Z)-flupentixol and by a specific DA D-2 antagonist YM 09151-2. Different reference antagonists: bicuculline (GABAergic), propranolol (beta-adrenergic), scopolamine (muscarinic), yohimbine (alpha 2-adrenergic), prazosin (alpha 1-adrenergic) were all without an antagonist effect on the SCH 23390-induced increase of the flexor reflex. Ketanserin, a selective 5-HT2 receptor antagonist, showed a weak and short-lasting inhibition of the SCH 23390 effect in high doses, whereas ritanserin showed only 35% inhibition of the SCH 23390-induced flexor reflex at a dose of 1.3 mumol/kg i.v. The mixed 5-HT1/5-HT2 antagonists methiothepin and metergoline showed a marked inhibitory effect at 2.6 mumol/kg i.v. and 3.1 mumol/kg i.v., respectively (1.3 mg/kg i.v.). These findings suggest that SCH 23390 might possess 5-HT1 receptor agonist activity.     

Different dopamine receptor subtypes mediate the neurogenic vasodilation produced by fenoldopam and SK & F 85174 in the dog hindlimb

The present study was performed to examine the effects of the mixed DA-1/DA-2 receptor agonist. SK & F 85174, on hindlimb vascular resistance and identify the DA receptor subtypes involved in the neurogenic hindlimb vasodilation produced by this compound. Bilateral hindlimb perfusion at controlled flow rates was carried out in anesthetized dogs and one hindlimb was surgically denervated whereas the other limb was kept neurally intact. Intravenous administration of SK & F 85174 and fenoldopam, a DA-1 receptor agonist, produced decreases in mean blood pressure and in the perfusion pressure in the innervated limb. Perfusion pressure in the denervated limb was not altered by fenoldopam and was increased by SK & F 85174. The DA-2 receptor antagonist, S-sulpiride, inhibited the neurogenic vasodilation produced by SK & F 85174 but not that produced by fenoldopam. The DA-1 receptor antagonist, SCH 23390, did not alter the hindlimb vasodilatory effects of either SK & F 85174 or fenoldopam in these animals, but it antagonized the hypotensive responses to both of these agents. Intra-aortic administration of SK & F 85174 and fenoldopam also resulted in neurogenic hindlimb vasodilation with the maximum response to fenoldopam occurring significantly faster than SK & F 85174 (2.5 +/- 0.16 vs. 9.8 +/- 1.2 s). S-Sulpiride antagonized the hindlimb vasodilation produced by SK & F 85174 but not by fenoldopam. R-Sulpiride antagonized the hindlimb vasodilatory effect of fenoldopam.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of SK&F 85174, a DA-1/DA-2 receptor agonist, on pre- and postganglionic sympathetic neurotransmission to the heart

We have performed experiments to determine the effects of SK&F 85174, a mixed DA-1/DA-2 receptor agonist, on the tachycardia elicited during pre- and postganglionic stellate stimulation in anesthetized dogs in order to identify a possible action of this compound on the stellate ganglia. SK&F 85174 produced hypotension and caused significant impairment of positive chronotropic responses elicited during pre- and postganglionic stellate stimulation. Pharmacological analysis of SK&F 85174-induced inhibition of cardiac sympathetic function with selective DA-1 and DA-2 receptor antagonists revealed that prior treatment with either S-sulpiride or domperidone (DA-2 receptor antagonists) significantly attenuated the inhibitory effects of SK&F 85174 on responses to pre- and postganglionic stellate stimulation. R-sulpiride (DA-1 receptor antagonist) failed to antagonize SK&F 85174-induced inhibition of tachycardia elicited during preganglionic stellate stimulation. Pretreatment with SCH 23390 (DA-1 receptor antagonist) did not modify the inhibitory effect of SK&F 85174 on responses to postganglionic nerve stimulation. However, SCH 23390 was most effective in antagonizing the hypotensive effect of SK&F 85174. These results show that SK&F 85174 inhibits sympathetic neurotransmission to the heart by activating presynaptic and possibly ganglionic DA-2 receptors, whereas the hypotension produced by SK&F 85174 results predominantly from the activation of the vascular DA-1 receptors. SK&F 85174 does not seem to exert any effect on the ganglionic DA receptors which are reported to be activated by the selective DA-1 receptor agonist, fenoldopam.     

