SCH 23390 is a very potent and selective antagonist at vascular dopamine receptors

Hilditch, A.; Drew, G. M.; Naylor, R.J.

doi:10.1016/0014-2999(84)90471-0

Cited by 57 publications

(26 citation statements)

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“…The mechanism involved is two fold, involving stimulation of both vascular P2-adrenoceptors and DA,-receptors since P2-adrenoceptor block produced by ICI 118551 (Bilski et al, 1983) partially reduced the response leaving a renal vasodilatation sensitive to antagonism by the specific DA,-receptor antagonist, SCH 23390 (Hilditch et al, 1984). Dopexamine thus differs from dopamine, which is slightly more potent as a DA,-receptor agonist but does not display 02-adrenoceptor-mediated renal vasodilatation.…”

Section: Discussionmentioning

confidence: 99%

“…Following the establishment of control renal vasodilator responses, the effects of dopexamine and dopamine (i.a.) were re-examined after DA,-receptor blockade produced by SCH23390 (Hilditch et al, 1984) at a dose of l0#tgkg-' (i.v.). The doses of dopexamine and dopamine required to reduce RVR by 20% (referred to as ED20 doses) were calculated before and after DA,-receptor blockade.…”

Section: Methodsmentioning

confidence: 99%

“…Cardiac accelerans nerve stimulation in the cat DA2-receptor agonist responses were also detected as inhibition of sympathetically mediated tachycardia in the cat (Ilhan & Long, 1975;Hilditch et al, 1984). The cats (2.5-3.9 kg of either sex) were anaesthetized with chloralose (80mg kg-', i.v.)…”

Section: Methodsmentioning

confidence: 99%

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Dopexamine: a novel agonist at peripheral dopamine receptors and β₂‐adrenoceptors

Brown¹,

Dixon²,

Farmer³

et al. 1985

British J Pharmacology

204

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1 Dopexamine is an agonist at peripheral dopamine receptors and at P2-adrenoceptors.2 Dopexamine has approximately one-third the potency of dopamine in stimulating the vascular DA,-receptor in the dog, resulting in a fall in renal vascular resistance of 20% at 2.3 x 10-8 mol kg-' (i.a.). 3 Prejunctional DA2-receptors are also stimulated by dopexamine, resulting in a reduction of neurogenic vasoconstriction in the rabbit isolated ear artery (IC5o of 1.15 x 10-6 M) and of neurogenic tachycardia in the cat (ID5o of 5.4 x 10-8mol kg-', i.v.), with a potency six and four times less respectively than that of dopamine. 4 By contrast, dopexamine is approximately 60 times more potent than dopamine as an agonist at the P2-adrenoceptor of the guinea-pig isolated tracheal chain, with an EC50 of 1.5 x 10-6 M.5 Both dopexamine and dopamine are weak agonists at the guinea-pig atrial P,-adrenoceptor over the concentration range 10-7 to 10-4 M, but dopexamine has an intrinsic activity ofonly 0.16 relative to dopamine. 6 Dopexamine does not stimulate postjunctional a,-or M2-adrenoceptors in the canine isolated saphenous vein, whereas dopamine is an agonist, approximately 120 times less potent than noradrenaline. 7 Unlike dopamine and salbutamol, dopexamine does not cause arrhythmias in the guinea-pig isolated perfused heart at doses of up to 10 5mol, which is a thousand times the minimum cardiostimulant dose.8 The combination of agonist properties at peripheral dopamine receptors and at V2-adrenoceptors, with little or no activity at a-and P3-adrenoceptors gives dopexamine a novel pharmacological profile. This may confer advantages over dopamine in the treatment of acute heart failure.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Dopexamine: a novel agonist at peripheral dopamine receptors and β₂‐adrenoceptors

Brown¹,

Dixon²,

Farmer³

et al. 1985

British J Pharmacology

204

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“…we chose to infuse the SCH 23390 at a dose of 2.5 pg/kg.min-I. which was derived from studies previously reported (5,(17)(18)(19) and pilot studies from our lab. SCH 23390 is considered to be the gold standard for both pharmacologic blockade of DAI receptors and.…”

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confidence: 99%

Systemic and Pulmonary Vascular Effects of Selective Dopamine Receptor Blockade and Stimulation in Lambs

