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(Hypertension. 1999;34:876-881.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Role of Endothelin-1 in Hypertension

Ernesto L. Schiffrin

From the MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montréal (IRCM), Québec, Canada.

Correspondence to Ernesto L. Schiffrin, MD, PhD, Clinical Research Institute of Montréal, 110, Avenue des Pins Ouest, Montréal, Québec, Canada H2W 1R7. E-mail schiffe{at}ircm.qc.ca

	Abstract

Top Abstract Introduction Role of Endothelins in... Role of ET-1 in... Pathophysiology of the... Effect of Endothelin Antagonism... Conclusions References

 
Abstract—Endothelin-1 (ET-1) is overexpressed in the vascular wall in certain models of experimental hypertension: deoxycorticosterone acetate salt–treated rats, deoxycorticosterone acetate salt–treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt–sensitive rats, angiotensin II–infused rats, and 1-kidney 1 clip Goldblatt rats; it is not overexpressed in SHR, 2-kidney 1-clip hypertensive rats, or L-NAME–treated rats. In hypertensive rats without generalized vascular overexpression, however, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of endothelin in myocardial ischemia in hypertension. In rats overexpressing ET-1, ET_A/B and ET_A-selective receptor antagonists lowered blood pressure and reduced vascular growth, particularly in small arteries, beyond what could be attributed to blood pressure lowering, suggesting a direct effect of ET-1 on growth. Hypertensive rats treated with endothelin antagonists are protected from stroke and renal injury. The ET_A/B antagonist bosentan induced blood-pressure reductions in mildly hypertensive patients similar to those achieved with an angiotensin-converting enzyme inhibitor. Moderately to severely hypertensive patients presented with enhanced expression of prepro-ET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that these stages of hypertension may respond particularly well to endothelin antagonism. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1, and increased plasma levels of immunoreactive endothelin have been described in black patients. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor. Thus, ET-1 may be involved in experimental and human hypertension. Endothelin antagonists may prove effective as disease-modifying agents if they are shown clinically, as they are experimentally, to offer target organ protection and reduce long-term complications of hypertension. This remains to be demonstrated in humans.

Key Words: endothelin • hypertension, human essential • coronary artery disease • vascular hypertrophy

	Introduction

Top Abstract Introduction Role of Endothelins in... Role of ET-1 in... Pathophysiology of the... Effect of Endothelin Antagonism... Conclusions References

 
The endothelins are potent 21-amino acid vasoconstrictor peptides encoded by 3 genes and produced in many different tissues, particularly the endothelium of blood vessels.^{1 2} Endothelin-1 (ET-1), the main endothelin generated in the endothelium, acts in a paracrine or autocrine manner on ET_A and ET_B receptors on adjacent endothelial or smooth-muscle cells. The genes for ET_A and ET_B receptors have been cloned.^{3 4} ET_A and ET_B receptors on smooth muscle induce contraction and stimulate proliferation and cell hypertrophy.⁵ Endothelial ET_B receptors stimulate the production of nitric oxide and prostacyclin and, accordingly, elicit vasorelaxation.⁶ It is unclear whether the vasoconstrictor or vasorelaxant action of ET-1 is the predominant physiological effect. This may vary in different vascular beds.

Mice in which the ET-1 gene has been inactivated exhibit a slight elevation of blood pressure,⁷ which may result from hypoxemia resulting from the craniofacial developmental abnormalities that occur in this experimental paradigm or it may be an expression of a predominant vasodilator action of ET-1. A recent study evaluated this by using crosses of mice heterozygous for targeted disruption of the ET_B receptor (-/+) with mice homozygous for the piebald mutation of the ET_B gene (s/s).⁸ The progeny have ET_B receptor levels of 1/8 (-/s) to 1/5 (+/s) of the wild type (+/+). ET_B^-/s mice exhibit elevated blood pressure. If the mice were treated with the ET_B receptor antagonist BQ-788, blood pressure increased in the ET_B^+/s and ET_B^+/+ mice but not in the ET_B^-/s mice, suggesting that the endothelin system plays a hypotensive role via the ET_B endothelial receptor. Moreover, this phenomenon was mediated through the production of prostaglandins.

In some vascular beds, such as the coronary circulation, ET-1 acts as a vasoconstrictor as a result of the virtual absence of endothelial ET_B receptors.⁹ This may underlie, in part, the role of ET-1 in coronary ischemia. There may be species differences, and in some animal models, ET-1 may induce coronary dilatation. ET-1 is probably an important regulator of tissue blood flow through both its constrictor and dilator effects on blood vessels, and it may only act on smooth-muscle cells as a pathophysiologically important constrictor and growth promoter when it is overexpressed in the vascular wall under pathological conditions.

