Journal of Human Hypertension (2002) 16, 459–467 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh REVIEW ARTICLE Participation of renal and circulating endothelin in salt-sensitive essential hypertension F Elijovich, and CL Laffer Department of Medicine, College of Human Medicine, Michigan State University, Medical Education and Research Center of Grand Rapids, MI, USA Salt sensitivity of blood pressure is a cardiovascular depending on their site of generation and binding to dif- risk factor, independent of and in addition to hyperten- ferent receptors. We review the available data on endo- sion. In essential hypertension, a conglomerate of clini- thelin in salt-sensitive essential hypertension and con- cal and biochemical characteristics defines a salt-sensi- clude that abnormalities of renal endothelin may play a tive phenotype. Despite extensive research on multiple primary role. More importantly, the salt-sensitive patient natriuretic and antinatriuretic systems, there is no may have blood pressure-dependency on endothelin in definitive answer yet about the major causes of salt-sen- all states of salt balance, thus predicting that endothelin sitivity, probably reflecting the complexity of salt- receptor blockers will have a major therapeutic role in balance regulation. The endothelins, ubiquitous pep- salt-sensitive essential hypertension. tides first described as potent vasoconstrictors, also Journal of Human Hypertension (2002) 16, 459–467. doi: have vasodilator, natriuretic and antinatriuretic actions, 10.1038/sj.jhh.1001419 Keywords: endothelin; salt sensitivity; salt; blood pressure Introduction biochemical characteristics that are common in salt- sensitive hypertensive humans. They include high It has long been known that blood pressure (BP) prevalence in African Americans,4,6,7 increasing responses to salt-loading and unloading are hetero- prevalence with aging,1,8 low PRA with blunted geneous and exhibit a Gaussian distribution in both responses to its physiological stimuli2 or normal normotensive and hypertensive human beings. It PRA in so-called ‘non-modulators’ of renal blood took several decades to produce the evidence that flow,9 a suppressed kallikrein-kinin system10,11 and salt-sensitivity and salt-resistance of BP are pheno- excess activation of the arginine-vasopressin pressor types, rather than a reflection of random variability system.12 Associations with gender,4,13 a hyperactive of BP responses to salt. Hence, these responses are 4,14 1 sympathetic system, a hypoactive dopaminergic reproducible over time, reproducible when meas- system,15 obesity and insulin resistance are contro- ured with different protocols,2 and closely associa- 3 versial, which may be explained if salt-sensitivity of ted in mono and dizygotic twins. BP is not a pure phenotype. This is supported by Different methods have been employed to study the finding of opposite alterations of insulin sensi- salt-sensitivity of BP in humans, including rapid tivity in the low-renin vs non-modulating groups of intravenous salt loading and pharmacologic salt-sensitive hypertensive patients.16 (furosemide) salt depletion,4 and prolonged dietary Perhaps the most relevant findings emerging from salt manipulation.2 The magnitude of BP responses the studies of salt-sensitivity of BP are the prognos- employed as a cut-off for definition of salt-sensi- tic ones. There is evidence that salt-sensitive hyper- tivity vs salt-resistance has been set at different arbi- tensive patients exhibit excess prevalence or sever- trary levels by different laboratories.4,5 ity of left ventricular diastolic dysfunction17 and Despite these methodological issues, there has hypertrophy18 (perhaps linked to decreased noctur- been remarkable agreement on several clinical and nal ‘dipping’ of BP19) and increased incidence of stroke20 and severity of microalbuminuria.21 This end-organ damage pattern resembles that of salt- Correspondence: F Elijovich, MD, FAHA, Professor of Medicine, CHM, MSU, Grand Rapids Medical Education and Research sensitive hypertensive rats, such as DOC-salt and Center, 1000 Monroe Avenue NW, Grand Rapids, Michigan Dahl-salt-sensitive (SS). Most recently, Weinberger 49503, USA. E-mail: fernandoelijovichȰgrmerc.net and co-workers have provided evidence that salt- Endothelin and salt-sensitive hypertension F Elijovich and CL Laffer 460 sensitivity of BP of normotensive individuals carries All research on mechanisms of salt-sensitivity of with it the same detrimental long-term prognosis BP in humans or animals can be conceptualised, (mortality) as hypertension in salt-resistant within this framework, as experiments in which patients.22 This emphasises the need for continued either nature or the investigator has ‘clamped’ one