The Role of Endothelin in Strokes

Helena Kuhn
Ashley Hubbard
John Kannengieser
Catlaina Hackworth

Abstract:
The article discusses the correlation between endothelin-1, a potent vasoconstrictor, and cerebral vascular accidents, or strokes. Endothelin-1 is a 21-amino acid peptide that works through second messenger systems to regulate both vasoconstriction and vasodilatation of blood vessels and is thus a key regulator of vascular homeostasis. Endothelin-1 is involved in the pathophysiology of many diseases including coronary artery disease, cancer, shock, renal failure, and arthritis. The specific role of endothelin-1 in the pathogenesis of strokes is a controversial issue that remains under investigation, yet endothelin-1 displays clear involvement in intensifying the inflammatory effects of hypertension and atherosclerosis, the leading causes of strokes. These disease processes present with an increased level of endothelin-1 as the proinflammatory cytokines associated with the diseases increase the production. Thus, elevated levels of endothelin-1 have been noted in the cerebrospinal fluid and plasma of mammals following a cerebral vascular accident. Research has demonstrated that the most effective prevention methods for atherosclerosis and strokes are through risk factor control such as regulating the inflammatory response and correcting hypertension.

Key Words: endothelin, vasoconstrictor, stroke, cerebral vascular accident, atherosclerosis, ET-A receptor, ET-B receptor, cerebrospinal fluid, inflammatory response, cerebral thrombus, hypertension.
Endothelin is the most potent constrictor of human blood vessels known to man. In mammals, there are three structurally and pharmacologically separate ET isopeptides: ET-1, ET-2, and ET-3 (Volpe 46). Endothelin-1 is the primary isoform in the human cardiovascular system and is a 21-amino acid peptide produced chiefly by endothelial cells (Lüscher 2434). Endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases are responsible for the synthesis of ET-1 by means of autocrine regulation (Lüscher 2434). ET-1 operates through the initiation of two G-protein coupled receptors: ETA and ETB. Located on vascular smooth muscle cells, ETA receptors regulate vasoconstriction and cell proliferation. ETB receptors, situated on endothelial cells, mediate endothelium-dependent vasodilation through the release of nitric oxide and prostacyclin (Haapaniemi 721). In addition to its cardiovascular and mitogenic effects, endothelin-1 is involved in gastrointestinal and endocrine function, embryonic development, bronchoconstriction, and carcinogenesis (Lüscher 2435).

As a powerful and long-acting vasoconstrictor peptide, endothelin-1 plays a large role in the pathophysiology of many diseases. Endothelin-1 can be attributed to such conditions as atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure (Lüscher 2434). Clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis (Lüscher 2434), and thus it is generally accepted that an increased production of endothelin-1 may contribute to the pathogenesis of a number of cardiovascular diseases including hypertension, which can lead to cerebral infarcts, or strokes (Vople S46). Endothelin produces a continual vasoconstrictive effect on cerebral vessels during stroke progression, which is a quality that is often jeopardizing to the health status of an individual (Lampl 1951).

Endothelin and its role as a vasoconstrictor can have devastating effects upon the human body and normal function. Problems can result when the role of endothelin (ET-1) is altered by the presence of increased amounts, which counteract the body’s natural homeostatic mechanisms and often present with an inflammatory response. Usually, endothelin functions to maintain a healthy stability of vasoconstriction and vasodilatation, with the endothelium acting as a key regulator of vascular homeostasis. (Davignon III27). However, when counteractions occur, they can lead to serious attacks upon the body by interfering with its intrinsic protective means. Strokes, or cerebrovascular accidents, present with an interruption in the normal blood flow of cerebral vessels in a specific area. Endothelin’s main function involves a “sustained vasoconstrictive effect on cerebral vessels,” which works against the body’s natural defense of inflammation and vasodilation in the event of a stroke due to the occlusion of a cerebral blood vessel. Numerous endothelin receptors localize in the neurons, glial cells, and microvessel endothelial cells, accounting for a large volume of endothelin in the cerebral circulation. Cerebral endothelin-1 and its receptors have been implicated in having physiological and pathophysiological roles in the stroke process by modulating neuronal functions and regulating cerebral blood flow and metabolism (Matsuo 2142). Nonetheless, ET-1 causes constriction of the cerebral vessels at a time when the body’s homeostatic mechanisms attempt to create an inflammatory response and deliver oxygen and nutrients carried in the blood to the area in need.