There are important actions of endothelins in the central and peripheral nervous systems¹⁰ that may have an important impact on the pathophysiology of hypertension, but they will not be addressed here. ET-1 is also involved in the regulation of renal function and pathophysiologically in the progression of renal failure. This will only be superficially discussed because of space constraints, and this review will concentrate on blood vessels and the heart.

ET-1 is produced in the heart by endothelial cells, by smooth muscle cells of blood vessels, and by interstitial fibroblasts and cardiomyocytes. Wall stretch,¹¹ ischemia,¹² and angiotensin II are some pathophysiologically important stimuli that can trigger its production.¹³ Cardiomyocytes express mostly ET_A receptors. In cardiac fibroblasts, a mixed population of ET_A and ET_B receptors can be found.¹⁴ ET-1 stimulates the expression of fetal genes and protein synthesis and growth in cardiomyocytes.^{13 15} In the kidney, ET_A receptors induce vasoconstriction, which reduces renal blood flow, glomerular filtration rate, and K_f, and exert salt-retaining effects through their actions on renal tubuli.^{16 17} ET_B receptors have potentially important natriuretic actions on the distal nephron.¹⁸

	Role of Endothelins in Experimental Hypertension

Top Abstract Introduction Role of Endothelins in... Role of ET-1 in... Pathophysiology of the... Effect of Endothelin Antagonism... Conclusions References

 
The endothelin system is activated in several salt-sensitive models of hypertension: the deoxycorticosterone acetate (DOCA) salt hypertensive rat,^{19 20 21} DOCA salt–treated spontaneously hypertensive rats (SHR),²² Dahl salt–sensitive rats,²³ 1-kidney 1-clip Goldblatt hypertensive rats,²⁴ and stroke-prone SHR.²⁵ Endothelial overexpression of prepro-ET-1 mRNA²⁶ and a hypotensive response to endothelin antagonism^{21 26 27 28 29} have allowed an endothelin-dependent component to be identified (Table). The endothelin system does not appear to play an important role in SHR.^{19 22 30 31 32} However, some reports have suggested that increased vasoconstrictor responses to ET-1^{33 34} and a role for endothelins exist in SHR. These differences may reflect differences in strains of hypertensive rats and experimental approaches. Activation of vascular endothelin production is associated with hypertrophic remodeling of resistance arteries.^{21 22} When endothelin antagonists were given to rat models overexpressing ET-1, arterial hypertrophic remodeling regressed and blood pressure was lowered.^{21 28 29} This effect of endothelin antagonists may be due, in part, to a survival role of ET-1 on vascular smooth muscle cells as it was associated with an increased rate of apoptosis (programmed cell death) in the tunica media of the arterial wall.³⁵ ET-1 is produced in the kidney, in the endothelium of vessels, and in glomeruli and tubules, and expression is increased in the vasculature and glomeruli of the kidney of DOCA-salt hypertensive rats.³⁶ Enhanced renal ET-1 production in hypertension may result in renal vasoconstriction and water and sodium retention, and it may contribute to the progression of renal failure. DOCA salt–treated SHR develop malignant hypertension and vascular and glomerular fibrinoid necrosis, and endothelin antagonists reduce the renal injury score.²⁸

View this table: [in this window] [in a new window]   Table 1. Forms of Experimental Hypertension That Have an Endothelin-Dependent Component

Although the mechanism involved in the induction of the prepro-ET-1 gene in DOCA-salt hypertensive rats remains obscure, recent data have provided some insight into potential factors that play a role. It is known that plasma vasopressin is increased and its effects are enhanced in DOCA-salt hypertensive rats.³⁷ Thus, vasopressin seems to play a role in blood pressure elevation in DOCA-salt hypertension. We therefore investigated the possibility that vasopressin, which stimulates endothelin expression in vitro, could be responsible for the stimulation of prepro-ET-1 gene expression in the vasculature of DOCA-salt hypertensive rats by examining the effect of a vasopressin type 1 receptor (V₁)-vasopressin antagonist. We demonstrated that together with blood pressure lowering and regression of vascular growth, treatment with a V₁-vasopressin antagonist resulted in the abolition of enhanced vascular prepro-ET-1 gene expression in the treated rats.³⁸ More recently, we found that vasopressin-deficient Brattleboro rats do not develop hypertension with DOCA-salt treatment, in part because they are unable to upregulate prepro-ET-1 gene expression.³⁹ These studies, taken together, support the hypothesis that vasopressin stimulates prepro-ET-1 gene expression by the endothelium in DOCA-salt hypertensive rats and that part of the effects of vasopressin in this hypertensive model are mediated by ET-1.