Differential involvement of dopamine receptors in conditioned suppression induced by cocaine

Cocaine-paired stimuli can suppress food-reinforced operant behavior in rats, providing an animal model of conditioned drug effects. To study the neuropharmacological basis of this phenomenon, we examined the effects of various dopamine receptor antagonists on the acquisition and expression of cocaine-induced conditioned suppression in rats. Superimposed on an ongoing baseline of food-reinforced operant responding, a stimulus was paired with response-independent cocaine (3.0 mg/kg, i.v.) during each of 8 training sessions. To study acquisition, independent groups of rats were given saline, the dopamine D(1)-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) (0.001-0.03 mg/kg, i.p.), or the dopamine D(2)-like receptor antagonist eticlopride (0.001-0.03 mg/kg, i.p.) prior to each training session. To study expression, independent groups of rats were trained first, then given saline, SCH 23390, eticlopride, or N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide (BP 897) (a dopamine D(3) partial receptor agonist; 0.1-1.0 mg/kg, i.p.) before test sessions in which the stimulus was presented without cocaine. Pre-treatment with either SCH 23390 or eticlopride during acquisition reduced the direct suppressant effects of cocaine, but conditioning was blocked only in rats that were treated with SCH 23390 during acquisition training. Expression of conditioning was attenuated only by eticlopride. Thus, dopamine at least partially mediates both the acquisition and expression of cocaine-induced conditioned suppression, with activation of dopamine D(1)- and D(2)-like receptors underlying these respective processes.     

The dopamine receptors mediating inhibition of the sympathetic vasopressor outflow in pithed rats: pharmacological correlation with the D(2) -like type

This study investigated in pithed rats whether dopamine can inhibit the sympathetic vasopressor outflow and analysed the pharmacological profile of the receptors involved. Male Wistar pithed rats were pre-treated with intravenous (i.v.) bolus injections of gallamine (25 mg/kg) and desipramine (50 μg/kg). The vasopressor responses to electrical stimulation of the sympathetic vasopressor outflow (0.03-3 Hz; 50 V and 2 msec.) were analysed before and during i.v. continuous infusions of the agonists dopamine (endogenous ligand), SKF-38393 (D(1) -like) or quinpirole (D(2) -like). If inhibition was produced by any agonist, then its capability to inhibit the vasopressor responses to i.v. bolus injections of exogenous noradrenaline (0.03-3 μg/kg) was also investigated. Dopamine (3-100 μg/kg min.) inhibited the vasopressor responses to both electrical stimulation and noradrenaline. In contrast, SKF-38393 (10-100 μg/kg min.) failed to inhibit the vasopressor responses to electrical stimulation; whereas quinpirole (0.1-30 μg/kg min.) inhibited the vasopressor responses to electrical stimulation but not those to noradrenaline. The sympatho-inhibition by quinpirole (1 μg/kg min.) remained unaltered after i.v. SCH 23390 (300 and 1000 μg/kg; D(1) -like receptor antagonist), but was abolished after i.v. raclopride (1000 μg/kg; D(2) -like receptor antagonist). These doses of antagonists did not modify per se the sympathetically-induced vasopressor responses. In conclusion, quinpirole-induced inhibition of the sympathetic vasopressor outflow is primarily mediated by activation of dopamine D(2) -like receptors.     

Dopaminergic Involvement in Improving Effects of Dynorphin A-(1-13) on Galanin-Induced Impairment of Passive Avoidance Learning in Mice

