Impaired Vasodilation in the Pathogenesis of Hypertension: Focus on Nitric Oxide, Endothelial‐Derived Hyperpolarizing Factors, and Prostaglandins

Abstract

J Clin Hypertens (Greenwich). 2012;14:198–205. ©2012 Wiley Periodicals, Inc.

Under resting conditions the arterial vasculature exists in a vasoconstricted state referred to as vascular tone. Physiological dilatation in response to increased flow, a function of normal endothelium is necessary to maintain normal blood pressure. Endothelial dysfunction in vascular smooth muscle cells thus results in loss of normal vasorelaxant function and the inability of arteries to appropriately dilate in response to increased blood flow in either a systemic or regional vascular bed, resulting in increased blood pressure, a sequence that may represent a common pathway to hypertension. Normal vasorelaxation is mediated by a number of endothelial systems including nitric oxide (NO), prostaglandins (PGI₂ and PGE₂), and a family of endothelial‐derived hyperpolarizing factors (EDHF). In response to hemodynamic shear stress, endothelium continuously releases NO, EDHF, and PGI₂ to provide vasodilatation. EDHF, not a single molecule but rather a group of molecules that includes epoxyeicosatrienoic acids, hydrogen peroxide, carbon monoxide, hydrogen sulfide, C‐natriuretic peptide, and K⁺ itself, causes vasodilatation by activation of vascular smooth muscle cell K⁺ channels, resulting in hyperpolarization and thus vasorelaxation. The understanding and effective management of blood pressure requires an understanding of both physiologic and pathophysiologic regulation of vascular tone. This review describes molecular mechanisms underlying normal endothelial regulation and pathological states, such as increased oxidative stress, which cause loss of vasorelaxation. Possible pharmacological interventions to restore normal function are suggested.

The biomarker par excellence of hypertension is chronic elevation of systemic arterial blood pressure (BP) above normal. When BP is abnormally and chronically elevated, it is often assumed that either the cardiac output is too high or abnormal vasoconstriction has increased peripheral vascular resistance. ¹ , ² However, the arterial vasculature basally exists in a vasoconstricted state, known as “vascular tone.” ¹ , ² Thus, the inability of the blood vessels to dilate in response to increased flow may result in an increase in BP. Inability to appropriately vasodilate may occur on a systemic or a regional basis.

Vasodilation in response to increased flow is the function of the normal endothelium through the secretion of nitric oxide (NO), prostacyclin (PGI₂), and endothelial‐derived hyperpolarizing factors (EDHFs). The loss of normal endothelial function results in impaired vasodilation and increased BP and may be a common pathway to the disease hypertension.

Below we describe endothelial systems that mediate vasodilation, ie, NO, EDHFs, and prostaglandins, that have been linked to experimental increases in BP. Also discussed are mechanisms that induce endothelial dysfunction and thus may be of importance in the pathogenesis of hypertension, eg, oxidative stress and diabetes mellitus.

Mechanisms Associated With Endothelial‐Mediated Vasodilation

The Figure illustrates the various mechanisms involved in endothelial‐mediated vasodilation. The reader is encouraged to refer frequently to the Figure to fully appreciate the integrated nature of the response.

Figure 1.

 Vascular smooth muscle relaxation results from cellular hyperpolarization due to a variety of mechanisms that ultimately cause increases in cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP), or transmembrane K⁺ and Na⁺ transport that may occur via gap junctions, ion pumps, direct receptor or channel activation, or direct action of nitric oxide (NO) donors. An array of endothelial‐derived hyperpolarizing factors contributes to the hyperpolarization. ADMA indicates asymmetric dimethylarginine; CaM, calmodulin; COX, cyclooxygenase; CNP, C‐type natriuretic peptide; EET, epoxyeicosatetraenoic acid; eNOS, endothelial nitric oxide synthase; EOX, epoxygenase; HETE, hydroxyleicosa‐tetraenoic acid; K_Ca, Ca²⁺‐activated K⁺ channels; K_IR, inward rectifier; K_ATP, ATP‐dependent; L_Ca, L‐type Ca channel; LOX, lipoxygenase; LT, leukotriene; PLA₂, phospholipase A₂; NPR_B, natriuretic peptide receptor subtype B; PLC, phospholipase C; PRMT, protein arginine N‐methyltransferases. (+), stimulates; (↑), increases. Adapted from Félétou et al ²¹ and Miura et al. ⁴⁴

