Low-dose felodipine treatment attenuates endothelial dysfunction in rabbits fed an atherogenic diet.
Loss of endothelium-dependent relaxation is an early step in atherogenesis. To test the effect of low-dose felodipine on the progression of this dysfunction, male New Zealand white rabbits were rendered hypercholesterolemic with a diet containing 0.25% cholesterol and 3% coconut oil. After a 1-month induction period on this diet, during which the rabbits were identified as low or normal responders to cholesterol, 0.46 mg/kg of felodipine (FELO) or placebo (CON) were given by gavage once daily for a further 3 months. This regimen established FELO plasma levels (14.2 +/- 1.3 nM, week 9) corresponding to therapeutic concentrations in humans and an average 13-fold increase in plasma cholesterol from below 1 mM. At the end of the treatment period, relaxation of norepinephrine (1 x 10(-8) M)-precontracted proximal thoracic aorta strips to acetylcholine (ACh: 1 x 10(-8)-1 x 10(-5) M) was determined. Cholesterol exposure was calculated as the area under the curve for serum cholesterol x time [AUC (mM x day 1)]. Despite equal cholesterol load [FELO (n = 17): 1,856 +/- 182 mM x day) and CON (n = 22): 1,851 +/- 167 mM x day], maximal relaxation to 1 x 10(-7) M ACh was well preserved in strips from FELO-treated rabbits (29.5 +/- 5.7%) but suppressed in strips from untreated rabbits (11.0 +/- 2.9%). For comparison, relaxation in strips from standard diet controls was 49.8 +/- 2.9% (n = 15). Moreover, there was a significant inverse correlation (r = -0.74) between percentage ACh relaxation and cholesterol exposure in FELO-treated rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)
Becker
R H
RH
SBU Cardiovascular Agents, Hoechst AG, Frankfurt/Main, Germany.
Linz
W
W
Wiemer
G
G
Nordlander
M
M
D000109:Acetylcholine / Q000008:administration & dosage; D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism / Q000503:physiopathology*; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D015736:Felodipine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation; D011817:Rabbits; D013895:Thoracic Arteries / Q000187:drug effects
D002784:Cholesterol; D000109:Acetylcholine; D015736:Felodipine