The present study was designed to clarify whether dopaminergic systems are involved in the effects of dynorphin A-(1-13), an endogenous κ-opioid receptor agonist, on the galanin-induced impairment of passive avoidance learning in mice. Galanin (0·3 μg, i.c.v.) shortened step-down latency of passive avoidance learning, while the dopamine D₁ receptor agonist SKF 38393 (3 and 10 mg/kg, s.c.), the dopamine D₂ receptor agonist RU 24213 (0·3 and 1 mg/kg, s.c.), the dopamine D₁ receptor antagonist SCH 23390 (0·01 and 0·03 mg/kg, i.p.) or the dopamine D₂ receptor antagonist S(−)-sulpiride (10 and 30 mg/kg, i.p.) failed to influence it. Dynorphin A-(1-13) (3 μg, i.c.v.) and SKF 38393 (10 mg/kg, s.c.) markedly improved the galanin (0·3 μg, i.c.v.)-induced shortening of step-down latency. However, RU 24213 (0·3 and 1 mg/kg, s.c.), SCH 23390 (0·01 and 0·03 mg/kg, i.p.) or S(−)-sulpiride (10 and 30 mg/kg, i.p.) did not affect the galanin (0·3 μg, i.c.v.)-induced shortening of step-down latency. In contrast, SCH 23390 (0·3 mg/kg, i.p.) significantly reversed the improving effects of dynorphin A-(1-13) (3 μg, i.c.v.) on the galanin (0·3 μg, i.c.v.)-induced dysfunction of passive avoidance learning, although SKF 38393 (1 and 3 mg/kg, s.c.), RU 24213 (0·3 and 1 mg/kg, s.c.) or S(−)-sulpiride (10 and 30 mg/kg, i.p.) did not influence the effects of dynorphin A-(1-13) (3 μg, i.c.v.). These results suggest that dynorphin A-(1-13) improves the galanin-induced amnesia resulting from indirect stimulation of dopamine D₁ receptors. © 1997 John Wiley & Sons, Ltd.     

Effects of SCH 23390 on thyrotropin-releasing hormone-induced behaviour in rabbits

The influence of the dopamine D-1 receptor antagonist, SCH 23390, on thyrotropin-releasing hormone (TRH)-induced behaviour was assessed in adult male rabbits. SCH 23390 prevented the effects of TRH (100 micrograms i.c.v.), starting at a very low dose (0.01 mg/kg i.v.). This finding seems to indicate that dopamine D-1 receptors are involved in TRH-induced behaviour.     

SCH 23390 antagonizes apomorphine- and ergot-induced hypothermia

The reportedly specific D-1 dopamine (DA) receptor antagonist SCH 23390 significantly reduced the hypothermia elicited by various DA receptor agonists like apomorphine, pergolide and lisuride. When tested against equihypothermic doses of each agonist, SCH 23390 significantly reduced the hypothermia elicited by apomorphine (0.2 mg/kg s.c.) and by pergolide (0.1 mg/kg i.p.) at doses of 0.025 mg/kg s.c. Doses of 0.050 mg/kg s.c. of SCH 23390 were necessary to reduce the hypothermia elicited by 0.012 mg/kg s.c. of lisuride. Pretreatment with the specific D-2 antagonist (-)sulpiride (50 mg/kg i.p.) completely prevented the hypothermia elicited by lisuride (0.012 mg/kg i.p.), pergolide (0.1 mg/kg i.p.) and apomorphine (0.2 mg/kg s.c.) and shifted to the right the dose-response curve for agonist-induced hypothermia. A study of the interaction between 0.05 mg/kg s.c. of SCH 23390 with various doses of the agonists showed that the effectiveness of SCH 23390 in antagonizing the hypothermia was maximal towards apomorphine and least towards lisuride for which significant antagonism was observed only against the lowest dose tested (0.012 mg/kg s.c.). The reportedly specific D-1 receptor agonist SKF 38393 given in doses up to 20 mg/kg i.p. or intracerebroventricularly up to 100 micrograms failed to influence body temperature while it evoked intense grooming and stimulated motility.     

Blood pressure effects of intravenous apomorphine in conscious deoxycorticosterone-acetate salt-hypertensive rats

SUMMARY: The present study reports the effects of apomorphine (APO) on blood pressure and the principal site of action of this agonist in 4-week deoxycorticosterone-acetate (DOCA)-hypertensive conscious rats. In these preprations, intravenous (i.v.) administration of APO (0.50-1 mg/kg) induced short-lasting and dose-dependent decreases in mean arterial pressure. The hypotensive response to APO (0.3 mg/kg) was reversed into a significant pressor effect by i.v. hexamethonium (30 mg/kg), whereas it was enhanced by i.v. pretreatment with the vasopressor antagonist of arginine vasopressin (AVP) d(CH2)5Tyr(Me)AVP (10 microg/kg) and/or prazosin (1 mg/kg). This depressor effect was suppressed by the central and peripheral dopamine D2 receptor antagonist metoclopramide (5 mg/kg i.v.), unaffected by the selective dopamine D1 receptor antagonist SCH 23390 (0.2 mg/kg i.v.), partly reduced by intrathecal domperidone (40 microg per rat at T9-T10 level), a dopamine D2 receptor antagonist which does not cross the blood-brain barrier, and reversed into a significant pressor effect by i.v. domperidone (0.5 mg/kg). The latter pressor effect was fully abolished by combined i.v. pretreatment with the vasopressor antagonist of AVP and prazosin. These results show that, in conscious DOCA salt-hypertensive rats, APO induced a brief, initial depressor effect, which is opposed to a central pressor component. The depressor component is related to an inhibition of norepinephrine transmission through activation of dopamine D2 receptors, some of which are located in the spinal cord and some of which are located in the peripheral circulation. The central pressor component, which became manifest after peripheral dopamine D2 receptor blockade, appears to be related to an increase in vasopressin release and sympathetic tone through activation of brain dopamine D2 receptors.     