Nitric Oxide

The principal regulator of endothelial vasodilator function through NO is vascular shear. Shear is the frictional force exerted on the vascular wall secondary to the flow of blood. These forces open calcium channels on endothelial cells, thus promoting the calcium‐dependent activation of endothelial NO synthase (eNOS), which, in turn, induces the release of NO. NO then diffuses to the underlying vascular smooth muscle, where it activates soluble guanylate cyclase, causing an increase in cyclic guanosine monophosphate (cGMP) and smooth muscle relaxation. Constitutive NO synthase (NOS) can be competitively inhibited by guanidine‐substituted analogues of l‐arginine, such as N ^G‐monomethyl‐l‐arginine (L‐NMMA). ³ It is not surprising that administration of these substances to experimental animal results in large increases in systemic arterial BP.

In response to hemodynamic shear stress, the endothelium continuously releases NO, EDHF, and prostaglandins and up‐regulates the gene that expresses NOS; NO provides vasodilation. ⁴ This mechanotransduction is truly remarkable with realization that shear stress is in the range of 10 to 20 dynes/cm² whereas BP, measured in mm Hg, is orders of magnitude greater (1 mm Hg=1333.22 dynes/cm²).

The production of NO is catalyzed by NOS, which convert the amino acid l‐arginine to l‐citrulline and NO. ⁵ , ⁶ NOSs are members of a family of cytochrome P450–like reductases linked to a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme. ⁷ , ⁸ Modulation of NO production is also provided by asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS. ADMA concentrations are a reflection of oxidative stress. ⁹ , ¹⁰

NO plays an important role in regulating systemic vascular resistance, arterial relaxation, and distensibility. Collectively, these actions reduce cardiac hemodynamic load, thereby reducing myocardial hypertrophy and left ventricular dysfunction and protecting target organs. ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ Thus, NO plays a major role in maintaining and regulating BP. ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰

Endothelial‐Derived Hyperpolarizing Factor(s)

The recognition of another endothelial vasodilatory mechanism resulting from K⁺ channel activation led to the concept of an “endothelial‐derived hyperpolarizing factor,” or EDHF. This topic has recently been extensively reviewed. ²¹ , ²² , ²³ While initially thought to be a single substance, it is now apparent that there is no “universal” EDHF. Regional differences in vascular function reflect the complex mechanisms of EDHF, with 2 primary mechanistic pathways implicated: myoendothelial gap junctions mediating the spread of endothelial cell hyperpolarization and/or small signaling molecules to the smooth muscle and diffusible mediators released from the endothelium. What has become apparent is that there are a number of molecules, including at least K⁺ ions, arachidonic acid metabolites (epoxyeicosatrienoic acids), hydrogen peroxide (H₂O₂)_, carbon monoxide (CO), hydrogen sulfide (H₂S), and C‐natriuretic peptide, that cause vasodilation by hyperpolarization and hence relaxation of vascular smooth muscle by activating different K⁺ channels. Furthermore, there exists a separate pathway that produces relaxation of smooth muscle vascular cells by increasing endothelial cell intracellular Ca²⁺ concentration, resulting in the opening of K⁺ channels. ²¹

Potassium Channels

Three subtypes of Ca²⁺‐activated K⁺ channels have been identified in the vascular wall, characterized by large (BK_Ca), intermediate (IK_Ca or K_Ca3.1 isoform), and small (SK_Ca or K_Ca2.3 isoform) conductance. IK_CA and SKCA, especially the SK3 α subunit, are expressed in endothelial cells, but with very specific cellular and subcellular locations.

