Dana Glock

Selective DA2 versus DA1 antagonist activity of domperidone in the periphery

Relative activity of domperidone as an antagonist of the two peripheral dopamine (DA) receptors, DA1 and DA2, was studied in pentobarbital-anesthetized dogs. Renal vasodilation produced by intra-arterial injection of DA into the phenoxybenzamine-pretreated renal vascular bed was the DA1-mediated response, while femoral vasodilation induced by dipropyl dopamine injected into the femoral artery with intact nerve supply was the DA2-mediated response. Domperidone, 0.5-5 micrograms/kg intravenously, inhibited the DA2 response by 15-75%. In contrast, doses up to 5 mg/kg had no effect on DA1-mediated or bradykinin-induced renal vasodilation. Domperidone has thus proved to be more selective than other DA2 antagonists, differentiating between the two peripheral DA receptors by a margin of greater than 10(4). Furthermore, domperidone was found to be selective as a DA2 versus alpha 2-adrenergic antagonist as studied on the dog cardioaccelerator nerve, thus, enhancing its value as a selective DA2 antagonist.

Relative activities of SCH 23390 and its analogs in three tests for D1/DA1 dopamine receptor antagonism

Inhibitory activities of a series of analogs of SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) in which the 7-chloro group was substituted by bromo, fluoro, methyl and methoxy groups, respectively, were compared in three tests for D1 and DA1 dopamine (DA) receptor antagonism: inhibition of DA-induced renal vasodilation in the anesthetized dog (DA1 receptor model), inhibition of DA-stimulated adenylate cyclase in the striatum of adult female rats (D1 receptor model) and displacement of [3H]SCH 23390 in the striatal homogenates of male rats. In addition the D2 receptor affinity of each of the compounds chosen was assessed via displacement of [3H]spiperone binding from rat striatum. S-enantiomers of the Cl and CH3 analogs were 200- to 700-fold weaker than the respective R-enantiomers in all three tests. The activity of all the R-enantiomers was in the nanomolar range and varied no more than 8-fold in all three tests. The F analog in the ligand binding test was the only exception, which was 30-fold weaker than the C1 analog. All of the R-enantiomers studied showed much weaker affinity for the D2 receptor, as assessed by displacement of [3H]spiperone binding. Similar enantiomer selectivity and parallel affinities of the R-enantiomers in the prototype models for D1 and DA1 receptors strengthen the evidence in support of identity between the D1 and DA1 dopamine receptors. These results further indicate that displacement of SCH 23390 in the ligand binding test reflects affinity of a compound for D1 and DA1 dopamine receptors.

Preservation of renal blood flow during hypotension induced with fenoldopam in dogs

