Exploring Vascular Benefits of Endothelium-Derived Nitric Oxide

AJH 2005; 18:177S-183S Exploring Vascular Benefits of Endothelium-Derived Nitric Oxide John R. Cockcroft Although the regulation of arterial blood flow has been a subject of intensive medical research, the precise circulatory mechanisms involved are still not fully understood. It has been increasingly recognized that the endothelium plays a vital role in regulating vascular tone, structure, and function. A seminal discovery was made with the identification of endothelium-derived relaxing factor, a key mediator of vasodilation, which was later identified as nitric oxide (NO). Nitric oxide is synthesized from the amino acid L-arginine in the endothelium. Decreased bioavailability of NO is associated with arterial stiffness, hypertension, atherosclerosis, and cardiovascular disease (CVD). Nebivolol is a novel ␤-blocker that is highly selective for ␤1-adrenergic receptors. Nebivolol also causes vasodilation through a mechanism involving endotheliumderived NO. In clinical studies in hypertensive subjects, nebivolol significantly improves vasodilator responses to endothelium-dependent agonists such as acetylcholine. In addition, nebivolol significantly reduces pulse wave velocity (PWV), a measure of arterial stiffness, whereas the ␤-blocker atenolol has no effect on PWV. Because endothelial dysfunction and arterial stiffness play an integral part in the early atherosclerotic process and are associated with poor outcomes and increased mortality, independent of blood pressure, the ability of nebivolol to enhance release of endothelium-derived NO may have significant clinical implications for the use of this agent in the treatment of hypertension and CVD. Am J Hypertens 2005; 18:177S-183S © 2005 American Journal of Hypertension, Ltd. M soactive substances, including NO.2,3 Endothelial dysfunction, characterized by decreased bioavailability of NO, contributes to hypertension, atherogenesis, and the progression of CV disease (CVD).2– 4 Therefore, the effects of an antihypertensive agent on endothelial dysfunction may be important in terms of that drug’s ability to provide end-organ protection, independent of blood pressure (BP) lowering, and to reduce the risks of CV morbidity and mortality.5–7 This article reviews the known functions of endothelium-derived NO and the effects of the novel ␤-blocker nebivolol on the NO pathway. Key Words: Nitric oxide, endothelium, hypertension, cardiovascular disease, arterial stiffness, pulse wave velocity, nebivolol. odern understanding of the circulation of blood and the cardiovascular (CV) system may be traced to the publication in 1628 of Dr. William Harvey’s famous treatise “On the Motion of the Heart and Blood in Animals.”1 Harvey, an eminent English physician, showed that blood is passed through the lungs, propelled through the arteries by the pulsations caused by the contractions of the left ventricle of the heart, and returned to the heart through the veins. He also hypothesized that the arteries close to the heart are larger and thicker than veins, and are distensible because they “sustain the shock of the impelling heart and streaming blood.” Almost 400 years later, however, the precise mechanisms of the arteries in regulating the flow of blood in health and in disease states remain elusive. A major research focus remains on the functions and effects of the endothelium, the inner lining of the epithelial cells of the heart and blood vessels, and its release of the vasodilator nitric oxide (NO). The endothelium is a dynamic organ that regulates vascular tone, structure, and function by sensing various physiologic stimuli and triggering release of multiple va- The endothelium plays an essential role in vasodilation. In an early, seminal in vitro experiment, Furchgott and Zawadzki8 found that unintentional rubbing of the intimal surface of a helical strip of a rabbit descending aorta decreased the vasodilating effect of acetylcholine (ACh) on the strip. The investigators then compared the effects of Received September 19, 2005. First decision September 21, 2005. Accepted September 21, 2005. From the Department of Cardiology, Wales Heart Research Institute, Cardiff University, Cardiff, United Kingdom. Address correspondence and reprint requests to Dr. John R. Cockcroft, Department of Cardiology, Wales Heart Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom; e-mail: © 2005 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc. Benefits of Endothelium-Derived Nitric Oxide 0895-7061/05/$30.00 doi:10.1016/j.amjhyper.2005.09.001 178S NITRIC OXIDE AND HEMODYNAMICS % Change in TPRI % Change in MAP N-monomethyl-L-arginine (3 mg/kg) IV/5 min (shaded area) 15 * * * 10 * 5 0 –5 60 50 40 30 20 10 0 * * –30 –15 0 * 15 30 45 60 75 90 Minutes FIG. 1. Infusion of 3 mg/kg N-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, significantly increased mean arterial pressure (MAP) by 10% (P ⬍ .05) and increased total peripheral resistance by 46%, compared with saline placebo, in eight healthy subjects.14 TPRI ⫽ total peripheral resistance index. *P ⬍ .05. Healthy Male Subjects (n = 8) Blood Flow (ml/min/100 mL of forearm volume) ACh on rubbed and unrubbed strips and found that the unrubbed strips were markedly more sensitive to the vasodilating effect of ACh. However, rubbing had no effect on response to vasoconstrictive agents, and rubbing of the adventitial surface of the strip, in contrast to the intimal surface, had no effect on the response to ACh, suggesting that the response observed was selectively endotheliumderived and involved vasodilation of vascular smooth muscle cells. Furchgott and Zawadzki were unable, however, to identify the vasodilating substance or substances released by the endothelium, which became known as endothelium-derived relaxing factor. Endothelium-derived relaxing factor has subsequently been identified as NO.9,10 A number of other vasodilators have since been shown to depend on the integrity of the vascular endothelium for their activity, including bradykinin and substance P.11,12 An important component of such endothelium-dependent responses consists of calciumdependent activation of a constitutive enzyme NO synthase, which catalyses the conversion of the amino acid 10 L-arginine to L-citrulline and NO. Once synthesized, NO diffuses to the underlying vascular smooth muscle where it activates soluble guanylate cyclase, leading to an increase in cyclic guanosine-3,5=-monophosphate and relaxation.10 Constitutive NO synthase can be competitively inhibited by guanidine-substituted analogs of L-arginine, such as N-monomethyl-L-arginine (L-NMMA).13 Inorganic nitrates, such as sodium nitroprusside, can activate the same effector pathway by providing an inorganic source of NO. Their activity is thus not dependent on the functional integrity of the vascular endothelium.13 Endothelium-dependent relaxation is reduced in patients with essential hy (...truncated)