Effect of nebivolol on endothelial nitric oxide and peroxynitrite release in hypertensive animals: Role of antioxidant activity.
We tested the activity of nebivolol, a beta1-selective blocker with respect to nitric oxide (NO) and peroxynitrite (ONOO) generation in the endothelium of normotensive Wistar Kyoto (WKY rats) and spontaneously hypertensive rats (SHR). The endothelial effects of nebivolol and its 2 optical enantiomers were correlated with its antioxidant activity and compared to another beta-blocker, atenolol, and 2 agonists of nitric oxide synthase (eNOS), calcium ionophore (CI) and acetylcholine (ACh). The effects of nebivolol on the bioavailability of NO and ONOO, indicators of endothelial function and dysfunction, respectively, were measured in vitro using nanosensors placed in mesenteric arteries. Compared with WKY rats, treatment of SHR vessels either with ACh (1 micromol/L) or CI (1 micromol/L) showed marked deficiencies (>40%, P < 0.01) in bioavailable NO concomitant with increased ONOO levels (>50%, P < 0.01). The [NO]/[ONOO] ratio measured after stimulation with CI was 2.77 +/- 0.05 in WKY rats and much lower (1.14 +/- 0.11) in SHR indicating significant eNOS uncoupling and endothelial dysfunction in hypertensive animals. Treatment with nebivolol (10 micromol/L) inhibited eNOS uncoupling and reduced endothelial dysfunction in SHR, as evidenced by an increase in the [NO]/[ONOO] ratio to 3.09 +/- 0.04. The basis for nebivolol activity is attributed to its unique membrane interactions as determined by small-angle x-ray diffraction, as well as its antioxidant activity at nanomolar to micromolar levels. The antioxidant effects of nebivolol and its enantiomers were not reproduced by atenolol. These results demonstrate that nebivolol inhibits endothelial dysfunction through a potent antioxidant mechanism attributed to its physicochemical interactions with the membrane, independent of beta1-blockade activity.
Mason
R Preston
RP
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Kubant
Ruslan
R
Jacob
Robert F
RF
Walter
Mary F
MF
Boychuk
Bohdan
B
Malinski
Tadeusz
T
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology; D001262:Atenolol / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004983:Ethanolamines / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005583:Fourier Analysis; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D008051:Lipid Bilayers / Q000737:chemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D036103:Nanotechnology / Q000379:methods; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012995:Solubility; D013237:Stereoisomerism; D014961:X-Ray Diffraction / Q000379:methods
D000959:Antihypertensive Agents; D000975:Antioxidants; D001578:Benzopyrans; D004983:Ethanolamines; D008051:Lipid Bilayers; D000068577:Nebivolol; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D000001:Calcimycin; D001262:Atenolol; D000109:Acetylcholine