NebivololThe Somewhat-Different β-Adrenergic Receptor Blocker
Thomas Münzel, MD* and
Tommaso Gori, MD, PhD
II Medizinische Klinik für Kardiologie/Angiologie, Mainz, Germany
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Figure 1 Mechanisms Underlying Endothelial (Vascular) Dysfunction in Vascular Disease
An unbalanced production of nitric oxide (NO) and superoxide (O2
–) leads to inappropriate formation of peroxynitrite (ONOO–). Peroxynitrite and superoxide cause vascular dysfunction through several mechanisms (reviewed in Forstermann and Munzel [1]). Peroxynitrite is a strong inhibitor of NO and prostacyclin (PGI2) signaling, and it may cause eNOS uncoupling, causing this enzyme to produce superoxide instead of NO. ADMA = asymmetrical dimethylarginine; cGMP = guanosine 3',5'-cyclic monophosphate; cGK = cGMP-dependent kinase; eNOS = endothelial nitric oxide synthase; ET = endothelin; sGC = soluble guanylate cyclase; TXA = thromboxane.
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Figure 2 Oxygen Free Radicals in Cardiovascular Pathophysiology
(Left) Kaplan-Meier analysis demonstrating cumulative proportion of patients without cardiovascular events during follow-up. Effect of vitamin C on acetylcholine-induced vasodilation is divided into values below and above the median. Interestingly, patients who responded well to vitamin C treatment had a worse prognosis compared with patients with a weak response to vitamin C. Thus, a strong vitamin C-induced improvement of endothelial dysfunction may point to increased oxidative stress in coronary arteries as well. (Right) Mechanistic hypothesis: vitamin C may restore eNOS function by either direct scavenging of superoxide (red) or by recoupling of the eNOS. Details in Forstermann and Munzel (1). NOS = nitric oxide synthase; Vit = vitamin; other abbreviations as in Figure 1.
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Figure 4 Mechanisms Underlying Release of NO in Response to Acute Nebivolol Challenges
In renal glomeruli, nebivolol activates mechanosensitive ion channels, which subsequently release adenosine triphosphate (ATP) and stimulate P2Y receptors, causing calcium-dependent eNOS activation (24). Nebivolol or its metabolite may also activate β2 (in conduit arteries) (22) or β3-receptors (in resistance arteries) (23), which also increase intracellular calcium, thereby activating eNOS. cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; ERβ = estrogen receptor beta; other abbreviations as in Figure 1.
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Figure 5 Impact of Nebivolol on Endothelial Responses and Free Radicals Production
Effects of intra-arterial infusion of nebivolol on forearm blood flow in healthy control subjects (A) and patients with essential hypertension (B) (26,27). In both groups, nebivolol but not atenolol caused vasodilation, an effect that was antagonized by endothelial nitric oxide synthase (eNOS) inhibition. (C) Percent change in forearm blood flow in response to the endothelium-dependent vasodilator acetylcholine after treatment with atenolol or nebivolol, respectively. Nebivolol alone markedly improved endothelial function in hypertensive patients (30). (D) Nebivolol, but not other β-blockers, inhibits phorbolester (PDBu)-induced superoxide production in neutrophils from hypercholesterolemic rabbits (34). EPR = electron paramagnetic resonance.
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Figure 6 Typical Tracings of the Changes in NO, O2
–, and ONOO– Concentrations Recorded by Nanosensors From a Single Endothelial Cell Harvested From Age-Matched White and Black Americans
Treatment with nebivolol increased NO and decreased O2
– and ONOO– in cells from black patients compatible with recoupling of eNOS in these endothelial cells (36). Abbreviations as in Figure 1.
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