Following SK_Ca activation, smooth muscle hyperpolarization is preferentially evoked by electrical coupling through myoendothelial gap junctions, whereas following IK_Ca activation, K⁺ efflux can activate smooth muscle Kir2.1 and/or Na⁺/K⁺ATPase. ²¹ , ²² The in vivo relevance of these endothelial K_Ca has been demonstrated in a mutant mouse model with deletion of genes encoding for either or both endothelial SK3 (SK_Ca, K_Ca2.3) and IK1 (IKCa, K_Ca3.1). K⁺ channels in EDHF responses are severely impaired and arterial BPs are elevated. ²⁴ , ²⁵ Combined IK1/SK3 deficiency in IK1(−/−)/SK3(T/T) mice abolished endothelial K_Ca currents and impaired acetylcholine‐induced smooth muscle hyperpolarization and EDHF‐mediated dilation in conduit arteries and in resistance arterioles in vivo. IK1 deficiency had a severe impact on acetylcholine‐induced EDHF‐mediated vasodilation, whereas SK3 deficiency impaired NO‐mediated dilation to acetylcholine and to shear stress stimulation. As a consequence, SK3/IK1‐deficient mice exhibited an elevated arterial BP, which was most prominent during physical activity. Overexpression of SK3 in IK1(−/−)/SK3(T/T) mice partially restored EDHF‐ and NO‐mediated vasodilation and lowered elevated BP. The IK1‐opener SKA‐31 enhanced EDHF‐mediated vasodilation and lowered BP in SK3‐deficient IK1(+/+)/SK3(T/T) mice to normotensive levels. ²⁵ Furthermore, pharmacologic opening of endothelial K_Ca3.1/K_Ca2.3 channels stimulates endothelium‐derived hyperpolarizing factor–mediated arteriolar dilation and lowers BP. ²⁴

C‐Natriuretic Peptide

C‐natriuretic peptide (CNP) has been demonstrated to cause hyperpolarization and relaxation of vascular smooth muscle cells, including those of human forearm resistance vessels. This response results from activation of the B subtype of the naturetic peptide receptor located on vascular smooth muscle. Receptor activation, in turn, leads to stimulation of particulate guanylate cyclase, thus increasing cGMP and subsequent opening of BK_Ca and K_ATP channels. ²⁶ , ²⁷ However, it is most likely that the physiologic effects of CNP are directed more toward preventing smooth muscle proliferation, leukocyte recruitment, and platelet reactivity. As such, endothelium‐derived CNP is likely to exert a strong antiatherogenic influence on blood vessel walls preventing smooth muscle proliferation and thus exerting antiatherogenic activity. ²⁸ , ²⁹

Gasotransmitters

In addition to NO, CO and H₂S are also water‐soluble low molecular weight molecules that easily cross lipid membranes and diffuse homogeneously from synthetic site to target. This novel family of endogenous gaseous transmitters has been termed “gasotransmitters.” Functionally, H₂S has been implicated in the induction of hippocampal long‐term potentiation, brain development, and BP regulation. By acting specifically on K_ATP channels, H₂S can hyperpolarize cell membranes, relax smooth muscle cells, or decrease neuronal excitability. ³⁰ The physiologic cardiovascular effects of H₂S (inflammatory and antioxidant properties, vasodilation, and a decrease in BP) have been linked to the activation of cystathionine beta‐synthase by calcium‐calmodulin; H₂S is produced and released by endothelial cells, in a Ca²⁺‐dependent manner following neurohumoral stimulation and evokes hyperpolarization and relaxation of vascular smooth muscle cells by activating K_ATP. ³⁰ , ³¹ , ³² H₂S production from vascular tissues appears to be enhanced by NO. ³³ Genetic deletion of cystathionine beta‐synthase (cystathionine gamma‐lyase) in mice markedly reduces H₂S levels in the serum, heart, aorta, and other tissues, resulting in pronounced hypertension and diminished endothelium‐dependent vasorelaxation. Such observations support the concept that H₂S is a physiologic vasodilator and regulator of BP. ³⁴

The majority of endogenous CO is catalyzed by inducible (HO‐1) and constitutive (HO‐2) heme oxygenases. The release of CO by vascular cells may modulate blood flow and fluidity by inhibiting vasomotor tone, smooth muscle cell proliferation, and platelet aggregation. CO may also maintain the integrity of the vessel wall by directly blocking vascular cell apoptosis and by inhibiting the release of proapoptotic inflammatory cytokines from the vessel wall. These effects of CO are mediated via multiple pathways, including activation of soluble guanylate cyclase, potassium channels, p38 mitogen‐activated protein kinase, or inhibition of cytochrome P450. ³⁵ , ³⁶

In a chronic renovascular hypertension model, hypertension, cardiac hypertrophy, acute renal failure, and acute mortality induced by one kidney‐one clip surgery were more severe in HO‐1‐null mice. In contrast, mice with cardiac‐specific overexpression of HO‐1 had an improvement in cardiac function, smaller myocardial infarctions, and reduced inflammatory and oxidative damage after coronary artery ligation and reperfusion. ³⁷ Systolic BP of spontaneously hypertensive rats (SHRs) was normalized and this normalization maintained for 9 months after hemin infusion; HO‐1 expression, HO activity, soluble guanylyl cyclase expression, and cGMP content increased, but phosphodiesterase‐5 expression was downregulated in the mesenteric arteries. The infusion also reversed SHR‐featured arterial eutrophic inward remodeling and decreased expression levels of vascular endothelial growth factor. ³⁸ Taken together, these studies suggest that an absence of HO‐1 has detrimental consequences, whereas overexpression of HO‐1 plays a protective role in hypoperfusion and ischemia/reperfusion injury.

