Cholesterol induces renal vasoconstriction and anti-natriuresis by inhibiting nitric oxide production in anesthetized rats.
Although hypercholesterolemia is implicated in the pathophysiology of many renal disorders as well as hypertension, its direct actions in the kidney are not yet clearly understood. In the present study, we evaluated renal responses to administration of cholesterol (8 microg x min(-1).100 g body wt(-1); bound by polyethylene glycol) into the renal artery of anesthetized male Sprague-Dawley rats. Total renal blood flow (RBF) was measured by a Transonic flow probe, and glomerular filtration rate (GFR) was determined by Inulin clearance. In control rats (n = 8), cholesterol induced reductions of 10 +/- 2% in RBF [baseline (b) 7.6 +/- 0.3 microg x min(-1).100 g(-1)], 17 +/- 3% in urine flow (b, 10.6 +/- 0.9 microg x min(-1).100 g(-1)), 29 +/- 3% in sodium excretion (b, 0.96 +/- 0.05 mumol.min(-1).100 g(-1)) and 24 +/- 2% in nitrite/nitrate excretion (b, 0.22 +/- 0.01 nmol.min(-1).100 g(-1)) without an appreciable change in GFR (b, 0.87 +/- 0.03 ml.min(-1).100 g(-1)). These renal vasoconstrictor and anti-natriuretic responses to cholesterol were absent in rats pretreated with nitric oxide (NO) synthase inhibitor, nitro-l-arginine methylester (0.5 microg x min(-1).100 g(-1); n = 6). In rats pretreated with superoxide (O(2)(-)) scavenger tempol (50 microg x min(-1).100 g(-1); n = 6), the cholesterol-induced renal responses remained mostly unchanged, although there was a slight attenuation in anti-natriuretic response. This anti-natriuretic response to cholesterol was abolished in furosemide-pretreated rats (0.3 microg x min(-1).100 g(-1); n = 6) but remained unchanged in amiloride-pretreated rats (0.2 microg x min(-1).100 g(-1); n = 5), indicating that Na(+)/K(+)/2Cl(-) cotransport is the dominant mediator of this effect. These data demonstrate that cholesterol-induced acute renal vasoconstrictor and antinatriuretic responses are mediated by a decrease in NO production. These data also indicate that tubular effect of cholesterol on sodium reabsorption is mediated by the furosemide sensitive Na(+)/K(+)/2Cl(-) cotransporter.
Physiology, Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Libor
L
Kopkan
Md Abdul H
MA
Khan
Agnieszka
A
Lis
Mouhamed S
MS
Awayda
Dewan S A
DS
Majid
D000042:Absorption / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002784:Cholesterol / Q000008:administration & dosage*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004337:Drug Carriers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007261:Infusions, Intra-Arterial; D007668:Kidney / Q000098:blood supply* / Q000502:physiology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009318:Natriuresis / Q000187:drug effects*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011092:Polyethylene Glycols; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D013113:Spin Labels; D014661:Vasoconstriction / Q000187:drug effects*
D000975:Antioxidants; D003497:Cyclic N-Oxides; D004337:Drug Carriers; D004791:Enzyme Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D013113:Spin Labels; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D005665:Furosemide; D002784:Cholesterol; D019001:Nitric Oxide Synthase; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester