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(Hypertension. 1995;25:1135-1143.)
© 1995 American Heart Association, Inc.

Articles

Endothelin: Potential Role in Hypertension and Vascular Hypertrophy

E. L. Schiffrin

From the MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal (Canada).

	Abstract

Top Abstract Introduction The Endothelin System in... Plasma Levels of ET-1... Effects of Endothelin on... Vascular Production of... Effects of Endothelin... Results of Targeted ET-1... Molecular Genetics of the... Conclusion References

 
Abstract The endothelins are a family of 21–amino acid peptides that are powerful vasoconstrictors. They may also induce vascular hypertrophy. These peptides may participate through these two mechanisms in the pathogenesis of the elevation of blood pressure and/or in the maintenance of hypertension in both experimental animal models and human essential hypertension. This review presents evidence both in favor and against the involvement of endothelins in hypertension. Plasma levels of endothelin-1 are either normal or slightly elevated in experimental and human essential hypertension. Responses of blood vessels to endothelin-1 may be normal or depressed in many models of experimental hypertension and also in essential hypertension in humans. It has recently been demonstrated that endothelin content and mRNA are increased in blood vessels of deoxycorticosterone acetate–salt hypertensive rats. When endothelin receptor antagonists are administered chronically, elevation of blood pressure and development of vascular hypertrophy are blunted in this experimental model of hypertension. In contrast, spontaneously hypertensive rats do not exhibit any increase in either endothelin-1 mRNA or immunoreactive endothelin in blood vessels and fail to respond with lowering of blood pressure to long-term treatment with endothelin receptor antagonists. Blood pressure development in young spontaneously hypertensive rats is also unaffected by long-term administration of endothelin antagonists. Molecular genetic studies appear to support a genetic role of components of the endothelin system in Dahl salt-sensitive rats. In human essential hypertension, there is some evidence of activation of the endothelin system despite depressed responses of small arteries to endothelin-1 and normal circulating levels of endothelin-1 in plasma. Thus, a role of endothelins in high blood pressure is possible. Further research is necessary to establish in a more definitive way whether endothelins are involved in the pathophysiology of human essential hypertension.

Key Words: aorta • arterioles • endothelium • hypertension, mineralocorticoid • hypertension, malignant • RNA, messenger • receptors, endothelin

	Introduction

Top Abstract Introduction The Endothelin System in... Plasma Levels of ET-1... Effects of Endothelin on... Vascular Production of... Effects of Endothelin... Results of Targeted ET-1... Molecular Genetics of the... Conclusion References

 
The endothelin family includes a group of structurally related peptides that are powerful vasoconstrictors.¹ Accordingly, their discovery generated a flurry of speculation that these peptides might be involved in blood pressure (BP) elevation, as well as research activity attempting to establish the potential involvement of endothelins in hypertension. Generally, the data collected since the discovery of these peptides have not supported initial hopes that endothelins have a role to play in the pathogenesis of hypertension. However, recent results suggest new mechanisms whereby endothelins could be involved in the pathophysiology of hypertension, namely, by enhancing the vascular hypertrophy induced by elevated BP. This hypothesis is now supported by studies that have used endothelin receptor antagonists. It has been 2 years since two reviews appeared presenting conflicting views on the putative role of endothelins in hypertension.^{2 3} This brief review will attempt to put into perspective current results both supporting and negating an involvement of endothelins in hypertension.

	The Endothelin System in Brief

Top Abstract Introduction The Endothelin System in... Plasma Levels of ET-1... Effects of Endothelin on... Vascular Production of... Effects of Endothelin... Results of Targeted ET-1... Molecular Genetics of the... Conclusion References

 
Endothelin-1 (ET-1), ET-2, and ET-3 are 21–amino acid peptides of very similar structure. ET-1 was initially isolated from the endothelium,¹ and the structure of the other two peptides was deduced from their cDNAs.⁴ Today, ET-1 and ET-3 are known to be produced ubiquitously.^{5 6 7} The genes encoding the different endothelins have been cloned, and their regulation has been investigated.^{4 5 6} ET-1, the most important endothelin synthesized by blood vessels, is produced both in the endothelium^{1 4} and by smooth muscle cells.⁸ ET-1 is released in response to different stimulating agents. Among stimuli capable of eliciting endothelin release are low shear stress,⁹ although high shear stress is a potent inhibitor of ET-1 secretion,¹⁰ hypoxia, thrombin, angiotensin II (Ang II), vasopressin, norepinephrine, bradykinin, and transforming growth factor-ß1.^{1 11 12} Endothelins interact with type A (ET_A) and type B (ET_B) receptors.¹³ ET_A receptors are present on smooth muscle cells¹⁴ and are responsible for mediating contraction in response to ET-1. ET_B receptors¹⁵ are present on the endothelium. ET-1 and ET-3 are equally potent in their ability to stimulate ET_B receptors and induce release of nitric oxide and prostacyclin as well as vascular relaxation. Vascular ET_B receptors have been found in vivo to mediate not only vasodilation but also vasoconstriction.¹⁶ Indeed, ET_B receptors have been demonstrated on vascular smooth muscle cells of large vessels, including aortic cells, which had previously been considered a prototype model for the exclusive presence of ET_A receptors.^{17 18} ET_B-mediated vasoconstriction has also been identified in pulmonary¹⁹ and coronary²⁰ arteries, in veins^{21 22} of different species, and in mammary arteries of humans.²³ Thus, ET_B receptors are not only endothelial but are also present on smooth muscle cells of blood vessels, although they may represent a predominantly venous or pulmonary artery vasoconstrictor receptor. ET_B receptors are also found in resistance arteries, although possibly at a low density, and their actual contribution to resistance artery contraction and BP elevation is possibly minor.²⁴ Interestingly, it has recently been shown that ET_B receptors in resistance arteries undergo rapid desensitization on exposure to either ET-1 or ET_B selective agonists.²⁵ This may influence our ability to recognize their contribution to vasoconstriction. Because of the existence of endothelial ET_B receptors, ET-1 infusion into the circulation produces a transient vasodilation and hypotensive response, followed by the ET_A receptor–mediated vasoconstriction and a pressor response. If endothelin production were increased or the constrictor response to endothelins enhanced, or alternatively, ET_B-dependent vasodilatation mediated by nitric oxide or prostacyclin release were attenuated, endothelins could contribute to BP elevation. ET-1 is not only a vasoconstrictor but may also induce hypertrophy of smooth muscle cells and is a mitogen as well,^{26 27} albeit a relatively weak one. This is another important mechanism whereby endothelins could potentially have an effect on BP, by induction of vascular hypertrophy (see below). Endothelins may also affect BP in hypertension by other effects, such as their actions on the kidney.²⁸ Finally, the central and peripheral nervous system is another site of action of endothelins; their effects there could also affect BP but will not be the subject of this review.

	Plasma Levels of ET-1 in Hypertension

Top Abstract Introduction The Endothelin System in... Plasma Levels of ET-1... Effects of Endothelin on... Vascular Production of... Effects of Endothelin... Results of Targeted ET-1... Molecular Genetics of the... Conclusion References

 
ET-1 is the member of the endothelin system that is present in the greatest abundance in the circulation under normal conditions. Different reports have shown plasma ET-1 to be very slightly increased or normal in different models of hypertension in the rat and in hypertensive humans.^{29 30 31 32 33} However, in experimental malignant hypertension induced in spontaneously hypertensive rats (SHR) by administration of deoxycorticosterone acetate (DOCA) and salt or by treatment of two-kidney, one clip hypertensive rats with caffeine,³⁴ plasma immunoreactive endothelin may be elevated. ET-1 secretion, however, is mostly abluminal, toward the vascular wall,³⁵ and circulating levels are the result of spillover into the bloodstream. Thus, it is not surprising that in general increases in circulating levels of ET-1 are found only in some pathophysiological conditions and that plasma levels of ET-1 are similar in normotensive and hypertensive individuals.^{31 33} This is in agreement with the increasing understanding of ET-1 as a hormone that acts in a paracrine fashion. Two cases of hemangioendothelioma have been reported, in which overproduction and increased plasma concentration of ET-1 were demonstrated. In these cases, surgery was followed by a reduction in plasma levels of ET-1 and decrease in the elevated BP, suggesting a pathogenic role of the endothelin secreted by the tumor in BP elevation in these patients.³⁶ Thus, in these rare cases, it appears that circulating ET-1 does indeed have a confirmed BP-raising effect in humans. ET-1 gene expression has been detected in human pheochromocytoma.³⁷ However, the potential physiopathologic significance of this finding must await studies in other patients bearing pheochromocytoma. Cyclosporin A stimulates ET-1 secretion, and in patients receiving the drug after heart, liver, or kidney transplantation, the ET-1 concentration in plasma was found to be elevated.^{38 39} ET-1 could thus play a role in hypertension associated with cyclosporine treatment. Patients with chronic renal failure on hemodialysis receive, as part of the treatment of anemia, administration of human recombinant erythropoietin, and this may be associated with increased levels of ET-1 in plasma, which could contribute to hypertension in these patients.^{40 41 42} In preeclampsia, elevated plasma concentrations of ET-1 have been reported. The endothelium has been shown to be significantly altered in preeclampsia, and the rise in ET-1 plasma levels occurs together with increases in the concentration of von Willebrand factor, which is a well-known marker of endothelial damage.⁴³ This suggests that the endothelial abnormality in preeclampsia could participate, via endothelin secretion, in BP elevation. A possible implication of ET-1 in preeclampsia requires more extensive experimentation, as does establishing the source of the increase in plasma levels reported in these studies.

	Effects of Endothelin on Blood Vessels in Hypertension

Top Abstract Introduction The Endothelin System in... Plasma Levels of ET-1... Effects of Endothelin on... Vascular Production of... Effects of Endothelin... Results of Targeted ET-1... Molecular Genetics of the... Conclusion References

 
Several studies have examined the vasoconstrictor effects of ET-1 on both conduit and resistance arteries of hypertensive animals and resistance arteries of humans to determine whether these effects are enhanced in hypertension. Some investigators have shown the responses to ET-1 of the aorta of SHR to be blunted,^{44 45} others to be normal,⁴⁶ and still others to be enhanced.⁴⁷ Recently, aging was reported to be associated with a significant attenuation of aortic contraction elicited by ET-1 in SHR but not in control Wistar-Kyoto rats (WKY).⁴⁸ In another hypertensive model, the DOCA-salt hypertensive rat, aortas exhibited a significantly attenuated contraction in response to ET-1.⁴⁹ The density of endothelin receptors in blood vessels of DOCA-salt hypertensive rats is significantly decreased.⁴⁹ Blunted intracellular signal transduction in response to ET-1 (inositol phosphate and diacylglycerol generation as well as calcium transients) has also been reported in the DOCA-salt hypertensive rat.^{49 50} In mesenteric resistance arteries of SHR, responses are similar to those of normotensive WKY or slightly reduced.^{45 51 52} Similar effects are found in cultured smooth muscle cells of SHR,⁵³ in which endothelin receptors have been shown to be slightly decreased in number.^{44 53} In contrast, other investigators found that responses of renal⁵⁴ and mesenteric⁵⁵ arteries of SHR were increased and that this agreed with slightly enhanced pressor responses to endothelin obtained in vivo.⁵⁶ In the case of perfused vessels in which pressor responses are examined, it is likely that the enhancement of responsiveness to ET-1^{56 57} may be due to amplification by the structural changes present in the blood vessel wall in hypertension. Remodeled resistance arteries in most experimental hypertensive models and in human hypertension exhibit a reduced circumference,^{51 58 59} which acts as an amplifier of pressor stimuli. This structurally based amplification may explain enhanced responses found in isolated perfused vascular beds of SHR⁵⁶ and renovascular hypertensive rats.⁵⁷ This remodeling is also found in resistance arteries of the mesenteric circulation of rats with DOCA-salt⁵⁸ and renovascular⁵⁹ hypertension. These arteries exhibit an attenuation of media stress developed in response to ET-1, which is compensated and amplified by the structural remodeling, resulting in normal or augmented pressor responses. Depressed responsiveness of resistance arteries to ET-1 may return to normal under effective antihypertensive treatment with an Ang I–converting enzyme inhibitor.⁵⁹

In humans with mild essential hypertension, resistance arteries dissected from subcutaneous gluteal biopsies also present attenuated responses of media stress to ET-1.^{60 61} However, these blunted responses are enhanced when evaluated as transmural pressor responses because of the amplification resulting from the reduced vascular circumference characteristic of the remodeling of small arteries in hypertension. In a way similar to the results referred to in the rat,⁵⁹ effective antihypertensive treatment with an Ang I–converting enzyme inhibitor normalizes these responses to ET-1 in human small arteries from hypertensive patients.⁶² The mechanism responsible for the depression of responsiveness to ET-1 in blood vessels in experimental models of hypertension and in human essential hypertension is unclear, except that in some of these cases, decreased endothelin receptor density^{44 49 53} and the associated blunting of signal transduction (decreased inositol phosphate and diacylglycerol generation or calcium transients)^{49 50 53} have been demonstrated in blood vessels or in cultured vascular smooth muscle cells. In some pathophysiological situations, the depression of media stress responses to ET-1 may be a consequence of downregulation of endothelin receptors, resulting from increased vascular production of endothelin (see below). The improvement of blood vessel responses after antihypertensive treatment may depend in some experimental models of hypertension on reduction in vascular overexpression of endothelin when this is present. Another potential mechanism for this improvement of responses of blood vessels to endothelin under Ang I–converting enzyme inhibitor treatment may be a regression to normal of the smooth muscle cell phenotype during treatment with these agents, resulting in normalization of vasoconstrictor responses. Although a similar trend toward improvement of responses to other vasoconstrictors was also noted in both experimental⁵⁹ and human⁶² hypertension during Ang I–converting enzyme inhibitor treatment, the change was most dramatic for ET-1 responses, suggesting that a selective change in endothelin receptors or signal transduction could be part of the mechanism underlying these findings.

ET-1 and ET-3, through their interaction with ET_B receptors present in endothelial cells, may stimulate the release of nitric oxide and prostacyclin, which relax the underlying vascular smooth muscle. Depression of these vasorelaxant responses could contribute to the exaggeration of vasoconstriction in some models of hypertension. The ET_B receptor–mediated vasorelaxation induced by ET-1 may be greater in SHR and DOCA-salt hypertensive rats than in their respective normotensive controls according to some studies.^{63 64 65} Thus, endothelins would not appear to release less vasorelaxant agents in hypertensive rats, which suggests that this is not a mechanism through which endothelins participate in the pathophysiology of hypertension. However, other studies have provided opposite results, suggesting that endothelin may indeed release less endothelium-derived relaxing factor in SHR blood vessels.⁶⁶ It has also been demonstrated that Ang II may stimulate the production of endothelin in SHR vessels, perhaps to a greater degree than in normotensive control vessels.⁶⁷ This mechanism could explain the enhancement of the contractile response to norepinephrine by subpressor concentrations of Ang II. This potential role of endothelin in the amplification of responses to norepinephrine by Ang II was demonstrated by the putative inhibition of this effect by phosphoramidon (an endothelin-converting enzyme inhibitor) and by endothelin-specific antibodies.⁶⁷ Thus, endothelin may amplify the pressor effects of the renin-angiotensin system and its interactions with adrenergic pathways. The exact significance of this potentially important mechanism remains to be ascertained. In contrast to the attenuated contraction shown in vitro in human small arteries,^{60 61} enhanced venoconstriction in response to endothelins, in part sympathetically mediated, was demonstrated in recent studies when the effect of endothelins was tested on veins of essential hypertensive patients in vivo.⁶⁸ Further investigation is required to determine the significance of these exaggerated venous responses in relation to BP control and the pathogenesis of hypertension.

	Vascular Production of Endothelin in Hypertension

Top Abstract Introduction The Endothelin System in... Plasma Levels of ET-1... Effects of Endothelin on... Vascular Production of... Effects of Endothelin... Results of Targeted ET-1... Molecular Genetics of the... Conclusion References

 
Since ET-1 secretion by endothelial cells mostly occurs abluminally,³⁵ ET-1 concentrations found in the circulation may not reflect vascular production. The finding of reduced endothelin receptor density,⁴⁹ the probable basis for the decreased vascular responsiveness demonstrated in DOCA-salt hypertensive rats, suggested that the receptors could be downregulated by increased vascular production of endothelin in some vascular beds. In the aorta and mesenteric arteries of DOCA-salt hypertensive rats, an increased content of immunoreactive endothelin was shown by radioimmunoassay and immunohistochemistry, and with the latter technique the source of elevated endothelin in the vascular wall of these hypertensive rats was localized in endothelial cells (Fig 1).⁶⁹ The abundance of ET-1 mRNA in blood vessels of these hypertensive rats was also increased.⁷⁰ In situ hybridization histochemistry demonstrated unambiguously that the enhanced expression of ET-1 was localized in endothelial cells, which were heavily and selectively labeled by the ET-1 cRNA probe in arteries of DOCA-salt hypertensive rats (Fig 2).⁷¹ In contrast to the latter, SHR vessels exhibited a similar or lower content of immunoreactive endothelin compared with control WKY vessels.⁶⁹

View larger version (122K): [in this window] [in a new window]   Figure 1. Photomicrographs show immunohistochemical localization of immunoreactive endothelin-1 in small mesenteric arteries from uninephrectomized rats (A) and deoxycorticosterone acetate–salt hypertensive rats (B). A significant increase in immunostaining was detected in the endothelial cell layer of the mesenteric arteries of hypertensive rats (B and C). Immunostaining in endothelial cells was almost completely abolished by addition of excess synthetic endothelin-1 (D). Original magnification x250 in A and B; x1000 in C and D. L indicates lumen; m, media. From Larivière et al69 ; reproduced with permission from the American Heart Association.

View larger version (106K): [in this window] [in a new window]   Figure 2. Dark-field photomicrographs show in situ hybridization histochemistry of mesenteric arteries using antisense endothelin-1 cRNA probes. A, Uninephrectomized control rat; B, deoxycorticosterone acetate–salt hypertensive rat. The antisense cRNA probe was radioactively labeled with both 35S-UTP and 35S-CTP. Note the large increase in endothelin-1 mRNA signal in B (small arrows). The observed changes occur only in endothelial cells. V indicates the position of the lumen of small blood vessels. Original magnification x170. Similar results were reported in Day et al.71

Vascular hypertrophy is very severe in arteries from DOCA-salt hypertensive rats, with a prominent thickening of the media.⁵⁸ It was demonstrated that these severely hypertrophied arteries from DOCA-salt hypertensive rats overexpress the ET-1 gene.^{69 70 71} In contrast, in SHR blood vessels, which do not exhibit enhanced ET-1 expression,⁶⁹ remodeling is more apparent, with little vascular hypertrophy.⁵¹ We have speculated that endothelin, which has growth-promoting properties,^{26 27 72} could play an important role in the hypertrophy of smooth muscle in hypertension and specifically in DOCA-salt hypertensive rats.^{69 70} The increased ET-1 production in the blood vessels of DOCA-salt hypertensive rats could be causally involved in the very severe form of vascular hypertrophy characteristic of this model of hypertension. Cardiac hypertrophy is also prominent in DOCA-salt hypertensive rats and is associated with an enhancement of the expression of the ET-1 gene and the amount of immunoreactive ET-1 in the heart.⁷³ However, this enhanced cardiac ET-1 expression occurs mostly in the endothelium of large and small coronary arteries and in the endocardium. Thus, enhanced ET-1 expression in the heart of DOCA-salt hypertensive rats could participate in coronary microvascular hypertrophy rather than in myocardial hypertrophy (see below). In both young and adult SHR vessels, the endothelin immunoreactive content of blood vessels is either not increased or lower than that present in control WKY vessels,⁶⁹ as mentioned above. We have speculated that even if ET-1 expression were increased, since the peptide is not stored in endothelial cells, turnover of the peptide could mask the increases in peptide synthesis. However, when ET-1 mRNA abundance was measured, it was normal or reduced in blood vessels of SHR relative to those of WKY,⁷⁴ rejecting the previous hypothesis. Only when SHR were treated with DOCA and salt to induce malignant hypertension (DOCA-salt SHR) was the ET-1 gene overexpressed in SHR blood vessels.⁷⁵ Interestingly, in these malignant DOCA-salt SHR, enhanced expression of the ET-1 gene was associated with severe exaggeration of vascular hypertrophy, albeit accompanying significant further BP elevation. It should be noted that no studies are currently available of vascular endothelin in stroke-prone SHR, and it is possible that in this more severe form of hypertension in SHR, vascular ET-1 gene expression is enhanced.

Practically no studies of tissue endothelin have been performed in hypertensive humans. Using in situ hybridization histochemistry, we have found that in some isolated individuals with essential hypertension, ET-1 gene expression was enhanced in the wall of small arteries dissected from subcutaneous tissue (L.Y. Deng, E.L. Schiffrin, unpublished observations, 1994). It is possible but as yet unproved that the percentage of hypertensive patients in whom evidence of enhanced expression of ET-1 in the walls of blood vessels is obtained will increase if severe forms of hypertension are investigated, because it is essentially in the more severe or malignant forms of hypertension that increases in plasma endothelin have been demonstrated.³⁴ Also, as stated above, in SHR, in which endothelin is not overexpressed in blood vessels, induction of malignant hypertension by treatment with DOCA and salt results in enhanced vascular ET-1 expression.⁷⁵ It is thus possible that endothelial damage associated with severe hypertension is responsible for the enhancement of vascular ET-1 gene expression found in severe and malignant forms of experimental hypertension and that similar mechanisms are operative in human essential hypertension. This remains to be demonstrated.

It has been demonstrated in blood vessels obtained from hypertensive patients subjected to coronary artery bypass surgery for coronary heart disease that the more severe the elevation of BP and the greater the thickness of the intima of internal mammary arteries, the greater the abundance of ET_A receptor mRNA found in smooth muscle cells migrating into the intima.⁷⁶ This could indicate an enhancement of the activity of the endothelin system in smooth muscle cells in more severe forms of hypertension, in association with atherosclerosis. The atherosclerotic process has also been shown to contribute to augmented endothelin expression.^{77 78} This increase in endothelin expression may play a role in the migration into the intima or in the proliferation of these modulated smooth muscle cells. These observations also suggest that enhanced expression of components of the endothelin system in human blood vessels may be a secondary phenomenon to severe elevation of BP or to activation of mechanisms participating in the development of atherosclerosis, perhaps following increased expression of growth factors in the blood vessel wall^{79 80} or the action of vasoactive peptides such as vasopressin or Ang II.¹² This finding could be a counterpart of the results obtained in DOCA-salt hypertensive rats and DOCA-salt SHR described above in which ET-1 gene overexpression in the vascular wall is also a secondary phenomenon. Platelet and thrombin activation could also play a role in severe hypertension and atherosclerosis and contribute to the stimulation of enhanced expression of the ET-1 gene.³⁴

	Effects of Endothelin Antagonists in Hypertension

Top Abstract Introduction The Endothelin System in... Plasma Levels of ET-1... Effects of Endothelin on... Vascular Production of... Effects of Endothelin... Results of Targeted ET-1... Molecular Genetics of the... Conclusion References

 
Endothelin-specific antibodies slightly reduce BP in stroke-prone SHR and may increase glomerular filtration rate and renal plasma flow in this genetic model of hypertension.⁸¹ Phosphoramidon, an inhibitor of endothelin-converting enzyme, elicits similar responses,⁸² suggesting a potential involvement of endothelins in BP elevation in stroke-prone SHR. However, because these latter agents have a multiplicity of pharmacological effects, their BP-lowering action cannot be attributed unambiguously to inhibition of the conversion of big endothelin to endothelin. Selective ET_A receptor antagonists such as BQ-123^{82 83} and FR139317⁸⁴ have been used to investigate the possible involvement of endothelins in hypertensive animal models. Administration of BQ-123 produced a slight lowering of BP in SHR and DOCA-salt hypertensive rats^{82 85 86} but not in renovascular hypertension.⁸⁶ These rather modest results have suggested that endothelin involvement in hypertension could be minor. However, recently, potent orally active antagonists of both ET_A and ET_B receptors have been synthesized,⁸⁷ opening new perspectives regarding the possible implication of endothelin in elevated BP via both ET_A and ET_B receptors. Short-term intravenous infusions of a combined ET_A/ET_B receptor antagonist reduced BP in SHR and DOCA-salt rats.⁸⁸ We have recently found that when DOCA-salt hypertensive rats were treated orally for 3 weeks with the combined ET_A/ET_B receptor antagonist bosentan, the BP of treated rats rose less than that of untreated rats (a difference of approximately 20 mm Hg, significant but not very large).⁸⁹ The development of vascular hypertrophy and remodeling of resistance arteries was practically abolished by treatment (Fig 3), beyond what could be explained by the slightly lower BP found in the treated rats. Interestingly, cardiac hypertrophy was unaffected by bosentan treatment, although parallel studies had shown an enhancement in the expression of the ET-1 gene and in the amount of immunoreactive endothelin found in the hearts of DOCA-salt hypertensive rats.⁷³ However, this enhanced cardiac ET-1 expression occurs mostly at the level of coronary blood vessels and the endocardium and could therefore be involved in coronary microvascular hypertrophy rather than myocardial hypertrophy, as mentioned above. These data support the hypothesis that we initially proposed when we detected an increased vascular content of endothelin immunoreactivity in the blood vessels of DOCA-salt hypertensive rats—that endothelin may play a role in vascular hypertrophy in hypertension,^{69 70} in agreement with the potential growth-promoting action of the endothelins.^{26 27 72} In contrast to DOCA-salt hypertensive rats, long-term oral treatment with the combined ET_A/ET_B receptor antagonist bosentan did not modify BP or vascular hypertrophy or remodeling in adult SHR.⁹⁰ In young 4-week-old SHR treated for 10 weeks with bosentan, BP development was also unaffected by the endothelin antagonist.⁹¹ Thus, negative results with bosentan in SHR agree with the absence of enhanced vascular expression of ET-1 in these genetically hypertensive rats. The ability to respond to bosentan with both BP lowering and regression of vascular hypertrophy, such as found in DOCA-salt hypertensive rats⁸⁹ and DOCA-salt SHR (J.-S. Li, E.L. Schiffrin, unpublished observations, 1994), appears to correlate with the presence of vascular overexpression of ET-1.^{69 75} Treatment of SHR with DOCA and salt, even in the absence of unilateral nephrectomy, will result in the enhancement of ET-1 gene expression in blood vessels and render the BP sensitive to endothelin antagonists (see Reference 92⁹² and J.-S. Li, E.L. Schiffrin, unpublished observations, 1994). Although no studies are available on the effects of endothelin antagonists on BP in humans, evidence exists from experiments using ET_A receptor antagonists in the forearm circulation in humans⁹³ and in the human skin microcirculation⁹⁴ that endothelins may contribute to basal vascular tone.

View larger version (50K): [in this window] [in a new window]   Figure 3. Bar graphs show standardized parameters measured or calculated in small mesenteric arteries of uninephrectomized rats (open bars), deoxycorticosterone acetate (DOCA)–salt hypertensive rats (light gray bars), and bosentan-treated DOCA-salt hypertensive rats (dark gray bars). CSA indicates cross-sectional area. *P<.05. Figures are drawn from data of Li and Schiffrin90 with permission.

	Results of Targeted ET-1 Gene Disruption in Mice and Overexpression of Endothelin in Transgenic Rats

Top Abstract Introduction The Endothelin System in... Plasma Levels of ET-1... Effects of Endothelin on... Vascular Production of... Effects of Endothelin... Results of Targeted ET-1... Molecular Genetics of the... Conclusion References

 
A recent report has generated skepticism regarding the potential participation of the endothelin system in the pathophysiology of hypertension. After targeted disruption of the ET-1 gene in mice,⁹⁵ all homozygotes died, but surviving heterozygotes exhibited significant decreases in plasma ET-1 levels and, paradoxically, slightly elevated BP. This apparently paradoxical result is easily explained if one remembers that endothelins bind to endothelial ET_B receptors and stimulate the release of endothelium-derived relaxing factors,⁹⁶ which may in fact be the normal, physiological effect of endothelins. On the other hand, when normal ET-1 production is curtailed as a result of the gene "knock-out," this vasorelaxant tonic effect is lost, and the result is vasoconstriction and BP elevation despite the lowering of circulating levels of ET-1. This does not mean that when ET-1 production is significantly enhanced in the blood vessel wall, as in DOCA-salt hypertensive rats or DOCA-salt SHR, it will not exert a vasoconstrictor and vascular hypertrophic effect that will contribute to BP elevation. Furthermore, ET-1–deficient heterozygote mice suffer from severe craniofacial malformations, as a result of which they are hypoxemic, which could contribute, via stimulation of the sympathetic nervous system, to the apparently paradoxical BP elevation found in this experimental paradigm independently of the changes in ET-1 production after inactivation of the ET-1 gene.

Transgenic rats overexpressing ET-2, resulting in elevated plasma ET-2 levels, have been recently produced (M. Paul and D. Ganten, personal communication). Plasma levels of endothelin are raised in the circulation of the rats expressing the transgene, but BP is not elevated. This has been taken as evidence of a lack of a hypertension-producing effect of endothelins. However, since endothelin concentration is elevated in the circulation but not in blood vessels, as the transgene is not expressed in the endothelium, this experimental paradigm resembles the result of intravenous infusion of ET-1 into rats, which also does not result in elevated BP (unless the rats are salt loaded⁹⁷ ). Thus, these experiments do not contradict the hypothesis that in physiopathologic conditions in which ET-1 is overexpressed in the blood vessel wall, such as DOCA-salt hypertensive rats, DOCA-salt SHR, and potentially other hypertensive models and perhaps some subsets of moderately or severely hypertensive humans, endothelin may play a pathogenic role in BP elevation.

	Molecular Genetics of the Endothelin System in Hypertension in Rats

Top Abstract Introduction The Endothelin System in... Plasma Levels of ET-1... Effects of Endothelin on... Vascular Production of... Effects of Endothelin... Results of Targeted ET-1... Molecular Genetics of the... Conclusion References

 
Molecular genetic studies have provided some evidence that ET-3 could contribute to BP elevation in Dahl salt-sensitive rats.⁹⁸ Similarly, ET-2 and the ET_B receptor⁹⁹ have been linked, albeit weakly for the ET_B receptor, to BP elevation in some studies of the F₂ generation of backcrosses of Dahl salt-sensitive rats and Lewis normotensive rats. The precise significance of the linkage of these components of the endothelin system with susceptibility to BP elevation after exposure to a high salt intake remains to be further developed. In humans, no polymorphisms associated with hypertension have been identified as yet in endothelin genes.

	Conclusion

Top Abstract Introduction The Endothelin System in... Plasma Levels of ET-1... Effects of Endothelin on... Vascular Production of... Effects of Endothelin... Results of Targeted ET-1... Molecular Genetics of the... Conclusion References

 
The role of the different endothelins that make up this family of peptides in elevated BP is currently unclear. It is likely that ET-1 plays an important vasoconstrictor and growth-promoting role in peripheral resistance vessels and may contribute to BP elevation in some animal models of hypertension, such as DOCA-salt hypertensive rats, and in malignant hypertension in SHR, such as in DOCA-salt SHR and possibly stroke-prone SHR. ET-3 appears to be a predominantly central nervous system peptide and may be involved in a variety of ways at this level in hypertension. The potency of combined ET_A/ET_B receptor antagonists to lower BP may indicate a peripheral involvement of ET-3 as well as of ET-1. Immunohistochemistry, Northern blot analysis of ET-1 mRNA, and in situ hybridization data, together with results of the effects of combined ET_A/ET_B receptor antagonists, suggest an involvement of endothelin in the pathogenesis of hypertension and in vascular hypertrophy in DOCA-salt hypertensive rats and in malignant DOCA-salt SHR (summarized in the Table). There is also some indication that endothelins may play a role in stroke-prone SHR. Further studies are required to accumulate evidence for the involvement of endothelins in the mechanisms underlying human hypertension.

View this table: [in this window] [in a new window]   Table 1. Summary of Role of Endothelin in Hypertension and Vascular Hypertrophy

	Acknowledgments

 
The work described in this review was supported by a group grant from the Medical Research Council of Canada to the Multidisciplinary Research Group on Hypertension and grants from the Fondation des maladies du coeur du Québec. The author thanks Angie Poliseno for secretarial help.

	Footnotes

 
Reprint requests to Ernesto L. Schiffrin, MD, PhD, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec H2W 1R7, Canada.

Received December 15, 1994; first decision January 30, 1995; accepted February 27, 1995.

	References

Top Abstract Introduction The Endothelin System in... Plasma Levels of ET-1... Effects of Endothelin on... Vascular Production of... Effects of Endothelin... Results of Targeted ET-1... Molecular Genetics of the... Conclusion References

 
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