Site of action of moxonidine in the rat nephron.
Moxonidine is a centrally acting antihypertensive agent which has been found to exert its blood pressure lowering effect by interaction with (alpha2-adrenoceptors and imidazoline receptors of the I(1)-type. These receptors have also been demonstrated to be present in the rat kidney. In the present study, clearance and micropuncture techniques were applied to anaesthetized rats to localize the site of action of moxonidine within the nephron. The clearance data show that moxonidine (0.25 mg/kg i.v., followed by a continuous i.v. infusion of 0.25 mg/h) induced a marked increase in urine flow and urinary excretion of sodium, chloride and potassium. The changes in urine flow and urinary solute excretion were accompanied by an enhanced glomerular filtration rate. The micropuncture experiments revealed that moxonidine significantly increased glomerular filtration rate of superficial nephrons, and significantly inhibited fractional reabsorption of fluid, sodium, potassium and chloride by similar amounts (by 9.0%-9.8%) in superficial proximal tubules. Regarding fluid and sodium reabsorption, the proximal effect of moxonidine was continuously weakened by a compensatory increase of reabsorption in the loop of Henle and the subsequent distal nephron segments. The inhibitory effect of moxonidine on fractional proximal potassium reabsorption was completely compensated in the loop of Henle, but the drug induced a net secretion of potassium into the segments lying beyond the early distal tubule, probably as a consequence of the increased tubule fluid and sodium load delivered to them. The experiments have identified the proximal tubule as the principal nephron site where the diuretic action of moxonidine arises. The proximal effect may be related to the increased glomerular filtration rate and to a direct inhibitory interaction of moxonidine with the proximal Na+/H+ exchanger.
Greven
J
J
Department of Pharmacology and Toxicology, Rheinisch-Westfalische Technische Hochschule Aachen, Germany.
von Bronewski-Schwarzer
B
B
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004232:Diuretics / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000502:physiology; D008297:Male; D009399:Nephrons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology
D000959:Antihypertensive Agents; D004232:Diuretics; D007093:Imidazoles; D017923:Sodium-Hydrogen Exchangers; C043482:moxonidine