Journal of Human Hypertension (2000) 14, 617–630 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh REVIEW ARTICLE Working under pressure: the vascular endothelium in arterial hypertension LE Spieker, G Noll, FT Ruschitzka, W Maier and TF Lu¨ scher Cardiology, University Hospital, Zu¨ rich, Switzerland The vascular endothelium synthesizes and releases a dative stress plays an important role in the pathogen- spectrum of vasoactive substances like nitric oxide (NO) esis of hypertension. Superoxide anions, ie, oxygen rad- and endothelin (ET). In hypertension, the delicate bal- icals produced in part by angiotensin II-activated ance of endothelium-derived factors is disturbed. ET NAD(P)H oxidase, can scavenge NO to form peroxy- acts as the natural counterpart to endothelium-derived nitrite, which can nitrosylate membrane proteins and NO, which exerts vasodilating, antithrombotic, and anti- oxidize lipids. Another source of superoxide is cyclo- proliferative effects, and inhibits leukocyte-adhesion to oxygenase. Paradoxically, dysfunctional endothelial NO the vascular wall. Besides its blood pressure rising synthase may also be a source of superoxide anions. effect also in man, ET induces vascular and myocardial Surprisingly and in contrast to animal experiments, not hypertrophy, which are independent risk factors for car- all antihypertensive treatments consistently restore diovascular morbidity and mortality. The derangement endothelium-dependent vasodilation in patients with of endothelial function in hypertension is likely to be arterial hypertension. Endothelial dysfunction in hyper- caused in part by genetic factors, but also due to elev- tension is crucial both for the development of the ated blood pressure itself. Due to its position between disease process in the vasculature and an important blood pressure and smooth muscle cells responsible for therapeutic target. peripheral resistance, the endothelium is thought to be Journal of Human Hypertension (2000) 14, 617–630 both target and mediator of arterial hypertension. Oxi- Keywords: nitric oxide; endothelin; atherosclerosis; free radicals; superoxide anions Introduction ate cyclase leading to relaxation of the smooth mus- cle cells.7 The vascular endothelium synthesizes and releases NO is synthesized by NO synthase from L-argi- a spectrum of vasoactive substances and therefore nine.7 The conversion from L-arginine to NO can be plays a fundamental role in the basal and dynamic inhibited by false substrates for the NO synthase, eg, 1 regulation of the circulation. Due to its strategic by NG-monomethyl-arginine (L-NMMA).8 Since anatomical position, the endothelium is constantly there is a continuous basal release of NO which exposed to the different risk factors for atheroscler- determines the tone of peripheral blood vessels, sys- osis. This review will focus on the role of the vascu- temic inhibition of NO synthesis causes an increase lar endothelium in arterial hypertension, a major in arterial blood pressure.9–13 There are two types of risk factor for the development of cardiovascular NO synthases: a constitutive and an inducible iso- disease. form. The former, which is present in endothelial cells, is therefore called endothelial NO synthase Nitric oxide (eNOS), the latter is an important inflammatory mediator released by macrophages in response to Nitric oxide (NO)—originally described as endo- immunological stimuli.14 NO has also antithrombo- thelium-derived relaxing factor (EDRF)—is released genic, antiproliferative, leukocyte-adhesion in- from endothelial cells in response to shear stress hibiting effects, and influences myocardial contrac- produced by blood flow, and in response to acti- tility.10,13,15,16 vation of a variety of receptors (Figure 1).2–4 NO is a free radical gas with an in vivo half-life of a few seconds, which is readily able to cross biological Nitric oxide in experimental hypertension membranes.2,5,6 After diffusion from endothelial to Endothelium-derived NO-mediated vascular relax- vascular smooth muscle cells, NO increases intra- ation is impaired in spontaneously hypertensive cellular cyclic guanosin-monophosphat (cGMP) animals.17–20 Thus, the bioavailability of NO is concentrations by activation of the enzyme guanyl- reduced. Surprisingly, the NO pathway is paradoxi- cally upregulated in the resistance circulation and the heart of spontaneously hypertensive rats 21,22 Correspondence: Dr Thomas F Luscher, Cardiology, University (SHR). Adult SHR possess a higher activity of ¨ 23 Hospital, CH – 8091 Zu¨rich, Switzerland eNOS than their normotensive counterparts. Very Received and accepted 2 February 2000 young pre-hypertensive SHR have, in contrast, The endothelium in hypertension LE Spieker et al 618 Figure 1 