The role of presynaptic receptors in the cardiovascular actions of N,N-di-n-propyldopamine in the cat and dog

Abstract

Intravenous administration of N,N-di-n-propyldopamine (DPDA: 50 and 200 micrograms/kg/min, i.v.) produces hypotensive and bradycardic effects in anaesthetized cats and dogs. These effects were abolished by ganglionic blockade and antagonized by haloperidol or (SR)-sulpiride suggesting a neurogenic mechanism of action, mediated by specific dopamine receptors. The renal blood flow increases to DPDA in dogs were resistant to ganglionic blockade indicating some activity at postsynaptic vascular dopamine receptors. Studies with DPDA in vivo administered via the intravertebral and intravenous routes suggested a peripheral site of action for the hypotensive effects of this compound. In vitro, in isolated perfused cat spleens prelabeled with 3H-noradrenaline, DPDA (0.01--1 microM) produced a concentration-dependent inhibition of tritium release elicited by nerve stimulation at 1 Hz which was selectively antagonized by 1 microM (SR)-sulpiride implicating presynaptic inhibitory dopamine receptors in the mediation of this effect. In isolated rabbit splenic arteries, contracted by prostaglandin-F2 alpha, dopamine,ADTN (2-amino-6,7-dihydroxytetrahydronaphthalene) and apomorphine produced concentration-dependent relaxations while DPDA exhibited only weak postsynaptic dopamine-like effects. In vivo DPDA reduced, in a frequency dependent manner, the end organ responses to sympathetic nerve stimulation in the cat nictitating membrane and in the dog renal vascular bed. Both effects were mediated through activation of presynaptic inhibitory dopamine receptors by DPDA. In conclusion these results suggest a predominantly presynaptic agonist effect for DPDA in vitro and a similarly important action in vivo, mediated mainly via dopamine receptors. Furthermore evidence is presented which suggests that pre- and postsynaptic dopamine receptors may differ in their pharmacological properties and that presynaptic dopamine receptors could be important target receptors in the development of novel antihypertensive drugs.