Dopamine DA2-receptor activation inhibits noradrenaline release in human kidney slices

Abstract

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 μM), 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 μM) did not alter but fenoldopam ( 1 μM) increased S-I outflow of radioactivity. However, in the presence of either the non-selective α-adrenoceptor antagonist phentolamine (1 μM) or the selective α2-adrenoceptor antagonist idazoxan (1 μM) fenoldopam (1 μM) had no effect. The DA2-receptor agonist quinpirole (LY 171555; 1 μM) inhibited S-I outflow of radioactivity, an effect blocked by the selective DA2-receptor antagonists S(-)-sulpiride (10 μM) and domperidone (0.3 μM) but unaltered either by the DA1-receptor antagonist SCH 23390 (1 μM) or by phentolamine (1 μM). The α2-adrenoceptor agonist UK 14304 (0.1 μM) inhibited S-I outflow of radioactivity, and this effect was blocked by phentolamine (1 MM) and idazoxan (1 μM) but unaltered by S(-)-sulpiride (10 μM). Phentolamine and idazoxan, in contrast to S(-)-sulpiride, domperidone and SCH 23390, enhanced S-I outflow of radioactivity by themselves. The DA2-receptor agonist carmoxirole (EMD 45609; 0.03 μM) inhibited S-I outflow of radioactivity but carmoxirole (0.003 and 0.3 μM) did not. However, in the presence of phentolamine carmoxirole (0.3 and 0.03 μM) inhibited S-I outflow of radioactivity to a similar extent. Moreover, in the presence of idazoxan carmoxirole (0.3 μM) also inhibited S-I outflow of radioactivity. The inhibitory effect of carmoxirole (0.03 μM) was blocked by S(-)-sulpiride (10 μM) but not by SCH 23390 (1 μM). The data suggest that activation of prejunctional DA2-receptors by either quinpirole or carmoxirole (0.03 μM) inhibits noradrenaline release in human kidney cortex. The inhibitory DA2-receptor mediated effect of carmoxirole (0.3 μM) seems to be masked by simultaneous blockade of prejunctional inhibitory α-autoreceptors. There is no evidence that activation of DA1-receptors modulates noradrenaline release. Endogenous noradrenaline, in contrast to endogenous dopamine, seems to activate its respective prejunctional receptor system, since phentolamine and idazoxan but neither S(-)-sulpiride nor domperidone enhanced S-I outflow of radioactivity.