Endothelium-derived vasoactive substances. Nitric oxide (NO) is released from endothelial cells in response to shear stress and to activation of a variety of receptors. NO exerts vasodilating and antiproliferative effects on smooth muscle cells and inhibits thrombocyte-aggregation and leukocyte-adhesion. Endothelin-1 (ET-1) exerts its major vascular effects—vasoconstriction and cell pro- liferation—through activation of specific ETA receptors on vascular smooth muscle cells. In contrast, endothelial ETB receptors mediate vasodilation via release of nitric oxide and prostacyclin. Additionally, ETB receptors in the lung were shown to be a major pathway for the clearance of ET-1 from plasma. ACE denotes angiotensin-converting enzyme; ACh, acetylcholine; AII, angiotensin II; AT1, angiotensin 1 recetor; BK, bradykinine; COX, cyclooxygenase; ECE, endothelin-converting enzyme; EDHF, endothelium-derived hyper- polarizing factor; ETA and ETB, endothelin A and B receptor; ET-1, endothelin-1; L-Arg, PGH2, prostaglandin H2; PGI2, prostacyclin; S, serotoninergic receptor; Thr, thrombine; T, thromboxane receptor; TXA2, thromboxane; 5-HT, 5-hydroxytryptamine (serotonine). Modified from Lu¨ scher and Noll.231 lower eNOS activity than young normotensive rats phyrinic microsensor in SHRSP confirmed that without a genetic background for hypertension, hypertension is associated with increased NO indicating that the increased activity of eNOS in decomposition by superoxide anions, ie, free oxygen adult SHR is indeed related to hypertension (Figure radicals (Figure 3).26 2). Moreover, the plasma concentrations of the oxi- In other models of hypertension—ie, in Dahl salt- dative product of NO metabolism, nitrate, are higher sensitive rats, in two-kidney, one clip experimental in hypertensive rats than in normotensive con- hypertension, and in DOCA-salt hypertensive rats— trols.21 These results indicate that the basal release endothelium-dependent relaxation is also im- of NO is increased in hypertensive rats. paired.27–31 However, NO production by eNOS is Thus, it appears that in SHR, there must be a fac- rather reduced than upregulated in Dahl salt-sensi- tor blunting the haemodynamic effect of NO.24 tive rats (Figure 3).29,32,33 L-arginine, the substrate of Indeed, NO production is increased in stroke-prone NO production by eNOS, normalizes blood pressure SHR (SHRSP), but bioavailability is reduced.25 and simultaneously increases urinary excretion of Direct in situ measurement of NO release by a por- nitrate, the degradation product of NO, in Dahl salt- Figure 2 Increased activity of constitutive nitric oxide synthase in cardiac endothelium of spontaneously hypertensive rats (SHR, black bars). Adult SHR possess a higher activity of constitutive nitric oxide synthase (NOS) than their normotensive counterparts (Wystar– Kyoto rats, WKY; open bars). Very young pre-hypertensive SHR have, in contrast, lower constitutive NOS activity than the normotens- ive, indicating that the increased activity of NOS in adult SHR is indeed related to hypertension. Modified from Nava et al.23 Journal of Human Hypertension The endothelium in hypertension LE Spieker et al 619 Figure 3 Heterogeneity of endothelial dysfunction in experimental hypertension. In spontaneous hypertension (left panel) nitric oxide synthase (NOS) is upregulated and nitric oxide (NO) is inactivated by superoxide anions. In addition, the production of thromboxane (TXA2) and prostaglandin H2 (PGH2) is increased. In salt-related hypertension (right panel) NO production is reduced and the endothelin (ET) system is upregulated. ACE denotes angiotensin-converting enzyme; ACh, acetylcholine; AII, angiotensin II; AT1 angiotensin 1 recetor; cGMP, cyclic guanosine monophosphate; COX, cyclooxygenase; ETA and ETB, endothelin A and B receptor; ET-1, endothelin- − 1; L-Arg, L-arginine; M, muscarinergic receptor; O2, superoxide anion; PGI2, prostacyclin; S, serotoninergic receptor; T, thrombine receptor; Thr, thrombine; TX, thromboxane receptor; 5-HT, 5-hydroxytryptamine (serotonine). Modified from Lu¨ scher and Noll.231 sensitive rats.34–37 Further mechanisms contribute to human forearm and coronary vascular beds are the pathogenesis of salt-sensitive hypertension, eg, strongly correlated.56,57 decreased expression of endothelial endothelin B Basal NO activity is decreased in hypertensive receptors, which mediate NO release,30,32,38 and alt- patients.58 Furthermore, urinary excretion of the ered expression of the constitutive brain NOS as metabolic oxidation product of NO, 15N nitrate, after well as the inducible NOS isoform, possibly leading administration of 15N-labelled arginine (ie, the sub- to alterations in renal sympathetic nervous activity strate for the generation of NO) is