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Since its discovery in 1988, endothelin-1 (ET-1) has been widely studied in a diverse number of fields including neurology, cardiology, development, and to a greater extent, nephrology and hypertension.1, 2 Through the activation of its two receptors, ETA and ETB, ET-1 influences blood pressure by numerous mechanisms, making it an attractive target for treatment of hypertension and other diseases.3-10 While antagonists of the ET-1 system are highly effective in experimental models of hypertension and recently have been shown effective in resistant essential hypertension,7, 11, 12 their translation to the clinic has been disappointing thus far due to various side effects, including fluid retention/edema and liver toxicity.13, 14 In fact, only two ET-1 receptor antagonists have been approved by the FDA for the use in humans, ambrisentan and bosentan, an ETA antagonist and dual ETA/ETB antagonist, respectively. The sole indication thus far approved is for the treatment of pulmonary hypertension.15 However, several receptor specific antagonists are available and are going through animal testing and clinical trials. This review will focus on the recent progress of how ET-1 affects blood pressure and the future use ofET-1 receptor antagonists for the treatment of kidney disease and hypertension.14
Either ETA or ETB or both receptors are located on almost every cell type throughout the body. ETA receptors are mostly located on vascular smooth muscle cells and activation is normally pro-hypertensive through potent vasoconstriction, but also have significant effects to increase inflammation, oxidative stress, as well as increases in proteinuria through direct changes on renal glomerular permeability.12, 16, 17 ETB receptors, however, function quite the opposite, being mostly antihypertensive. Vascular ETB receptors are mainly located on the endothelium, and activation leads to vasodilation through enhanced nitric oxide production.18 The highest concentration of ETB receptors are located on renal collecting duct cells and are important in long term blood pressure regulation by directly inhibiting sodium uptake.18 Chronic disruption of the ETB receptor, either genetically or pharmacologically, results in salt sensitive hypertension.18 Since the hypertensive actions of ETB receptor disruption can be abolished by ETA receptor antagonism, it is widely believed that ETB receptors protect against ETA receptor activation, and a balance between the two receptor subtypes is required for the maintenance of blood pressure. For greater details into the known mechanisms of endothelin receptor activation, especially within the kidney, the authors direct you to a recent review by Kohan et. al.18
Depending on which part of the kidney ET-1 is produced (cortex vs. medulla), and which receptor is activated, renal ET-1 can have dramatically different effects on blood pressure. For instance, cortical ET-1 causes hypertension by increasing renal vascular resistance and reducing glomerular filtration rate. Furthermore, cortical ET-1 expression is up-regulated in a number of hypertensive models.11, 19, 20 Even more specifically, glomerular ETA activationmay lead to hypertension by increasing inflammation through enhanced production of monocyte chemoattractant protein-1 (MCP-1) and other pro-inflammatory factors such as cell adhesion molecules, thereby sequestering macrophages and lymphocytes.17 These immune cells, in turn, release a number of factors that act within to kidney to cause vasoconstriction and increases in sodium reabsorption, resulting in higher blood pressure. This has been proposed to play a role in the pathophysiology of numerous hypertensive states including AngII hypertension and early life stress.21-24 Interestingly, ET-1 causes glomerular and vascular inflammation in the absence of hypertension, suggesting that ET-1 antagonists could have even greater beneficial outcomes beyond that of blood pressure reduction17. Therefore, cortical ET-1 is pro-hypertensive by increasing renal vascular resistance, as well as directly promoting infiltration of inflammatory cells, specifically to the glomerulus.
In contrast to the renal cortex, renal medullary ET-1 reduces blood pressure by directly inhibiting sodium reabsorption on the collecting duct and increasing medullary blood flow through activation of the ETB receptor. Inner medullary collecting ducts produce the most ET-1 within the kidney (around 10 times more than any other nephron segment). Known mediators of ET-1 effects on tubular and vasa recta function include increased production of nitric oxide and 20-HETE.18 Under normal circumstances, activation of this system is directly dependent upon the level of salt intake.25 Moreover, at least half of the immunoreactive ET-1 found in urine is derived from the renal collecting duct.26 Blockade of ETB receptors, either genetically or pharmacologically results in hypertension that is highly sensitive to salt intake18, 27. Impairment of this pro-natriuretic pathway as evidenced by reductions in medullary ET-1 production in hypertension observed in the Dahl salt sensitive rat 27. These data suggest that alterations in medullary ETB receptor function could be an important mediator of salt sensitive hypertension; however, until we understand the specific mechanisms that are responsible for regulating ETB receptor function, it will be difficult to discern how to overcome salt-sensitivity attributed to this pathway.