Blood pressure elevation can be blunted by endothelin antagonists in angiotensin II–infused rats, suggesting that in this model, ET-1 mediates the effects of angiotensin II to a large extent.^{40 41} Together with a hypotensive action, endothelin antagonists reduced cardiac and small-artery hypertrophic remodeling in the angiotensin II–infused rat.⁴¹ We have examined the effects of angiotensin II infusion in rats and, using in situ hybridization, found increased message for ET-1 in the endothelium of blood vessels (E.L. Schiffrin, unpublished observations, 1999). These results contrast with the lack of effect of endothelin antagonists in renin-dependent 2-kidney 1-clip Goldblatt hypertensive rats, which do not exhibit generalized vascular overexpression of ET-1²⁴ or respond to endothelin antagonists with blood-pressure lowering.^{42 43} Other models that respond to angiotensin antagonism, such as SHR^{30 31 32} and long-term N-nitro-L-arginine methyl ester (L-NAME)-treated rats,⁴⁴ do not seem to have a significant endothelin contribution. Thus, the endothelin system is activated in low-renin, salt-sensitive, and moderate to severe forms of hypertension. In addition, the endothelin system may be stimulated by exogenous angiotensin II infused at a constant rate but, at least in rat hypertensive models, it does not appear to be under the influence of endogenous angiotensin II. This paradoxical finding could be related to the steady-state concentration of angiotensin II in response to a constant rate of infusion by Alzet osmotic minipumps in the exogenous angiotensin II–infused rat model, in which angiotensin succeeds in stimulating ET-1 expression by both endothelium and smooth-muscle cells in the vascular wall in vivo⁴⁰ as it does in vitro.¹³ In contrast, pulsatile concentrations of angiotensin II resulting from endogenously generated angiotensin II may be less effective in stimulating ET-1 generation by the vascular wall.

The relationship between angiotensin II and the endothelin system is complex, and its participation in pathophysiology remains to be clarified. The 2 systems, renin-angiotensin and endothelin, may actually be parallel rather than in series. This could have important implications for the potential association and interaction of drugs that interrupt the renin-angiotensin system and block endothelin receptors; this association would probably be more effective if both systems are parallel, redundant, blood pressure control systems that can be blocked by different agents. This would then enhance the resulting blood pressure lowering effects and the potential direct beneficial actions on target organ damage in the therapeutic association of these agents.

	Role of ET-1 in Target Organ Damage in Experimental Hypertension

Top Abstract Introduction Role of Endothelins in... Role of ET-1 in... Pathophysiology of the... Effect of Endothelin Antagonism... Conclusions References

 
Severe hypertrophy of small arteries characterizes salt-sensitive, severe, or exogenous angiotensin II–infused models of hypertension in which ET-1 expression is enhanced. The mitogenic and cell hypertrophic actions of ET-1 on smooth-muscle cells^{6 45 46} mediate the vascular hypertrophy associated with hypertension in some hypertensive models and, presumably, in hypertensive humans.⁶ We have proposed that exaggerated growth in relation to the level of blood pressure elevation in DOCA-salt hypertensive rats suggests a direct hypertrophic action of ET-1.^{21 47} Indeed, endothelin antagonist treatment can regress the hypertrophic remodeling of small arteries, despite exerting only moderate blood-pressure lowering action, in those models that overexpress ET-1. This was initially shown in DOCA-salt hypertensive rats²¹ and DOCA salt-treated SHR,²⁸ and, more recently, in Dahl salt–sensitive rats,²⁹ stroke-prone SHR,⁴⁸ and angiotensin II–infused rats.⁴¹ Myocardial arteriolar density in the subendocardial myocardium of the left ventricle of DOCA-salt hypertensive rats is increased, suggesting a growth response.⁴⁹ Associated with this and also limited to the subendocardial myocardium is capillary rarefaction. The resulting lengthening of the high-resistance arteriolar segment of the arterial tree and the shortening and reduction of the number of capillaries suggest that the oxygen/nutrient exchange may be compromised. These abnormalities may, in part, underlie the greater vulnerability of the subendocardium to injury in hypertension. Their correction by ET_A receptor antagonism⁴⁹ suggests that clinical application of these agents may greatly benefit compromised coronary circulation. In stroke-prone SHR, vascular protection⁴⁸ is associated with significant protection from stroke.⁵⁰