Hydrogen Peroxide

Endothelial cells express enzymes that produce reactive oxygen species (ROS) in response to various stimuli, and H₂O₂ is a potent relaxant of vascular smooth muscle and has been postulated to represent yet another endogenous HDHF, playing a key role in the control of resistance artery tone. H₂O₂ itself can mediate endothelium‐dependent relaxations in some vascular beds by potentiating Ca²⁺ release from endothelial stores, probably via redox modification of the InsP₃ receptor with some contribution of gap junctions, leading to the opening of hyperpolarizing endothelial K_Ca channels and an electrotonically mediated relaxant response. Paradoxically, H₂O₂ is a potent vasoconstrictor if K_Ca channels are blocked. ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ Thus, the mechanism of H₂O₂‐induced hyperpolarization appears to be complex, depending on the blood vessel used and the type of vascular wall cells examined. ⁴³ , ⁴⁴ Arterioles from human right atrial appendages obtained at the time of cardiac surgery dilate and hyperpolarize in response to exogenous H₂O₂; dilation is reduced by catalase, providing evidence that shear stress induces endothelial release of H₂O₂ and may contribute to flow‐mediated dilatation in patients with heart disease. ⁴⁵ H₂O₂ flow and agonist‐dependent relaxation has also been reported in endothelium‐stripped human mesenteric arteries. In this model, relaxations to bradykinin were markedly inhibited by catalase. ⁴³

By using rabbit iliac artery rings, hydrogen peroxide, generated by pro‐oxidant effects of ascorbic acid and tetrahydrobiopterin, has been demonstrated to amplify IK_Ca‐ and SK_Ca‐driven hyperpolarization‐mediated relaxation by facilitating IP₃‐mediated Ca²⁺ release from endothelial stores. ²¹ , ⁴⁶

Oxidases

Oxidases, including cytochrome P‐450 epoxygenases, cyclooxygenases (COXs), lipoxygenases, and xanthine oxidases; mitochondrial respirator chain enzymes; and NADPH oxidases can also produce superoxide, which is dismutated by superoxide dismutase into H₂O₂. ⁴³ , ⁴⁵ , ⁴⁷

Epoxyeicosatrienoic Acid

Endothelial epoxyeicosatrienoic acid (EET) hyperpolarized bovine coronary smooth muscle cells by activating BK_Ca (K_Ca1.1) channels. ⁴⁸ Bradykinin induces hyperpolarization of endothelial cells; it also hyperpolarizes myocytes by a mechanism independent of endothelial cell hyperpolarization, which involves endothelial cell production of EETs (most likely 14,15‐ and/or 11,12‐EET), that, in turn, open endothelial IK_Ca and SK_Ca channels and also activate large‐conductance calcium‐sensitive K⁺ channels (BK_Ca) on the surrounding myocytes. ⁴⁹ The 11,12‐EET causes relaxation by activating smooth muscle cell BK_Ca channels in human internal mammary artery. ⁵⁰

Potassium

Lastly, K⁺ ions activate Na⁺/K⁺ pumps and inward rectifier K⁺ channels (K_ir) to cause hyperpolarization. ²³ , ⁵¹ , ⁵²