It is well established that sex differences exist in the development of cardiovascular disease and hypertension, in that premenopausal women are less likely to develop hypertension compared to men.28-30 There is growing evidence that ET-1 may play a role in the differential regulation of blood pressure between men and women. Some of the more compelling data comes from very intricate studies by Nakano et. al, where it was shown that direct infusion of an ETB agonist into the renal medulla increases urine flow rate and sodium excretion of male and female rats.31 Interestingly, the natriuretic response was only present in females when the endogenous ligand, ET-1, was infused. The lack of natriuresis in the males in response to ET-1 was attributed to an ETA mediated reduction in medullary blood flow, thereby offsetting any ETB mediated tubular effects. Furthermore, female rats also displayed a component of ETA dependent natriuresis that was absent in males.31 Therefore, it appears there is an ETA mediated protection against hypertension in female rats that does not exist in males.
A number of labs have provided clear evidence that ET-1 plays a role in angiotensin II (AngII) salt induced hypertension since ETA or combined ETA/ETB antagonists can block the hypertensive effects of chronic Ang II infusion.32 It is known that female rats are not as susceptible to AngII hypertension, and so it has become increasingly evident that ET-1 may be important in the protection against salt-induced hypertension afforded to female rats.33 For instance, renal medullary ETB receptor function is completely lost in AngII hypertensive male rats while still intact in females. This reduced ETB function is associated with a reduction in ETB ligand binding in male rats, but not female rats.6 Furthermore, blockade of ETB receptors increases blood pressure to a more significant extent in female AngII hypertensive rats compared to males (unpublished data). Taken together, these data suggest that AngII, either directly or indirectly, reduces ETB receptor function in male rats; however, ETB receptor function in female rats in preserved in AngII hypertension, providing a potential mechanism of protection against high blood pressure.
Several lines of evidence suggest that ET-1 is a major factor in the development of chronic kidney disease (CKD), and more specifically, contributes to hypertension, proteinuria, and renal inflammation in CKD. In fact, ET-1 directly stimulates inflammation both in the vasculature and the kidney, and this occurs in the absence of hypertension.7, 17, 34 Recently, it was shown that an ETA receptor specific antagonist reduces blood pressure and proteinuria in patients with CKD.34 These reductions were in addition to the normal treatments already being administered, including angiotensin receptor blockers and converting enzyme inhibitors. Therefore, while the initial insult in the development of chronic kidney disease may be multi-factorial and complex, ET-1 appears to play an important role in the development and progression of the disease. Thus, treatment with ETA receptor antagonists may prove to be beneficial in cases where standard treatments are not sufficient, especially when blood pressure reduction is needed.
More recent data suggest that selective ETA antagonism improves outcomes in diabetic nephropathy. The ASCEND study shows significant reductions in proteinuria among diabetic nephropathy patients given the ETA antagonist, avosentan; however, this study was cut short due to fluid retention among the treatment group. While this was disappointing, it must be pointed out that the doses used in this trial were very high relative to the known dose-response effect on fluid retention observed in prior phase 2 trials and the lack of a dose-response effect on proteinuria.35 In fact, a much lower dose of atrasentan, another selective ETA antagonist, reduces albuminuria, but with far less peripheral edema than the ASCEND trial.18 These studies not only highlight the importance of the ETA receptor in mediating kidney disease in diabetes, but also the great potential that these drugs may have in treating renal disease associated glomerular injury and proteinuria.