Enhanced expression of ET-1 may be topographically localized when no generalized increase exists. The endothelium of coronary arteries presents increased message for ET-1 in several forms of hypertension^{51 52} because it may be particularly vulnerable to the effects of elevated blood pressure.⁵³ In 2-kidney 1 clip hypertensive rats²⁴ or in the L-NAME–treated rat that becomes hypertensive due to nitric-oxide deficiency,⁴⁴ increased prepro-ET-1 mRNA is found in the coronary endothelium.⁵² Thus, in hypertension, ET-1 may play a significant role in myocardial ischemia.⁵⁴ Pericoronary fibrosis may be improved by treatment with bosentan in SHR, even in the absence of a significant endothelin-dependent component in this model of genetic hypertension.⁵⁵ In hypertension, the effects of endothelin in the heart are not limited to blood vessels. The presence of ET_A and ET_B receptors on cardiomyocytes and fibroblasts, as described at the beginning of this review, results in hypertrophic responses to elevated pressure, as demonstrated in vivo⁵⁶ and to angiotensin II¹³ and norepinephrine in vitro.⁵⁷ Norepinephrine administration in vivo increased cardiac ET-1 in rats, and long-term administration of either selective ET_A or mixed antagonists reduced left ventricular hypertrophy.⁵⁸ Interestingly, in DOCA-salt rats, endothelin expression was not enhanced in the myocardium except at the level of blood vessels,⁵¹ and endothelin antagonism did not reduce left ventricular hypertrophy.²¹ Cardiac fibrosis is also a consequence of endothelin action resulting from fibroblast stimulation, as demonstrated in the hearts of rats with renal hypertension.⁴³ Activation of the cardiac endothelin system may initially contribute to improved heart function, but later it may participate in the progression of cardiac failure.⁵⁹

In malignant hypertension, endothelin-antagonist treatment was renoprotective.²⁸ Endothelin antagonists also improved renal function in SHR.^{60 61} Together with protection from stroke, endothelin antagonism improved kidney function in stroke-prone SHR.^{50 62} Significant improvement in renal function also occurred in Dahl salt–sensitive hypertensive rats with endothelin-antagonist treatment.⁶³ In 2-kidney 1 clip Goldblatt hypertensive rats or rats with L-NAME–induced hypertension, selective enhancement of renal ET-1 expression occurs.⁵² Although 1-kidney 1 clip Goldblatt hypertensive rats have generalized vascular enhancement of ET-1 production, the clipped kidney has no increase in ET-1 message.⁵² This may suggest that pressure or hemodynamics are involved in the activation of the renal endothelin system in this model. Endothelin antagonism also results in improved kidney function in rats with different forms of acute or chronic renal failure.^{64 65 66 67}

	Pathophysiology of the Cardiovascular Endothelin System in Human Hypertension

Top Abstract Introduction Role of Endothelins in... Role of ET-1 in... Pathophysiology of the... Effect of Endothelin Antagonism... Conclusions References

 
Endothelin plasma levels are usually normal in human hypertension.^{68 69 70} In some severely hypertensive patients and in black patients,⁷¹ particularly those who have rather severe forms of elevated blood pressure, plasma immunoreactive endothelin may be elevated. In blacks, plasma endothelin may not be higher than in whites if patients with similar severity of hypertension are compared.⁷² An endothelin-dependent vascular tone has been demonstrated in healthy subjects by their response to the acute, intravenous administration of TAK-044, a mixed ET_A/ET_B endothelin receptor antagonist, which induced an increase in forearm blood flow and slightly lowered blood pressure.⁷³ In a recent study by Cardillo et al,⁷⁴ an increased vasoconstrictor response to ET-1 in forearm blood flow was demonstrated in hypertensive patients. This contrasts with the reduced response to ET-1 found some years ago in vitro in vessels obtained from gluteal subcutaneous biopsies⁷⁵ and the results of forearm blood flow responses of other investigators.⁷⁶ The reasons for these discrepancies may be differences in the populations of hypertensive patients investigated. Normotensive offspring of hypertensive parents have enhanced plasma endothelin responses to mental stress, suggesting a genetically determined endothelial dysfunction present at an early stage preceding the development of hypertension.⁷⁷ In an examination of the expression of prepro-ET-1 mRNA in small arteries from gluteal subcutaneous biopsies, normotensive subjects and mildly hypertensive patients had a similar expression of endothelial prepro-ET-1 mRNA, whereas in moderately to severely hypertensive patients, ET-1 expression in the endothelium of small arteries was significantly increased.⁷⁸ This enhancement of the generation of ET-1 may play a role in the hypertrophic remodeling of small arteries in moderately to severely hypertensive patients and contribute to blood-pressure elevation.