Prostaglandins

The COX products PGI₂ and PGE₂ relax vascular smooth muscle. ⁵³ , ⁵⁴ , ⁵⁵ PGI₂ is continuously released into the circulation by the lungs to counter platelet aggregation from the release of thromboxane A₂ (TxA₂). ³³ The PGI₂/TxA₂ ratio has been observed to be important; manipulation of this ratio with small doses of aspirin has similar beneficial effects as antithrombotic therapy, ³³ , ⁵⁶ but with little (if any) role in maintaining vasoreactivity in normotensive type 2 diabetic patients. ⁵⁷ , ⁵⁸ Synthesis of PGI₂ is enhanced in the spontaneously hypertensive and Goldblatt hypertensive rat. Metabolism of PGE₂, PGF₂‐α, and PGI₂ by prostaglandin 15‐hydroxydehydrogenase is impaired in genetic models. Responses to endothelium‐dependent vasodilators are impaired in acute and chronic animal models of hypertension. Production of relaxing factor by the endothelium is not inhibited, but rather the vascular smooth muscle fails to respond. Acute, severe hypertension potentiates the response to serotonin, presumably by attenuating the release or response to relaxing factor(s). In the aorta of the SHR, the endothelium releases a constricting factor in response to acetylcholine. Pulmonary arterial endothelium (and other vessels) releases a vasoconstrictor that is blocked by inhibitors of COX; this pressor factor may be TxA₂. Certainly less, PGI₂ is produced in acute and chronic models of hypertension. In severe hypertension the response to serotonin is potentiated by the attenuated response to relaxing factors; this response is blunted in the presence of COX inhibitors. ⁵⁹ In patients with hypertension, production of vasoactive prostanoids is selectively impaired and may contribute to the increased systemic vascular resistance and increased incidence of thrombosis. ⁶⁰ Recent animal studies have shown that PGI₂ may, in fact, paradoxically induce vasoconstriction rather than vasodilatation in certain circumstances. In the aortic rings from SHR and aging Wistar Kyoto rats, the endothelium‐dependent contractions elicited by acetylcholine most likely involve the release of PGI₂ with a concomitant contribution of PGH₂. ⁶¹ , ⁶² Additional studies with rat aortic strips have indicated that PGI₂ induces relaxation through a PGI₂‐PGE₁ receptor; however, higher concentrations of PGI₂ act at the TxA₂‐PGH₂‐receptor to decrease PGI₂‐induced relaxation. ⁶³ , ⁶⁴ , ⁶⁵ Moreover, inhibition of NO with infusion of L‐NMMA has been shown to significantly increase BP and total peripheral artery resistance. ²⁰

Linking Endothelial Dysfunction to Hypertension—Implications for Disease States

Decreased NO Production and Cardiovascular Effects

The cardiovascular effects of reduced NO bioactivity per se are suggested by data from studies in animals and humans. ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ For example, inhibition of NO with L‐NMMA increases arterial stiffness. ¹³ Further, in the pulmonary circulation of eNOS‐deficient mice, there is an increase in pulmonary artery pressure. ⁷⁰ In patients with coronary heart disease, elevated C‐reactive protein level, an inflammatory marker, was shown to be significantly and independently associated with impaired NO bioavailability as measured by forearm blood flow (FBF) vasodilatory response to L‐NMMA. These findings further support the hypothesis that oxidative stress and inflammation are major causes of impaired NO. ⁷¹

Impaired NO and Hypertension

Endothelial dysfunction is often described in individuals with hypertension. ⁷² Multiple studies of flow‐mediated dilatation of the brachial artery, usually examined by venous occlusion plethysmography of FBF, have shown that patients with hypertension exhibit blunted arterial vasodilation in response to endothelium‐dependent vasodilators, such as Ach, while vasodilatory responses to endothelium‐independent vasodilators, such as sodium nitroprusside, are preserved.

Oxidative Stress and Endothelial Dysfunction

Many of those mechanisms contributing to vascular smooth muscle relaxation and vasodilation are depicted in the Figure. The discussion of all possible mechanisms for robbing the endothelium of its ability to vasodilate is beyond the scope of this discussion. However, evidence is accumulating at an ever‐increasing rate that the neutralization of NO by oxidative stress may underlie the endothelial dysfunction that leads to hypertension and atherosclerosis.

The importance of NO in promoting endothelial homeostasis is demonstrated by the association between impaired NO bioactivity and endothelial dysfunction, which is characterized by the imbalance of endothelium‐derived vasoconstrictive and vasodilatory substances, with a shift toward greater vasoconstriction, inflammation, and thrombosis. ⁷²