Levels of ET-1 have been discovered to drastically increase in the cerebral spinal fluid of stroke patients 18 hours after a stroke and have been shown to influence the neurological outcome of the patient (Lampl 1951). Most prominently, endothelin was detected in the cerebral spinal fluid within the first twenty-four hours following a stroke. (Volpe S45). Thus, a marked elevation of ET-1 levels has been reported in humans with ischemic stroke, yet the cause of the stroke-induced increase is unclear (Matsuo 2144). Therefore, the counteractive effects of the vasoconstrictor ET-1 impedes the body’s natural response and can cause permanent damage to the individual by necrosis of the tissues affected.

Strokes have unfortunately become the leading cause of death and disability in the United States with an estimated 700,000 events annually, leaving many Americans with severe and permanent damage to their body (Sucov 1). Often, therapy is needed to rehabilitate basic motor skills, such as speech and specific task movements. (McGovern 79). Two main types of strokes can occur: ischemic or hemorrhagic. Each form possesses the ability to cause severe brain damage and leave the individual with the possibility of various types of physical disabilities. An ischemic stroke involves a thrombus or embolus, which is a blood clot that blocks or severely occludes an artery in the cerebrum. This blockage represents about eighty percent of all strokes and strongly decreases the blood and nutrient flow to the region. Permanent damage can result in the patient as well as necrosis of the tissue in the affected area. Ischemic strokes are known to have fairly rapid effects upon the brain, as this vital organ is not able to engage in anaerobic metabolism or store glucose, its chief energy source. Brain tissue is dependent upon glucose and oxygen in order to function properly and efficiently. These substances provide nourishment for the cells as well as serve to remove waste products from the area that would otherwise become toxic. Once the blockage exists, little time need pass before the brain undergoes severe and damaging changes as a result of the lack of essential provisions. Regardless of the occlusion’s size or location, the risk for irreversible damage increases as the brain exists in a hypoxic state and void of nutrients and oxygen. A hemorrhagic stroke is much less common, involving a disruption in the connection pathways and results in a pressure injury in a localized portion of the brain (Shah 2). Both types of stroke elicit an inflammatory response, the homeostatic mechanism of the body that attempts to dilate the vessels and move much needed oxygen and nutrients past the block to the devoid area.

Strokes can occur within the brain for numerous reasons, but the leading causes surround hypertension, a high salt diet, diabetes, atrial fibrillation, and atherosclerosis, a form of arteriosclerosis (Sucov 1). Hypertension, more commonly known as high blood pressure, creates a strain on the vessels, reducing their caliber and general condition as blood flows through them. Diabetes increases the risk of plaque build-up upon the walls of vessels in the cerebrum through the substitution of fats instead of carbohydrates as the main energy source. Atherosclerosis involves an inflammatory response as plaque builds up on the walls, causing the vessels to harden and lose some of their elasticity. Atrial fibrillation can also impact the blood vessels of the cerebrum, as there is an irregular beating of the heart and thus abnormal blood flow. Specifically, if this irregularity continues without any treatment, the abnormal flow can lead to clots, which in turn create the blockage from which strokes occur (Sucov 1). A high salt diet may not appear to have an impact upon strokes, but unfortunately excess sodium in the diet causes the body retain water, which therefore increases blood volume and pressure on the walls of vessels. All of aforementioned factors reduce the caliber of the blood vessels in the cerebrum and escalate the probability of a stroke. Endothelin exacerbates the effects of these various factors upon the body by causing increased vasoconstriction and thus a greater potential for a stroke. Several studies show that the amount endothelin-1 found directly correlates with the severity of the stroke suffered (Volpe S46). The impact of a stroke upon the vessels of the cerebrum can be devastating and cause irreversible damage.

Although strokes may stem from a variety of factors, hypertension and inflammation (atherosclerosis) are the most prominent contributors to stroke pathophysiology. The intense vasoconstrictive effects of ET-1 augment the already detrimental cerebral vascular consequences associated with hypertension and atherosclerosis. These disease states present with increased levels of proinflammatory cytokines, such as tumor necrosis factor-? and interferon-?, which are associated with the elevated ET-1 levels in the disease pathophysiology (Woods 2). Under inflammatory conditions caused by the proinflammatory cytokines, the production of ET-1 from smooth muscle cells is increased. Although the intracellular signaling mechanism by which cytokines bring about the increase of ET-1 is not presently known, ET-1 further compounds and intensifies the inflammatory effects associated with hypertension and atherosclerosis.

Often considered the most important risk factor contributing to the incidence of stroke, hypertension is a condition in which the blood pressure is persistently higher than normal. The specific etiology of hypertension is unknown although a combination of genetic and environmental factors plays a large role in its pathogenesis. In those with hypertension, ET-1 is overexpressed in the vascular wall, which has been linked to increased vascular tone and vascular stiffness (Schiffrin 876, Cardillo 753). The increased blood pressure associated with hypertension results in endothelial damage while increasing stress on the arteries and accelerating the silting of plaque on the arterial wall. Hypertension, therefore, is also a risk factor for arteriosclerosis and can initiate damaging inflammatory reactions contributing to stroke pathogenesis. Thus, ET-1 may foster cerebral infarcts by promoting carotid atherosclerosis in individuals with essential hypertension (Minami 663).

Atherosclerosis is marked by the build-up of plaque in blood vessels, which can lead to a lack or loss of blood flow. When high levels of endothelin are found in cerebrospinal fluid, the constriction occurs in cerebral blood vessels. When cerebral blood vessels are constricted, it may facilitate the occurrence of a stroke in the individual. A study published by the American Heart Association concluded that ET-1 levels are elevated in patients with atherosclerosis (Nohria 43). When a blood vessel is already clogged with plaque constricting it further compromises the channel through which blood can flow properly. (See Figure 1, citation)

A strong link between endothelin and vasconstriction can be viewed through a study conducted Dr. Yair Lampl, which found that ET-1 can impact a residual vasoconstrictive effect on cerebral vessels. The study also revealed that elevation of ET-1 in plasma has been recorded 1 to 3 days after an ischemic stroke (Lampl 1951). This elevated level of ET-1 has also been found in the plasma of the cerebrospinal fluid of individuals. When the integrity of these cerebral blood vessels is worsened, the effects of atherosclerosis are made increasingly more dangerous to the vascular homeostasis of an individual. Other damaging effects of ET-1 were seen when the “intraventricular administration of ET-1 reduced cerebral blood flow and led to the development of brain infarction” (Lampl 1951). This study provides information, which shows that ET-1 may lead to more risk factors, including reduced blood flow, which would greatly increase the damaging effects of atherosclerosis. Much recent research has focused on blocking the ETA and ETB receptors in attempts to decrease endothelin production and thus greatly reduce the inflammatory risk factors that contribute to stroke progression. In this way, endothelin control can be considered a key element towards the prevention of ischemic stroke in people who suffer atherosclerosis.

In order to better understand the importance of endogenous ET-1 in blood flow in atherosclerotic patients, a study set out to test the effect of a combined ETA and ETB receptor inhibition in patients with atherosclerosis (Bohm 674). This study showed that a combined receptor blockade evoked a greater vasodilator response in the subjects. From this, the conclusion may be drawn that there is an enhanced “ETB-mediated vasoconstrictor tone” in patients with atherosclerosis (Bohm 677). This finding also is compliant with the fact that endothelin-1 is a potent vasoconstrictor.

Since atherosclerosis is already a dangerous condition, it does not need to be compounded by the vasoconstriction of endothelin-1. This is an important step in preventing ischemic and hemorrhagic stroke in humans because it offers hope that ETA and ETB receptor blocking drugs might help prevent vasoconstriction of clogged up cerebral blood vessels.

An episode of a stroke can cause extensive damage to a patient and therefore it must be addressed on how to prevent such occurrences. The most prophylactic measures control the factors that induce the stroke in the first place—factors which include hypertension, arteriosclerosis, diabetes, atrial fibrillation, a high salt diet, and many others. Trials conducted over the past 50 years have shown that no single treatment has ever produced more than 20-25% effectiveness in stroke patients (Caplan 1). Therefore, risk factor control in the simplest option and research has shown that it is the most successful, especially considering the great variation in types of stroke and more specifically their location in the brain.

Controlling risk factors are the only proven effective way to prevent strokes, therefore great attention must be paid to these factors in any case. Hypertension is one of the most common problems that can lead to a stroke in an individual, as high blood pressure affects the integrity of the blood vessels and leaves them irritated with decreased caliber. The decreased caliber of the vessels may create an inflammatory response, leaving them prone to the formation of a thrombus, which can be dislodged and travel to become a coronary or cranial obstruction. The presence of atrial fibrillation can lead to the increased probability of having a cerebral vascular accident due to the inconsistent flow of blood to the brain (Healy 9G). One of the greatest factors that can lead to the development of atrial fibrillation is hypertension.

One of the easiest ways to regulate hypertension is by inhibiting vasoconstrictive factors and promoting vasodilators. Other alterations that an individual may take to decrease his or her own risk involve a change in diet, such as by decreasing sodium intake. Sodium acts to help retain water within the body, so high levels of salt add to the overall blood volume as not as much water is lost. Therefore, a decreased level of sodium will yield a decreased blood volume and pressure, lessening the risk of stroke. The same principle applies to the use of diuretics, which will also decrease blood volume through an increase of urine production.

Cerebral vascular accidents can be regarded as reflections of the inflammatory process. As discussed, the role of endothelin is involved as vasodilatation and vasoconstriction. Studies conducted with rats have shown that nitric oxide is a successful antagonist to vasoconstriction. This administration resulted in counteracting the deterioration of blood flow to the cerebral area and restoring normal flow.

One example of a method aimed directly at treating strokes even after they occurred involves the introduction of AM-36, which is an “arylalkylpiperazine with combined antioxidant and Na+ channel blocking actions” (Callaway 1999). In studies conducted on conscious rats, it was shown that AM-36 had beneficial impacts on ET-1- induced cerebral vascular accidents up to 180 minutes after the stroke occurred. Although this substance may have worked in some cases, its effects and results were inconsistent and it is by no means a general treatment for stroke. It proved successful in some cases, but the fact still remains that prevention and treatment is best, when the focus lies more upon controlling the risk factors that could potentially lead to a stroke in the first place.

Other studies have been conducted that reveal that individuals who have had prior cerebral occlusions and accidents have a greater amount of ET-1 in their cerebral spinal fluid. This leads to an increased chance of the patient having future strokes and other cerebral incidents. This supports the hypothesis that prevention is the best way to avoid the occurrences of stroke because even if more prophylactic measures are undertaken after the cerebral vascular accident has occurred, there is still an increased probability due to the previous stroke. Prevention is also important due to the debilitating effects a stroke leaves on a survivor. Rehabilitation for patients who have suffered a cerebral vascular accident is very expensive due to the long term physical and mental disabilities created. In 2002, the United States spent over $49 billion dollars on treatment of stroke related causes (Mancia 631).

Clearly, a strong correlation exists between the potent vasoconstrictor ET-1, hypertension, atherosclerosis, and cerebral vascular accidents. Although the exact mechanisms of the relationship are unclear, the proinflammatory cytokines associated with the disease processes enhance endothelin-1 production. This increase in endothelin exacerbates the effects of atherosclerosis and hypertension on the body, leading to an increased risk for stroke pathogenesis (Matsuo 2148). Currently, there is promising research involving the blocking and manipulation of ETA and ETB receptors in the treatment of inflammatory disease and stroke. However, various studies have revealed that treatment of moderate or severe hypertension decreases the incidence of cerebral vascular accidents (Zuber 7). Current prevention and treatment must lie within the facts that are known, where controlling risk factors are the most effective means to protect the human body from the permanent effects that can result from a cerebral vascular accident.

ET1 level in CSF (pg/m)

1. Endothelin 1 (ET-1) levels in CSF of stroke (16.06 +/- 3.5 micro g/mL) vs control (5.1 +/- 1.47 micro/mL) group. The level is significantly higher in the stroke group (P<.001).
(Lampl: Stroke, Volume 28(10).October 1997.1951-1955)

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