Dopexamine Hydrochloride in the Human Kidney: Localization, Receptor Binding and Effect on 3’-5’-Cyclic Adenosine Monophosphate Generation

Abstract

Dopexamine hydrochloride is a synthetic dopamine analogue recently developed to improve myocardial and renal performance in patients suffering from low cardiac output states. The present study was designed to assess the pharmacological profile and the anatomical localization of [³H]-dopexamine binding sites within the human nephron. The effects of dopexamine on the 3’-5’-cyclic adenosine monophosphate (cAMP)-generating system in membrane particles of the human kidney were also investigated. It was found that [³H]-dopexamine was specifically bound by sections of the human kidney. The binding was partly inhibited by the DA-1 receptor antagonist SCH 23390, by the β2-adrenoceptor antagonist ICI 118,551 and by the DA-2 receptor antagonist domperidone. The 3 antagonists in combination reduced [³H]-dopexamine binding to nonspecific values. Light microscope autoradiography revealed the accumulation of silver grains, corresponding to [³H]-dopexamine binding sites, within the different portions of the human nephron. The incubation of sections of the human kidney with [³H]-dopexamine plus SCH 23390 caused a remarkable reduction in the density of silver grains within the proximal tubule and the macula densa and a moderate decrease in the density of silver grains within the ascending and descending limbs of the loop of Henle as well as within the distal tubule. The incubation of sections of human kidney with [³H]-dopexamine plus ICI 118,551 caused a pronounced reduction in the density of silver grains within the glomerulus, the limbs of the loop of Henle, the distal tubule and the medullary collecting tubules and a moderate decrease in the density of silver grains within the macula densa and the proximal collecting tubule. The incubation of sections of the human kidney with [³H]-dopexamine plus domperidone caused a moderate decrease in silver grain accumulation within proximal and distal tubules as well as within medullary collecting tubules. Dopexamine caused a dose-dependent accumulation of cAMP levels in membrane particles of the human kidney. This effect was in part reduced by SCH 23390 or by ICI 118,551. A combination of SCH 23390 and ICI 118,551 reduced cAMP levels to basal values. The present results clearly show that dopexamine binds to dopamine DA-1 and DA-2 receptor sites and to β₂-adrenoceptors in various regions of the human kidney. Moreover, they demonstrate that dopexamine stimulates cAMP formation in the human kidney by activating both DA-1 receptors and β₂-adrenoceptors. Stimulation of some or all of these receptors may contribute to the renal actions of dopexamine in humans.