ergoline and carmoxirole

Dopamine receptor modulation of noradrenaline release from renal sympathetic nerves was investigated. Human kidney slices were incubated with 3H-noradrenaline, placed into superfusion chambers between two platinum electrodes and field-stimulated at 5 Hz. The slices accumulated radioactivity. Pretreatment of the kidney slices with 6-hydroxy-dopamine (1.2 mM) prior to the 3H-noradrenaline incubation reduced the accumulation of radioactivity. The stimulation induced (S-I) outflow of radioactivity was mainly composed of intact 3H-noradrenaline. The sodium channel blocker tetrodotoxin (1 microM), 6-hydroxy-dopamine pretreatment and omission of calcium from the superfusion solution abolished S-I outflow of radioactivity. The DA1-receptor agonist fenoldopam (SKF 82526; 0.01 and 0.1 microM) did not alter but fenoldopam (1 microM) increased S-I outflow of radioactivity. However, in the presence of either the non-selective alpha-adrenoceptor antagonist phentolamine (1 microM) or the selective alpha 2-adrenoceptor antagonist idazoxan (1 microM) fenoldopam (1 microM) had no effect. The DA2-receptor agonist quinpirole (LY 171555; 1 microM) inhibited S-I outflow of radioactivity, an effect blocked by the selective DA2-receptor antagonists S(-)-sulpiride (10 microM) and domperidone (0.3 microM) but unaltered either by the DA1-receptor antagonist SCH 23390 (1 microM) or by phentolamine (1 microM). The alpha 2-adrenoceptor agonist UK 14304 (0.1 microM) inhibited S-I outflow of radioactivity, and this effect was blocked by phentolamine (1 microM) and idazoxan (1 microM) but unaltered by S(-)-sulpiride (10 microM). Phentolamine and idazoxan, in contrast to S(-)-sulpiride, domperidone and SCH 23390, enhanced S-I outflow of radioactivity by themselves.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Brimonidine Tartrate; Calcium; Dopamine Agents; Ergolines; Fenoldopam; Humans; In Vitro Techniques; Indoles; Kidney Cortex; Middle Aged; Norepinephrine; Oxidopamine; Pyridines; Quinoxalines; Quinpirole; Receptors, Dopamine D2; Sulpiride; Tetrodotoxin

The effects of the classical dopamine DA2-receptor agonist quinpirole (LY 171555) and the recently characterized DA2-receptor agonist, carmoxirole (EMD 45609), on neurotransmission in rat isolated kidney were investigated. After preincubation with 3H-noradrenaline, the renal nerves were electrically stimulated. The stimulation induced (S-I) outflow of radioactivity was taken as an index of noradrenaline release. Quinpirole (0.3 mumol/l) inhibited S-I outflow of radioactivity and pressor-responses to renal nerve stimulation (RNS) at 1 Hz. Both effects of quinpirole were blocked by the DA2-receptor antagonist S(-)-sulpiride (10 mumol/l). The alpha 1, alpha 2-adrenoceptor antagonist phentolamine (1 mumol/l) did not block the inhibitory effect of quinpirole. Carmoxirole (0.003 and 0.03 mumol/l) did not alter and carmoxirole (0.3 mumol/l) even enhanced S-I outflow of radioactivity, however, pressor responses to RNS were markedly reduced by carmoxirole (0.003-0.3 mumol/l). Pressor responses to RNS were also markedly reduced by the alpha 1-adrenoceptor antagonist prazosin (0.1 mumol/l). Carmoxirole (0.3 mumol/l), prazosin (0.1 mumol/l) and phentolamine (1 mumol/l) totally abolished pressor responses to exogenous noradrenaline (0.05 mumol/l). In contrast, quinpirole (0.3 mumol/l) did not alter pressor responses to exogenous noradrenaline (0.05 mumol/l). Furthermore, carmoxirole (0.003-0.3 mumol/l) markedly reduced pressor responses induced by the alpha 1-adrenoceptor agonist methoxamine (1 mumol/l) but even the highest concentration of carmoxirole (0.3 mumol/l) had no effect on pressor responses induced by bolus injections of either neuropeptide Y (1.5 ng) or angiotensin II (1 ng). Phentolamine (1 mumol/l) by itself markedly enhanced S-I outflow of radioactivity and pressor responses to RNS were virtually unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Dopamine Agents; Ergolines; Indoles; Kidney; Male; Norepinephrine; Phentolamine; Prazosin; Purines; Pyridines; Quinpirole; Rats; Rats, Inbred Strains; Synaptic Transmission; Tritium

A new potential antihypertensive drug, EMD 45609 (carmoxirole), has been characterized in various in vivo and in vitro models. EMD 45609 displayed high affinity for dopamine D2-receptors combined with negligible binding to D1-receptors in binding assays in vitro. However, in tests in vivo for central D2-receptor activity, EMD 45609 exhibited only weak activity. Thus, after p.o. administration, striatal L-DOPA accumulation in intact rats was unchanged up to 100 mg/kg p.o., i.e. doses 100 times higher than those reported to induce depressor activity. Central dopamine agonistic activity could only be verified in the more sensitive model of the reserpinized rat. EMD 45609 was more than 30 times less potent, however, than LY 141865 in reserpinized rats after s.c. administration. Similarly, in rats with 6-hydroxydopamine induced unilateral lesions of the substantia nigra, EMD 45609 was only marginally active. The shallow dose response curves and the submaximal effects obtained for central dopaminergic activity, as reflected in the inhibition of striatal L-DOPA accumulation, suggest that EMD 45609 is a partial dopamine D2-receptor agonist and in addition, owing to its ionizable structure, passes less readily into the brain than several reference compounds. A marked affinity was found towards 5-HT1A-receptors in vitro, whereas affinity for alpha 1- and alpha 2-adrenoceptors was low; accordingly, central alpha 2-adrenoceptor activity was not detected as EMD 45609 failed to affect hypothalamic L-DOPA accumulation even at 100 mg/kg s.c. In accordance with its high affinity for D2-receptors in vitro, EMD 45609 inhibited field stimulated noradrenaline release from rabbit ear arteries in nanomolar threshold concentrations at 0.5 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biogenic Amines; Brain; Clonidine; Corpus Striatum; Dopamine; Dopamine Agents; Drug Interactions; Ergolines; Heart; Hypothalamus; Indoles; Levodopa; Male; Motor Activity; Norepinephrine; Oxidopamine; Pyridines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine; Sulpiride