Dopamine receptors mediate cocaine-induced temperature responses in spontaneously hypertensive and Wistar-Kyoto rats.

The involvement of dopaminergic receptors in the responses of conscious, restrained spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats to cocaine was examined using antagonists selective for DA-1 (SCH 23390) or DA-2 (sulpiride) dopamine receptors. Following pretreatment with saline vehicle, SCH 23390 (50 mg/kg, SC), sulpiride (50 mg/kg, IP) or SCH 23390 and sulpiride, cocaine was infused (1.25 mg/kg.min, IV) until death. Cocaine caused an initial pressor and tachycardiac response, which was followed by a progressively developing secondary pressor response. Combined (DA-1 and DA-2) antagonist pretreatment abolished the initial tachycardic response to cocaine. Rectal temperature during cocaine infusion increased in 38.5% of vehicle-treated SHR (designated SHRH), but decreased in the remaining SHR (SHRL) and all vehicle-treated WKY. The time-to-onset of cocaine-induced convulsions (Tc) was reduced in vehicle-treated SHRH compared to vehicle-treated SHRL and WKY. Sulpiride elevated rectal temperature in response to cocaine in SHR and WKY but reduced Tc only in SHR. SCH 23390 abolished hyperthermic responses to cocaine in SHR without altering toxicity in SHR or WKY. Combined pretreatment virtually abolished temperature responses to cocaine in SHR and WKY, but increased the Tc only in WKY. Dopamine receptors, particularly the DA-1 subtype, are involved in cocaine-induced hyperthermia.     

Characterization of a rat liver glucuronosyltransferase that glucuronidates the selective D1 antagonist, SCH 23390, and other benzazepines.

SCH 23390 is a novel benzazepine that selectively blocks dopamine receptors of the D1 subtype. Glucuronidation of this selective D1 antagonist was studied in vitro using rat liver microsomes. Methods to separate SCH 23390 glucuronide from SCH 23390 were developed which utilized either HPLC techniques or solvent extraction of SCH 23390 with 3-heptanone. Formation of a SCH 23390 glucuronide was confirmed upon incubation of SCH 23390 and UDPGA with naive rat liver microsomes. Liver enzyme activity for SCH 23390 glucuronidation was also enhanced after addition of the detergents, Lubrol or Triton X-100, to the naive liver microsomes. Kinetic analyses indicated an apparent Vmax and Km for UDPGA as 120.9 pmol/mg protein/min and 0.63 mM, and an apparent Vmax and Km for SCH 23390 as 282.4 pmol/mg protein/min and 0.41 microM. Further characterization of the liver enzyme responsible for the glucuronidation of SCH 23390 revealed a stereoselective substrate preference similar to that seen with the D1 dopamine receptor. Substrate inhibition studies indicated that SCH 23390, haloperidol, apomorphine, and alpha-naphthol demonstrated the highest affinity for the glucuronosyltransferase enzyme. However, (-)-sulpiride, raclopride, and endogenous substrates such as dopamine, serotonin, epinephrine, and norepinephrine demonstrated low affinity for the liver enzyme. These studies describe a rat liver glucuronosyltransferase with a unique substrate specificity toward selected dopaminergic agents. Finally, induction profiles revealed that neither phenobarbital (100 mg/kg, ip, for 3 days), beta-naphthoflavone (100 mg/kg, ip, for 4 days), nor 3-methylcholanthrene (80 mg/kg, ip, for 4 days) enhanced liver glucuronosyltransferase activity for SCH 23390 glucuronidation.