Polak

Drummond

1993

Pediatr Res

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ABSTRACT. Vascular dopamine (DAI) receptors may modulate circulatory hemodynamics in lambs. We evaluated resting dopaminergic tone in lambs by pharmacologically manipulating peripheral DAI receptors with i.v. SCH 23390, (a highly selective, competitive DAI receptor antagonist) and i.v. fenoldopam, (a highly selective DAI receptor agonist) in unanesthetized lambs, instrumented for circulatory studies, while measuring the systemic and pulmonary vascular changes that the manipulations induced. We examined both the independent effects of DAI receptor stimulation and blockade as well as the effects of the agonist and the antagonist infused together (competitive interaction). SCH 23390, infused at 2.5 pg/kg.min-I, caused significant increases in left atrial, systemic, and pulmonary artery pressure, as well as an increase in systemic vascular resistance and a decrease in heart rate. Fenoldopam, infused at the dose of 60 pg/kg. min-' caused significant decreases in mean systemic artery pressure and systemic vascular resistance while increasing cardiac index and mean pulmonary artery pressure. SCH 23390 blunted the fenoldopam-induced effects. Our data suggest that dopaminergic influence may be active in the maintenance of resting hemodynamics of the lamb. (Pediatr Res 33: 181-184, 1993) Abbreviations models (6), which does not address the role of dopaminergic function under normal physiologic states.Dopamine concentrations in amniotic fluid and in plasma of fetuses are higher than plasma levels in adults (7. 8). These data provide some indirect evidence that endogenous dopamine is important in the fetus and newborn. Studies investigating dopamine receptor density and affinity in the fetal and newborn kidney. as well as studies examining the physiologic responses to dopaminergic stimulation in fetal and newborn animals. have not provided a concise answer, though they also point to a role of dopamine as a factor in fetal development (9-1 1). Most of this research has focused on renal tubular effects of dopamine. though vasodilating dopamine receptors are also present in mesenteric, coronary, and pulmonary vascular beds (6, 12, 13) of adult animals. Weir (14) has postulated that in the pulmonary circulation, the normal. low vascular tone is the active phase of the vascular response. If the factors causing the vasodilation are removed, vasoconstriction results (14). It is possible that active vasodilation also occurs in the systemic circulation where. as suggested by Bell ( 1 5). endogenous dopamine has a physiologic function in control of blood volume and blood pressure. Defects in the dopaminergic system may play an important role in the etiology of hypertensive states ( 16). Vascular receptors mediating vasodilation, such as DAI, may play a significant role in the maintenance of the vascular hemodynamics, especially for the fetus and during the transitional circulation period of the newborn. DAI, postsynaptic, vascular dopamine receptor We hypothesized that if systemic and pulmonary DAI recep-PAP, mean pulmonary arter...

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“…The absence of effect of quinpirole on resting perfusion pressure may be explained by the fact that the resting sympathetic tone to the superior mesenteric vascular bed is low, due to the proximal ligation of the periarterial sympathetic nerves; this observation further suggests that quinpirole does not interact with the postsynaptic dopamine receptors reported to be present in this vascular bed (Nichols & Hiley, 1985). In order to characterize the presynaptic receptors involved in the inhibitory effect of quinpirole, we studied the influence ofpretreatment with the selective DA,-receptor antagonist SCH 23390 (Hilditch et al, 1984;Goldberg et al, 1984) and with the selective DA2-receptor antagonist domperidone (Kohli et al, 1983;Hilditch & Drew, 1985). SCH 23390, in a dose (50 pg kg-') reported to antagonize, on intravenous administration, the blood pressure lowering effect of fenoldopam in the rat (Sengupta & Lokhandwala, 1985), did not affect the action of quinpirole.…”

Section: Discussionmentioning

confidence: 99%

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

Dupont

Lefebvre

Vanderniepen

1987

British J Pharmacology

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1 The effect of local administration of the dopamine2 (DA2)-receptor agonist quinpirole and of the DA,-receptor agonist fenoldopam was studied in the in situ, constant flow autoperfused, superior mesenteric vascular bed of the rat.2 Local infusion of quinpirole (30 pg kg-'min-' for 5min) 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.3 The inhibitory effect of quinpirole was antagonized by the selective DA2-receptor antagonist domperidone (10 pg kg-') but not by the selective DA,-receptor antagonist SCH 23390 (50 pg kg-'). 4 Local infusion of fenoldopam (30 pg kg-' min-' for 5 min) reduced baseline perfusion pressure to 89.9 ± 1.9%, increased the pressor response to electrical stimulation (4Hz, 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 a,-adrenoceptor agonist phenylephrine were also reduced by fenoldopam (to 38.4 ± 6.4%), but responses to locally administered angiotensin II were not modified.5 Pretreatment with SCH 23390 (50 pg kg-') 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.6 Pretreatment with the selective az-adrenoceptor antagonist rauwolscine (100 pg kg-') 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 a,-adrenoceptors, while its potentiating effect on neurogenic vasoconstriction is due to blockade of presynaptic oi2-adrenoceptors.

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SCH 23390 is a very potent and selective antagonist at vascular dopamine receptors

Cited by 57 publications

References 1 publication

Dopexamine: a novel agonist at peripheral dopamine receptors and β₂‐adrenoceptors

Dopexamine: a novel agonist at peripheral dopamine receptors and β₂‐adrenoceptors

Systemic and Pulmonary Vascular Effects of Selective Dopamine Receptor Blockade and Stimulation in Lambs

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

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SCH 23390 is a very potent and selective antagonist at vascular dopamine receptors

Cited by 57 publications

References 1 publication

Dopexamine: a novel agonist at peripheral dopamine receptors and β2‐adrenoceptors

Dopexamine: a novel agonist at peripheral dopamine receptors and β2‐adrenoceptors

Systemic and Pulmonary Vascular Effects of Selective Dopamine Receptor Blockade and Stimulation in Lambs

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

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Dopexamine: a novel agonist at peripheral dopamine receptors and β₂‐adrenoceptors

Dopexamine: a novel agonist at peripheral dopamine receptors and β₂‐adrenoceptors