Eur J Clin Pharmacol (2006) 62: 109–113 DOI 10.1007/s00228-005-0017-7 REVIEW ARTICLE James M. Ritter . Albert Ferro . Philip J. Chowienczyk Relation between β-adrenoceptor stimulation and nitric oxide synthesis in vascular control Published online: 8 November 2005 # Springer-Verlag 2005 Abstract This commentary reviews recent evidence that implicates nitric oxide (NO) as a mediator of β 2 -adreno- ceptor (β 2 -AR)-initiated vasodilatation. Emphasis is placed on the following: 1) in vivo studies that demonstrate potential physiological importance, 2) mechanistic studies performed in vitro in human umbilical vein endothelial cells (HUVEC), 3) effects of β 2 agonists on arterial pulse wave reflection, and 4) therapeutic opportunities offered by the combination of β 2 agonist action with selective β 1 antagonism. Vascular β 2 -AR-initiated mechanisms provide a physiologically important control mechanism during exercise. Activation of β 2 -AR in HUVEC leads to vasodilatation that is partly NO-mediated via activation of protein kinase A (PKA) and of phosphatidylinositol-3 kinase (PI3K)/Akt pathways, leading to serine phosphor- ylation of the endothelial NO synthase (eNOS). In vivo, β 2 -AR activation limits the rise in blood pressure during exercise and reduces arterial pulse wave reflection. Nebivolol is a selective β 1 -AR antagonist with vasodilator actions operating through these pathways, offering novel therapeutic opportunities. Keywords β 2 adrenoceptors . Nitric oxide . Pulse wave reflection Introduction The sympathetic nervous system contributes to basal vasoconstrictor tone via the release of norepinephrine from nerve terminals and activation of α 1 -adrenoceptors (α 1 -AR), whereas in human resistance arteries, the endo- thelial L-arginine/nitric oxide (NO) system contributes active basal vasodilator tone. Thus antagonists of α 1 -AR, such as phentolamine, or of NO biosynthesis, such as N G - monomethyl-L-arginine (L-NMMA), respectively reduce or increase resistance vessel tone and influence arterial blood pressure accordingly. β-AR are also present in resistance vessels, but conventional β-AR antagonists have little or no effect on basal resistance vessel tone [1]. Consequently, β-AR have been considered relatively unimportant in determining blood pressure or blood flow under basal conditions. However, it has recently been demonstrated that disruption of the β 2 -AR gene in knockout mice, while not affecting basal blood pressure, increases by approximately 10 mmHg the rise in mean blood pressure that accompanies exercise [2]. In humans, there is a positive correlation between serum total choles- terol (a metabolic risk factor for cardiovascular disease that is known to cause endothelial dysfunction) and the change in diastolic blood pressure accompanying mild exercise [3]. These authors also observed a greater rise in diastolic blood pressure in type 2 diabetic subjects compared with healthy matched controls. Taken together, these observations suggest the possibi- lities that vascular β-AR may be functionally important during exercise or other hemodynamic stimuli and that this mechanism could be deficient in conditions associated with impaired endothelial cell function. It is known that vascular endothelial cells contain β 2 -AR [4–6], adding plausibility to this latter possibility. In this commentary we do not attempt an exhaustive review of the literature but rather focus on the following: 1) evidence that β 2 -mediated vasodilatation is partly or completely NO-mediated in resistance vasculature in vivo, 2) studies with human umbilical vein endothelial cells (HUVEC) aimed to investigate mechanisms whereby β 2 -AR activation could increase NO biosynthesis, 3) effects of β 2 agonists on arterial pulse wave reflection, including evidence that this is mediated via NO, and 4) the possibility that β 2 -AR stimulation offers therapeutic opportunities. J. M. Ritter (*) . A. Ferro . P. J. Chowienczyk Division of Cardiovascular Medicine, Department of Clinical Pharmacology, St Thomas’ Hospital, GKT, London, UK e-mail: james.ritter@kcl.ac.uk Tel.: +44-20-71881502 Fax: +44-20-74012242