Abstract
This commentary reviews recent evidence that implicates nitric oxide (NO) as a mediator of β2-adrenoceptor (β2-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 β2 agonists on arterial pulse wave reflection, and 4) therapeutic opportunities offered by the combination of β2 agonist action with selective β1 antagonism. Vascular β2-AR-initiated mechanisms provide a physiologically important control mechanism during exercise. Activation of β2-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 phosphorylation of the endothelial NO synthase (eNOS). In vivo, β2-AR activation limits the rise in blood pressure during exercise and reduces arterial pulse wave reflection. Nebivolol is a selective β1-AR antagonist with vasodilator actions operating through these pathways, offering novel therapeutic opportunities.
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References
Robinson BF, Wilson AG (1968) Effect on forearm arteries and veins of attenuation of the cardiac response to leg exercise. Clin Sci 35:143–152
Chruscinski AJ, Rohrer DK, Schauble E, Desai KH, Bernstein D, Kobilka BK (1999) Targeted disruption of the β2-adrenergic receptor gene. J Biol Chem 274:16694–16700
Brett SE, Ritter JM, Chowienczyk PJ (2000) Diastolic blood pressure changes during exercise positively correlate with serum cholesterol and insulin resistance. Circulation 101:615–622
Steinberg SF, Jaffe EA, Bilezikian JP (1984) Endothelial cells contain beta adrenoceptors. Naunyn-Schmiedeberg’s Arch Pharmacol 325:310–313
Howell RE, Albelda SM, Daise ML, Levine EM (1988) Characterization of beta-adrenergic receptors in cultured human and bovine endothelial cells. J Appl Physiol 65:1251–1257
Molenaar P, Malta E, Jones CR, Buxton BF, Summers RJ (1988) Autoradiographic localization and function of β-adrenoceptors on the human internal mammary artery and saphenous vein. Br J Pharmacol 95:225–233
Ferro A, Queen LR, Priest RM, Xu B, Ritter JM, Poston L, Ward JP (1999) Activation of nitric oxide synthase by β2-adrenoceptors in human umbilical vein endothelium in vitro. Br J Pharmacol 126:1872–1880
Xu B, Li J, Gao L, Ferro A (2000) Nitric oxide-dependent vasodilatation of rabbit femoral artery by β2-adrenergic stimulation or cyclic AMP elevation in vivo. Br J Pharmacol 129:969–974
Benjamin N, Calver A, Collier J, Robinson B, Vallance P, Webb D (1995) Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension 25:918–923
Dawes M, Chowienczyk PJ, Ritter JM (1997) Effects of inhibition of the L-arginine/nitric oxide pathway on vasodilation caused by β-adrenergic agonists in human forearm. Circulation 95:2293–2297
Cardillo C, Kilcoyne CM, Quyyumi AA, Cannon RO, Panza JA (1997) Decreased vasodilator response to isoproterenol during nitric oxide inhibition in humans. Hypertension 30:918–921
Majmudar NG, Anumba D, Robson SC, Ford GA (1999) Contribution of nitric oxide to β2-adrenoceptor mediated vasodilatation in human forearm arterial vasculature. Br J Clin Pharmacol 47:173–177
Yao K, Xu B, Liu YP, Ferro A (2003) Effects of β-adrenoceptor stimulation on endothelial nitric-oxide synthase phosphorylation of human umbilical vein endothelial cells. Acta Pharmacol Sin 24:219–224
Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM (1999) Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399:601–605
Morikawa Y (1967) Characteristic pulse wave caused by organic nitrates. Nature 213:841–842
Nichols WW, O’Rourke MF (1998) McDonald’s blood flow in arteries: theoretical experimental and clinical principles. Arnold, London
Chowienczyk PJ, Kelly R, MacCallum H, Millasseau SC, Andersson T, Gosling RG, Ritter JM, Änggård EE (1999) Photoplethysmographic assessment of pulse wave reflection: blunted response to endothelium-dependent β2-adrenergic vasodilation in type 2 diabetes. J Am Coll Cardiol 34:2007–2014
Wilkinson IB, Hall IR, MacCallum H, Mackenzie IS, McEniery CM, van der Arend BJ, Shu YE, MacKay LS, Webb DJ, Cockcroft JR (2002) Pulse-wave analysis—clinical evaluation of a noninvasive, widely applicable method for assessing endothelial function. Arterioscler Thromb Vascul Biol 22:147–152
Gao YS, Nagao T, Bond RA, Janssens WJ, Vanhoutte PM (1991) Nebivolol induces endothelium-dependent relaxation of canine coronary arteries. J Cardiovasc Pharmacol 17:964–969
Cockcroft JR, Chowienczyk PJ, Brett SE, Chen CP, Dupont AG, Van Nueten L, Wooding SJ, Ritter JM (1995) Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO dependent mechanism. J Pharmacol Exp Ther 274:1067–1071
Dawes M, Brett SE, Chowienczyk PJ, Mant TG, Ritter JM (1999) The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension. Br J Clin Pharmacol 48:460–463
Broeders MAW, Doevendans PA, Bekkers BCAM, Bronsaer R, van Gorsel E, Heemskerk JWM, oude Egbrink MGA, van Breda E, Reneman RS, van der Zee R (2000) Nebivolol: a third generation β-blocker that augments vascular nitric oxide release. Endothelial β2-adrenergic receptor-mediated nitric oxide production. Circulation 102:677–684
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This work was funded in part by grants from the British Heart Foundation, the Wellcome Trust, and Menarini International.
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Ritter, J.M., Ferro, A. & Chowienczyk, P.J. Relation between β-adrenoceptor stimulation and nitric oxide synthesis in vascular control. Eur J Clin Pharmacol 62 (Suppl 1), 109–113 (2006). https://doi.org/10.1007/s00228-005-0017-7
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DOI: https://doi.org/10.1007/s00228-005-0017-7