research on the cause(s) of salt-sensitivity or on its of these systems, avoiding its normal regulation by intermediate mechanisms, particularly if the results salt intake and therefore producing salt-sensitivity of these studies can be exploited for the tailoring of BP (ie, a ‘shift’ in the pressure natriuresis curve, and targeting of specific therapy to salt-sensitive Figure 1, right panel). patients. ‘Clamping’ of pressor-antinatriuretic systems at a stimulated level that is only appropriate for a low- Complexity of the search for cause(s) of salt intake can be produced by: (a) exogenous administration (eg, experimental angiotensin II- salt-sensitivity of BP infusion and DOC-salt hypertension in the rat); (b) The identification of the gene or genes involved in inbreeding of a biochemical abnormality (eg, determining salt-sensitivity of BP would be facili- increased vasopressin levels24 or endogenous inhibi- tated by a precise characterisation of the salt-sensi- tors of nitric oxide synthase25 in Dahl SS rats; over- tive intermediate phenotype. There have been production of vasoconstrictor 20-HETE26,27 or innumerable studies of alterations in pressor/ impaired downregulation of sodium retaining insu- depressor and natriuretic/antinatriuretic systems in lin receptors28 in spontaneous hypertensive rat (SHR) kidney; and mutations in adducin with salt-sensitive animals and humans, attempting to + + refine the definition of this phenotype, and some increased Na /K pump activity in Milan rats29); or candidate genes have been proposed by linkage and (c) spontaneous gene polymorphisms in humans (eg, association studies (see review by Luft23). However, shorter intronic repeats of the 11-HSD2 gene with the search remains somewhat elusive, which is most decreased activity of the enzyme and increased cor- likely accounted for by the complexity of the factors tisol-induced mineralocorticoid effect,30 and and interactions that regulate salt balance. Figure 1 mutations in the G-protein ␤3 subunit with (left panel) provides a scheme, derived from the increased activity of the salt-retaining antiporter classical studies of Guyton and coworkers, indicat- transport system31). ing that the intact animal, as opposed to an isolated Analogously, depressor-natriuretic systems may kidney, is salt-resistant because during a salt load, be ‘clamped’ at their suppressed level only appro- several pressor-antinatriuretic systems are inhibited, priate for a low-salt intake, thus leading to salt-sen- while several depressor-natriuretic systems are con- sitivity of BP when the animal or subject is given a comitantly stimulated. This permits excretion of the salt-load. Examples include: (a) exogenous inhi- salt-load without the need to resort to pressure natri- bition of the natriuretic sensory nervous system,32 uresis. nitric oxide,33–35 or natriuretic eicosanoids;36 (b) knockout of the proANP gene in mice;37 (c) inbreed- ing of biochemical abnormalities such as deficient renal medullary natriuretic 20-HETE38 or nitric oxide33,34,39 in Dahl SS rats; and (d) blunting of ANP,40 nitric oxide,41 kallikrein,10,11 dopami- nergic,15 and ␤2 adrenergic42 systems as described in salt-sensitive hypertensive humans. Thus, alterations in any of the multiple mech- anisms that regulate salt balance may lead to salt- induced hypertension. This multiplicity, com- pounded by the interactions between these regulat- ory systems, has produced lack of definitive answers regarding the major causes of salt-sensitivity of BP. Kidney transplantation experiments and salt-sensitivity of BP Figure 1 Schematic representation of the mechanisms through Experiments conducted soon after the development which salt-sensitivity of BP is established. On the left, there is of the Dahl strains of salt-sensitive (SS) and salt- no change in BP from a low to a high salt intake because there is concomitant stimulation of depressor-natriuretic and inhi- resistant rats (SR), provided an important clue for bition of pressor-antinatriuretic systems. Thus, the sodium load research on the mechanisms of salt-sensitivity of BP, is excreted without the need for pressure natriuresis. In contrast, ie, that the recipient animal acquires the BP of the one or several of these salt-regulating mechanisms have been kidney donor.43 This is even observed when the kid- clamped in the right panel, at the level that is physiologic for a low salt intake. In the absence of these regulatory mechanisms, neys of young (8–9 weeks old) Dahl SR are trans- BP increases in response to a salt-load, to participate in the resto- planted into salt-fed, adult Dahl SS rats, with nor- ration of salt balance via pressure-natriuresis. malisation of the established hypertension of the Journal of Human Hypertension Endothelin