Preeclampsia is a disease of pregnancy in which the mother becomes hypertensive in the third trimester of gestation. It is thought to be caused by abnormal remodeling of uterine spiral arteries, leading to placental insufficiency and the release of factors, such as soluble fms-like tyrosine kinase (sFlt-1) and tumor necrosis factor alpha (TNF-alpha), from the placenta into the blood stream that result in overproduction of ET-1 by the vascular endothelium and the renal cortex.11, 36-39 In fact, a very well established model of preeclampsia in the rat, in which clamps are placed on the ovarian arteries as well as the descending aorta to reduce blood flow to the placenta, is characterized by hypertension that is abolished by ETA receptor antagonism.37, 40 Furthermore, sFlt-1 and TNF-alpha infusion into pregnant rats results in hypertension that is also mediated by ETA receptor activation.19, 20 While ETA receptor antagonists appear promising for the treatment of pregnancy-induced hypertension, there is the potential problem of teratogenicity. ETA receptor knockout mice have severe developmental defects that are lethal and so it is unlikely that any pharmaceutical company would want to or be able to test this idea.18 Whether drugs can be developed that do not cross the placenta is not well established.
While it is well established that ET-1 plays an important role in blood pressure control and alterations in this system can lead to hypertensive consequences, there are still no approved ET-1 antagonists for the treatment of arterial hypertension. Several fairly large clinical trials demonstrated that both ETA selective or combined ETA and ETB antagonists reduce blood pressure in patients with resistant essential hypertension.13, 41 However, further development of these drugs for use in resistant hypertension has been thwarted for several potential reasons that are not all scientific. The ETA antagonist, darusentan, produced a significant reduction in 24 hr blood pressure in hypertension subjects already being treated with at least three other anti-hypertensive medications, yet for reasons unclear, the primary endpoint of clinic blood pressure was not significantly different from placebo on the final day of the trial. This led to the decision of the company developing the compound, Gilead, to discontinue further development. This decision was particularly disappointing also because of the additional benefits observed in hypertensive patients including reduced glycemia, improved lipid metabolism, and reductions in proteinuria.13, 41
As mentioned above, another important factor that appears to have contributed to reduced enthusiasm for developing ET blockers for the treatment of hypertension is edema. Fluid retention is a serious side effect that has been observed with all of the various antagonists, but this was a particularly significant problem in patients with diabetic nephropathy in the ASCEND trial that was terminated early.35 However, lower doses that maintain efficacy have fewer issues with fluid retention and appears to be manageable by adjusting co-treatment with diuretics.18
The delicate balance between the ETA and ETB receptors is required for the normal regulation of fluid and water balance (Figure 1). For instance, as sodium intake is increased, the ETB receptor becomes increasingly more important in blood pressure control due to its role in reducing renal tubular sodium reabsorption.18 While disruption of the balance between receptor subtype activity may ultimately lead to hypertension, i.e., loss of ETB and gain of ETA receptor activity, knowledge of the distinct function of these receptors is needed when attempting to treat different forms of hypertension. Furthermore, there are a number of factors that shift balance between ETA and ETB receptors including salt intake,12, 42-46 gender,6, 31, 47 and angiotensin II (AngII) and may contribute to the somewhat confusing results from clinical trials compared to the very clear findings in experimental models.
Finally, one cannot ignore the business aspects of developing new drug therapies. New drugs that may require careful management and co-therapies in the early treatment phase may be difficult to manage when dealing with a chronic disease that is not immediately life threatening. Both patient and physician compliance can be difficult when focusing on what can be viewed as simple blood pressure management. However, patients with resistant hypertension are on many different medications without blood pressure control and so the effort should be worthwhile. In addition, it is important to note that most all of the endothelin antagonists are nearing the end of their initial patent life. While a limited degree of exclusivity may be allowable, the earning potential may not be worth the costly investment required for clinical trials. The mistakes of the previous clinical trials are also an obstacle to overcome from a perceptual basis. Companies are reluctant to invest in drugs that have been tainted by a failed trial even when there are rational scientific explanations. Nonetheless, when one studies the history and when one considers the scientific specifics, there remains the valid possibility that the endothelin antagonists are potentially useful, life-prolonging drugs in patients suffering from hypertension.
Sources of Funding: Dr. Speed was the recipient of a Post-doctoral Fellowship Award from the American Heart Association during the course of preparing the manuscript. Dr. Pollock was supported by National Institutes of Health grants, HL69999 and HL095499 as well as a grant from the Cardiovascular Discovery Institute at Georgia Regents University.