The introduction of drugs that could induce hypotension with different pharmacological actions would be advantageous because side effects unique to a specific drug could be minimized by selecting appropriate therapy. Specific dopamine-1, (DA1) and dopamine-2 (DA2) receptor agonists are now under clinical investigation. Fenoldopam mesylate is a specific DA1 receptor agonist that lowers blood pressure by vasodilatation. The hypothesis that fenoldopam could be used to induce hypotension and preserve blood flow to the kidney was tested. Systemic aortic blood pressure and renal blood flow were measured continuously with a carotid arterial catheter and an electromagnetic flow probe respectively, in order to compare the cardiovascular and renal vascular effects of fenoldopam and sodium nitroprusside in ten dogs under halothane general anaesthesia. Mean arterial pressure was decreased 30 ± 8 per cent from control with infusion of fenoldopam (3.4 ± 2.0 μg · kg− 1 · min− 1) and 34 ± 4 per cent with infusion of sodium nitroprusside (5.9 μg · kg− 1 · min− 1) (NS). Renal blood flow (RBF) increased during fenoldopam-induced hypotension 11 ± 7 per cent and decreased 21 ± 8 per cent during sodium nitroprusside-induced hypotension (P < 0.01). Sodium nitroprusside is a non-selective arteriolar and venous vasodilator that can produce redistribution of blood flow away from the kidney during induced hypotension. Fenoldopam is a selective dopamine-1 (DA1) receptor agonist that causes vasodilatation to the kidney and other organs with DA1 receptors and preserves blood flow to the kidney during induced hypotension.AbstractL’introduction d’agents qui induisent l’hypotension par des actions pharmacologiques différentes pourrait être avantageuse afin de minimiser les effets secondaires spécifiques des agents par une thérapie sélective appropriée. Des agonistes spécifiques des récepteurs dopamine-1 (DA1) et dopamine-2 (DA2) sont actuellement investigués. Le fénoldopam mésylate est un agoniste spécifique des récepteurs DA1 qui diminue la pression artérielle par vasodilatation. On a testé l’hypothèse que le fénoldopam pourrait être utilisé pour induire l’hypotension et préserver le flot rénal. Afin de comparer les effets cardiovasculaires et rénaux du fénoldopam et du nitroprussiate de soude chez dix chiens anesthésiés à halothane, on a mesuré la pression artérielle systémique et le flot rénal avec un cathéter carotidien et un débitmètre électromagnétique. La pression artérielle moyenne diminua de 30 ± 8 pour cent du contrôle avec la perfusion de fénoldopam 3,4 ± 2,0 μg · kg− 1) et 34 ± 4 pour cent avec l’infusion de nitroprussiate de soude (5,9 μg · kg− 1 · min− 1) (NS). Le flot sanguin rénal (RBF) augmenta durant l’hypotension induite par le fénoldopam 11 ± 7 pour cent et diminua de 21 ± 8 pour cent durant l’hypotension induite par le nitroprussiate de soude (P < 0,01). Le nitroprussiate de soude est un vasodilatateur non-sélectif artériolaire et veineux qui peut produire une redistribution de flot sanguin loin des reins durant l’hypotension induite. Le fénoldopam est un agoniste des récepteurs DA1 qui provoque une vasodilatation rénale et autres organes ayant des récepteurs DA1 préservant ainsi le flot sanguin rénal durant l’hypotension induite.

The Influence of Intravenous Albunex Injections on Pulmonary Arterial Pressure, Gas Exchange, and Left Ventricular Peak Intensity

Contrast ultrasonography may be used to assess regional tissue perfusion. The purpose of this study was to evaluate the safety and efficacy of a new, commercially prepared ultrasound contrast agent (Albunex) in dogs. The injections were administered from peripheral intravenous (IV), right atrial (RA), and pulmonary artery (PA) sites. Acute pulmonary hemodynamic and gas exchange effects of low-dose (0.5, 1.0, 2.0 ml) Phase I injections, and high-dose (2.0, 5.0, 10, 20 ml) Phase II injections of Albunex were evaluated in nine dogs. Immediately before and after each injection, pulmonary artery pressure (PAP) and oxygen tension (PO2) were determined. In addition, left ventricular cavity opacification was assessed visually and by videodensitometric off-line analysis. Visual assessment was performed by four blinded observers who graded on a scale of 0 to 3 (0 = no contrast enhancement of the left ventricular (LV) cavity; 1 = weak or suboptimal contrast enhancement; 2 = optimal or excellent contrast enhancement; and 3 = attenuation of the ultrasound signal following a contrast injection). Peak pixel intensity was also determined with videodensitometric analysis. Results showed that significant changes in PAP or PO2 were not noted after Albunex injections, regardless of injection site or dose range. The average change in PAP after Albunex injection was 1.0 mm Hg +/- 1.2 mm Hg (NS), and the average change in PO2 after Albunex injections was 6.2 mm Hg +/- 6.7 mm Hg (NS). The left ventricular cavity peak pixel intensity was dependent on both injection site (PA = RA > IV) and dose range (2.0 = 1.0 > 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of fenoldopam on renal blood flow and systemic hemodynamics during isoilurane anesthesia

The authors compared the systemic hemodynamic and renal vascular effects of hypotension induced by fenoldopam with those produced by the most commonly used hypotensive agent, sodium nitroprusside, in 10 dogs. Mean arterial pressure decreased 26% ± 3% from control following infusion with fenoldopem, and 30% ± 2% following infusion with sodium nitroprusside (these decreases were not significantly different between the groups). Renal blood flow (RBF) was preserved during fenoldopam-induced hypotension (214 ± 16 mL/min at baseline and 197 ± 16 mL/min after fenoldopam-induced hypotension). In contrast, RBF decreased from 223 ± 17 mL/min to 167 ± 12 mL/min during sodium nitroprusside induced hypotension (P < 0.02). The differences in RBF between the two groups occurred in spite of the fact that cardiac output and pulmonary capillary wedge pressure were kept similar between the two groups. The authors conclude that fenoldopam, a selective dopamine, (DA,) receptor agonist, preserves blood flow to the kidney during induced hypotension. On the other hand, sodium nitroprusside is a nonselective arteriolar and venous vasodilator that redistributes blood flow away from the kidneys during induced hypotension.

