Biochemical, autoradiographic and pharmacological evidence for the involvement of tubular DA-1 receptors in the natriuretic response to dopexamine hydrochloride.
Dopexamine hydrochloride (DPX) is a dopamine analog and it possesses agonistic action at DA-1 receptors and beta 2-adrenoceptors. It also is a weak agonist at DA-2 receptors. In the present study, we have examined the anatomical localization of DPX binding sites in rat kidney and their functional significance in terms of the renal effects of this compound. In receptor-ligand binding studies, [3H]-DPX was found to bind specifically to sections of rat kidney in a time (maximum binding at 60 min), temperature (optimal temperature 25 degrees C) and concentration (highest specific/non-specific ratio at 2 nmol/l) dependent manner. Autoradiographic studies revealed the presence of [3H]-DPX binding sites in renal tubules, glomerulus and various layers of small and large blood vessels. Inhibition studies with SCH 23390, ICI 118.551 and 1-sulpiride showed that DPX binds primarily to DA-1 receptors in tubules, only to beta 2-adrenoceptors in glomerulus and to beta 2-adrenoceptors, DA-1 and DA-2 receptors in blood vessels. Also, DPX caused concentration related increases in cyclic AMP levels in rat kidney membrane particles, which could be completely abolished by a combined presence of SCH 23390 and propranolol suggesting that both binding sites of DPX are linked to adenylate cyclase. In functional studies DPX (1 microgram/kg.min for 30 min) produced a modest fall in blood pressure, pronounced tachycardia and slight but significant increase in renal blood flow (11%). These responses were accompanied by increases in urine output (97%), urinary sodium excretion (89%), and fractional excretion of sodium (132%). There was no change in glomerular filtration rate. Propranolol pretreatment abolished DPX-induced hypotension and tachycardia but seemed to potentiate the natriuretic responses to DPX. On the other hand, SCH 23390, a DA-1 receptor antagonist completely abolished DPX-induced hypotension, natriuresis and diuresis without affecting tachycardia. These results indicate that (1) DPX binds predominantly to DA-1 receptors in renal tubules, to beta 2-adrenoceptors in glomerulus and to beta 2-adrenoceptors, as well as DA-1 and DA-2 receptors in renal blood vessels (2) DPX stimulates cAMP formation in the kidney by activating both DA-1 and beta 2-adrenoceptors and (3) DPX produces natriuresis and diuresis by selectively activating DA-1 receptors located on renal tubules.
Department of Pharmacology, University of Houston, TX 77204-5515.
S J
SJ
Vyas
S
S
Apparsundaram
A
A
Ricci
F
F
Amenta
M F
MF
Lokhandwala
D000262:Adenylyl Cyclases / Q000378:metabolism; D000322:Adrenergic Agonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D007684:Kidney Tubules / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure*; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism / Q000502:physiology*; D012079:Renal Circulation; D014316:Tritium
D000322:Adrenergic Agonists; D011954:Receptors, Dopamine; D014316:Tritium; C046318:dopexamine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D004298:Dopamine