Salt-sensitive hypertensive patients often have low plasma renin activity, and their endothelin in plasma responds in an exaggerated fashion, with a rise after sodium depletion in association with enhanced plasma catecholamines.⁷² This suggests a relationship between the sympathetic system, sodium sensitivity, and the reactivity of the endothelin system that may contribute to blood pressure elevation in these subjects. Interestingly, in these subjects, plasma immunoreactive endothelin correlated with the severity of blood pressure elevation, and because whites and blacks had similar stages of hypertension and were sodium sensitive, exaggerated activation of the endothelin system in blacks relative to whites was not detected, as mentioned above, in contrast to the findings of other authors.⁷¹ Thus, in human hypertension, results seem to agree with the activation of the endothelin system found in experimental models of severe and salt-sensitive hypertension. Chronic renal failure,⁷⁹ erythropoietin⁸⁰ and cyclosporine administration–induced,⁸¹ and pheochromocytoma-⁸² and pregnancy-induced hypertension⁸³ are other forms of hypertension in which endothelins may play a role.

	Effect of Endothelin Antagonism in Human Hypertension

Top Abstract Introduction Role of Endothelins in... Role of ET-1 in... Pathophysiology of the... Effect of Endothelin Antagonism... Conclusions References

 
Endothelin antagonists were initially studied in short trials in heart failure patients⁸⁴ ; these have now extended to longer,⁸⁵ multicenter studies.⁸⁶ Bosentan was given to mildly hypertensive patients for 4 weeks at a dose of 0.5 g once or twice daily; it was well tolerated and equieffective as 20 mg of enalapril daily.⁸⁷ The blunting of reflex neurohormonal vasoconstrictor activation was demonstrated in these patients after bosentan administration. Although bosentan will not be marketed for hypertension because of its side effects, trials of some ET_A selective endothelin antagonists in hypertensive patients are ongoing. We should soon know more about their efficacy and tolerability.

The definitive place of endothelins in the pathophysiology of human and experimental hypertension is still unclear, and the place of endothelium blockade in the therapeutic armamentarium awaits ongoing and future clinical trials of the different endothelin antagonists currently developed or in development. If the results obtained with bosentan⁸⁷ are reproduced with some of the newer endothelin antagonists, these agents may become interesting antihypertensive agents to add to those currently available. It still remains to be determined whether balanced ET_A/ET_B or selective ET_A receptors will be more effective. Some evidence suggests that selective ET_A antagonists may be superior vasodilators,⁸⁸ because the nitric-oxide stimulation mediated by ET_B receptors remains unblocked. However, this may be associated with a worse tolerance profile, mainly due to nitric oxide–mediated side effects.

	Conclusions

Top Abstract Introduction Role of Endothelins in... Role of ET-1 in... Pathophysiology of the... Effect of Endothelin Antagonism... Conclusions References

 
ET-1 may participate in blood-pressure elevation and vascular growth in moderate to severe hypertension, in salt-sensitive forms of hypertension and, perhaps, in special populations, such as black patients. Endothelial damage, which occurs as blood pressure rises, may activate the expression of ET-1 in vessels and in the heart,⁵³ which may initially be beneficial because wall stress is reduced when the vessel wall is thickened. As the damage increases, however, these changes may result in pathophysiological effects, and endothelin antagonists may then become useful agents. We propose that endothelin antagonists may function as disease-modifying agents, perhaps more than as blood pressure-lowering agents. This may be particularly important for moderately to severely hypertensive patients, for those hypertensive patients whose blood pressure cannot be controlled with the usual medications, and in subsets of subjects such as salt-sensitive hypertensives or blacks. These agents may also find a use in the prevention of the progression of renal failure in hypertension, slowing down the development of atherosclerosis, protecting patients from hypertensive ischemic heart disease and stroke,⁵⁴ and the treatment of heart failure.

	Acknowledgments

 
Work from the author's laboratory was supported by a group grant from the Medical Research Council of Canada to the Multidisciplinary Research Group on Hypertension.

Received May 9, 1999; first decision June 22, 1999; accepted July 1, 1999.

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