Relative DA1-Dopamine-Receptor Agonist and α-Adrenoceptor Antagonist Activity of Fenoldopam in the Anesthetized Dog

Relative DA1-dopamine-receptor agonist and alpha-adrenoceptor antagonist activities of fenoldopam were determined in pentobarbital anesthetized dogs. The renal vasodilating effect of intravenous infusions of fenoldopam was used as an index of its DA1-agonist activity. Inhibition by fenoldopam of femoral vasoconstriction produced by intraarterial administration of phenylephrine (a relatively selective alpha 1 agonist) and UK 14,304 ( a relatively selective alpha 2 agonist) was used to determine its alpha-adrenoceptor antagonist activity. Intravenous infusions of 0.1 and 0.2 microgram/kg/min of fenoldopam caused dose-related reductions in renal vascular resistance and mean arterial pressure. Higher rates of infusions of fenoldopam (2 and 5 micrograms/kg/min) were given after pretreatment with 50 micrograms/kg/min SCH 23390 (a DA1-selective antagonist) to attenuate DA1-mediated hemodynamic effects. After SCH 23390, the infusion of 5 micrograms/kg/min of fenoldopam produced approximately the same hypotensive and renal vasodilating actions as the 0.2 microgram/kg/min infusion without SCH 23390. Alpha-adrenoceptor blocking activity was not observed with the 0.1, 0.2, and 2 micrograms/kg/min infusions of fenoldopam. The 5 micrograms/kg/min infusion, however, produced 14 and 25% inhibition of the vasoconstrictor effects of phenylephrine and UK 14,304, respectively. These data indicate that fenoldopam decreases renal vascular resistance in doses which are 25 to 50 times less than the dose needed to antagonize alpha adrenoceptors.

Dihydrexidine : a new potent peripheral dopamine D1 receptor agonist

Dihydrexidine (trans-10,11-dihydroxyhexahydrobenzo-[a]phenanthridine) was found to be a full dopamine D1 receptor agonist with a potency five times that of dopamine. Dihydrexidine showed no agonist activity at peripheral dopamine D2 receptors, alpha- or beta-adrenoceptors at the doses which produced near maximal stimulation of dopamine D1 receptors. The chemical structure of dihydrexidine shows that addition of a phenyl ring to a benzo[f]quinoline moiety bestows potent D1 activity upon a structure which had no such activity previously. This observation introduces a new factor in structure-activity considerations for dopamine receptor ligands.

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 phenoxy‐benzamine 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.

Effects of the enantiomers of 3-PPP on DA1 and DA2 dopamine receptors in the dog

The (+)- and (-)-enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) were studied for their effects on DA1 and DA2 dopamine receptors in pentobarbital anesthetized dogs. 3-PPP enantiomers were administered into the renal artery after phenoxybenzamine pretreatment to determine possible DA1 activity; dopamine was also injected for comparison. DA2 activity was determined by injection of the enantiomers into the femoral vascular bed with intact nerve supply and without phenoxybenzamine; dipropyl dopamine (DPDA) or apomorphine were used as standard DA2 agonists. Antagonist activity of the enantiomers on DA1 or DA2 receptors was determined by simultaneous administration of the enantiomer with DA in the renal vascular bed and with DPDA or apomorphine in the femoral vascular bed. Neither enantiomer was active as a DA1 agonist, but both exhibited antagonist activity. Both enantiomers were found to be agonists of the DA2 receptor; in addition, both showed DA2 antagonist activity. In all actions the (-)-enantiomer was approximately 4 times more potent than the (+)-enantiomer.