Therapeutic dose of nebivolol, a nitric oxide-releasing beta-blocker, reduces atherosclerosis in cholesterol-fed rabbits.
Nitric oxide (NO) exerts a plethora of vascular beneficial effects. The NO-releasing beta-blocker nebivolol is a racemic mixture of D/L-enantiomers that displays negative inotropic as well as direct vasodilating activity. The in vivo antiatherogenic activity of therapeutic doses of the beta-blocker with antioxidant properties carvedilol (12.5mg/day) or nebivolol (5mg/day) was tested in cholesterol-fed rabbits. Animals received a 1% cholesterol-rich diet alone (controls) or mixed with drugs (treated animals) for 8 weeks. While it did not affect hyperlipidemia, nebivolol inhibited the development of atherosclerosis, expressed as computer-assisted imaging analysis of aortic area covered by lesions (23.3+/-4.1% in treated vs 38.2+/-6.4% in control animals, p<0.01). Differently, in our experimental condition of therapeutic drug doses, this antiatherogenic effect did not reach statistical significance in rabbits treated with carvedilol (32.5+/-5.1% aortic area covered by lesions, p=NS vs controls). Plasma nitrates increased in rabbits treated with nebivolol while both beta-blockers reduced LDL oxidation. Moreover, nebivolol induced a consistent increase of endothelial reactivity and aortic eNOS expression compared with control animals (p<0.05) and those receiving carvedilol (p<0.05). Since NO may exert beneficial effects in atherosclerosis, a NO-dependent mechanism could explain this data. These observations suggest that the NO-releasing beta-blocker, nebivolol, might represent an effective pharmacological approach for preventing atherosclerotic lesion progression.
de Nigris
Filomena
F
Department of General Pathology, Excellence Research Center on Cardiovascular Diseases, Complesso S. Andrea della Dame, Via de Crecchio 7, 1st School of Medicine, II University of Naples, 80138 Naples, Italy.
Mancini
Francesco Paolo
FP
Balestrieri
Maria Luisa
ML
Byrns
Russell
R
Fiorito
Carmela
C
Williams-Ignarro
Sharon
S
Palagiano
Antonio
A
Crimi
Ettore
E
Ignarro
Louis J
LJ
Napoli
Claudio
C
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000821:Animal Feed; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use*; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use; D000077261:Carvedilol; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D008077:Lipoproteins, LDL / Q000378:metabolism; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D011412:Propanolamines / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D001578:Benzopyrans; D002227:Carbazoles; D002791:Cholesterol, Dietary; D004983:Ethanolamines; D008077:Lipoproteins, LDL; D011412:Propanolamines; D012333:RNA, Messenger; D000068577:Nebivolol; D000077261:Carvedilol; D009569:Nitric Oxide