Vasodilatation of afferent arterioles and paradoxical increase of renal vascular resistance by furosemide in mice.
Loop diuretics like furosemide have been shown to cause renal vasodilatation in dogs and humans, an effect thought to result from both a direct vascular dilator effect and from inhibition of tubuloglomerular feedback. In isolated perfused afferent arterioles preconstricted with angiotensin II or N(G)-nitro-L-arginine methyl ester, furosemide caused a dose-dependent increase of vascular diameter, but it was without effect in vessels from NKCC1-/- mice suggesting that inhibition of NKCC1 mediates dilatation in afferent arterioles. In the intact kidney, however, furosemide (2 mg/kg iv) caused a 50.5 +/- 3% reduction of total renal blood flow (RBF) and a 27% reduction of superficial blood flow (SBF) accompanied by a marked and immediate increase of tubular pressure and volume. At 10 mg/kg, furosemide reduced RBF by 60.4 +/- 2%. Similarly, NKCC1-/- mice responded to furosemide with a 45.4% decrease of RBF and a 29% decrease of SBF. Decreases in RBF and SBF and increases of tubular pressure by furosemide were ameliorated by renal decapsulation. In addition, pretreatment with candesartan (2 mg/kg) or indomethacin (5 mg/kg) attenuated the reduction of RBF and peak urine flows caused by furosemide. Our data indicate that furosemide, despite its direct vasodilator potential in isolated afferent arterioles, causes a marked increase in flow resistance of the vascular bed of the intact mouse kidney. We suggest that generation of angiotensin II and/or a vasoconstrictor prostaglandin combined with compression of peritubular capillaries by the expanding tubular compartment are responsible for the reduction of RBF in vivo.
Oppermann
Mona
M
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Hansen
Pernille B
PB
Castrop
Hayo
H
Schnermann
Jurgen
J
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005665:Furosemide / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007684:Kidney Tubules / Q000098:blood supply / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011453:Prostaglandins / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects*; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters / Q000502:physiology; D064506:Solute Carrier Family 12, Member 2; D013777:Tetrazoles / Q000494:pharmacology; D014563:Urodynamics / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016861:Cyclooxygenase Inhibitors; D004232:Diuretics; D011453:Prostaglandins; C578877:SLC12A2 protein, human; C578878:Slc12a2 protein, mouse; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D013777:Tetrazoles; D005665:Furosemide; C081643:candesartan; D007213:Indomethacin