One proposed mechanism of impaired NO availability and endothelial dysfunction is oxidative stress. ⁷³ , ⁷⁴ Free radical molecules function normally as signals to modulate vascular tone. Oxidative stress exists when pro‐oxidant processes exceed the capacity of antioxidant mechanisms to maintain an appropriate balance. Oxidative stress is produced with increased production of ROS, including superoxide anion that is derived from xanthine oxidase, COX, and NADPH oxidase ⁷⁵ , ⁷⁶ enzyme systems. ROS react with NO forming peroxynitrite, thereby decreasing NO bioactivity. ⁷⁴ , ⁷⁷ Oxidative stress may cause a deficiency of l‐arginine and tetrahydrobiopterin (BH₄). ⁷⁷ , ⁷⁸ BH₄ is an essential cofactor of NOS, along with NADPH, Ca²⁺/calmodulin, and flavin nucleotides. ⁷ , ⁷⁹ , ⁸⁰ , ⁸¹ , ⁸² , ⁸³ , ⁸⁴ , ⁸⁵ , ⁸⁶ Reduced availability of BH₄ causes Enos to produce superoxide instead of NO, a process known as NOS uncoupling; ⁸⁷ , ⁸⁸ this results in increased formation of peroxynitrite (PN), a highly reactive oxidant that can be highly toxic. ⁷³ , ⁸⁹ , ⁹⁰ In certain circumstances, however, PN has been reported to have beneficial effects in the cardiovascular system; therefore, the biologic effects of PN can be paradoxical. ⁷³ , ⁸⁹ , ⁹⁰ , ⁹¹ However, these apparently contradictory responses could well be due to the environment in which studies were conducted. ⁹² The results observed in nonsanguineous studies may be due to the conversion of PN into deleterious mediators with hydroxyl radical‐like activities, whereas in physiologic studies, the beneficial action of PN may be due to reaction of PN with plasma, red cell glutathione, or plasma cysteine and albumin, with the production of NO or an NO donor–like compound. ⁹³ , ⁹⁴ , ⁹⁵ PN induces accumulation of cGMP in a glutathione‐dependent manner in endothelial and smooth muscle cells, and PN produces thiol‐dependent stimulation of purified guanylate cyclase. ⁹⁶

Endothelial‐Mediated Vasodilation and the Cardiometabolic Syndrome (Glucose Metabolism and Insulin Resistance)

Clinical studies have shown that the arterial vasodilating effect of insulin in skeletal muscle, a primary mechanism of insulin sensitivity, is dependent on endothelial NO release. ⁹⁷ , ⁹⁸ Overall, NO appears necessary for regulation of insulin secretion, normal β‐cell function, and insulin sensitivity. ⁹⁹

Insulin Resistance and Diabetes

Decreased NO bioactivity and endothelial dysfunction are associated with insulin resistance and diabetes mellitus. ¹⁹ , ¹⁰⁰ , ¹⁰¹ Because the arterial vasodilating effect of insulin in skeletal muscle is dependent on endothelial NO release, NO impairment would, theoretically, reduce insulin sensitivity. Recent studies suggest that the use of biomarkers of oxidative and nitrosative stress may be the earliest manifestation for the presence of endothelial dysfunction in the development of diabetes, and that some of these studies suggest that this dysfunction may be due to reduced bioavailability of endothelial‐derived NO. ⁷⁵ , ¹⁰² , ¹⁰³ , ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ , ¹⁰⁸ , ¹⁰⁹ , ¹¹⁰ , ¹¹¹ The observed dysfunction of the endothelial NOS/soluble guanylate cyclase/cGMP system is a common mechanism by which cardiovascular risk factors such as diabetes and hypertension mediate their deleterious effects on the vascular wall. ¹¹² , ¹¹³ , ¹¹⁴ , ¹¹⁵ , ¹¹⁶ , ¹¹⁷ , ¹¹⁸ , ¹¹⁹ , ¹²⁰

Conclusions

It is evident that endothelial‐dependent mechanisms play a major role in the regulation of blood flow and BP. There is abundant evidence that dysregulation of these mechanisms may be involved in the pathogenesis of arterial hypertension and the increase in BP that contributes to the target organ damage that ensues. One of the principal mechanisms by which the endothelium produces vasodilation is the production of NO. Interestingly, many pharmacologic agents currently used for the treatment of cardiovascular disease influence NO production, eg, statins, NO donors, antihypertensive drugs (CCBs, ACE inhibitors), use of stimulating sGC drugs, and the vasodilating β‐blocker, nebivolol. Furthermore, there is increasing evidence that manipulation of the various EDHF molecules may also have BP‐lowering effects. It is apparent that effective management of BP requires understanding of both physiologic and pathophysiologic regulation of vascular tone. The appropriate use of existing therapies and the development of new and novel approaches are necessarily based on such an understanding.