Impaired renal vascular endothelial function in vitro in experimental hypercholesterolemia.
Hypercholesterolemia (HC) induces alterations in systemic vascular reactivity, which can manifest as an attenuated endothelium-dependent relaxation, partly consequent to an impairment in nitric oxide (NO) activity. To determine whether experimental HC has a similar effect on renal vascular function, renal artery segments obtained from pigs fed a HC (n=5) or normal (n=5) diet were studied in vitro. Endothelium-dependent relaxation was examined using increasing concentrations of acetylcholine (Ach), calcium ionophore A23187, and Ach following pre-incubation with N(G)-monomethyl-L-arginine or L-arginine (L-ARG). The NO-donor diethylamine (DEA) was used to examine smooth muscle relaxation response and cyclic GMP generation in endothelium-denuded vessels. The expression of endothelial NO synthase (eNOS) in the renal arteries was examined using Western blotting. Endothelium-dependent relaxation to Ach was significantly attenuated in the HC group compared to normal (53.3+/-9.1 vs. 98.8+/-3.7%, P<0.005), but normalized after pre-incubation with L-ARG (82.3+/-13.8%, P=0.21). Receptor-independent endothelium-dependent relaxation to A23187 was also significantly blunted in HC (75.2+/-10.5 vs. 115.5+/-4.2%, P<0. 017). Smooth muscle relaxation and cyclic GMP generation in response to DEA were greater in denuded HC vessels, while relaxation of intact vessels to nitroprusside was unaltered. In the HC vessels eNOS was almost undetectable. In conclusion, experimental HC attenuates in vitro endothelium-dependent relaxation of the porcine renal artery, possibly due to low bioavailability of NO. These vascular alterations in HC could play a role in the pathogenesis of renal disease or hypertension, supporting a role for HC as a risk factor for renovascular disease.
Stulak
J M
JM
Department of Physiology and Biophysics, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Lerman
A
A
Caccitolo
J A
JA
Wilson
S H
SH
Romero
J C
JC
Schaff
H V
HV
Rodriguez Porcel
M
M
Lerman
L O
LO
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D006152:Cyclic GMP / Q000096:biosynthesis; D004048:Diethylamines / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006439:Hemodynamics; D006937:Hypercholesterolemia / Q000097:blood / Q000503:physiopathology*; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D012016:Reference Values; D012079:Renal Circulation; D013552:Swine; D014666:Vasomotor System / Q000503:physiopathology
D004048:Diethylamines; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D001120:Arginine; D002784:Cholesterol; C034281:diethylamine; D006152:Cyclic GMP