Endothelin Function and Potential Role in Muscle Hypertension Overview

Endothelins are peptides with receptors and effects in many several body organs. Therefore, Endothelin constricts blood vessels and it raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute to hypertension (high blood pressure, heart disease, and potentially other diseases.

Endothelins are 21-amino acid vasoconstricting peptides, therefore it produced primarily within the endothelium having a key role in vascular homeostasis. furthermore, Endothelins are implicated in vascular diseases of many organ systems, including the heart, kidneys, brain, and lungs. As of 2018, endothelins remain under extensive basic and clinical research or analysis to define their roles in several organ systems.

Endothelin Biosynthesis

Endothelin (ET-1) is a 21 amino acid peptide that’s produced by the vascular endothelium from a thirty-nine amino acid (39 amino acid) precursor, big ET-1, through the actions of an endothelin converting enzyme found on the endothelial cell membrane. ET 1 (ET one) formation and release are stimulated by thrombin, angiotensin II, antidiuretic hormone, cytokines, reactive oxygen species, and shearing forces performing on the vascular endothelium. Therefore, ET-1 release is inhibited by prostacyclin and atrial natriuretic peptide as well as by nitric oxide.

Etymology

Endothelins derived the name from their isolation in the cultured endothelial cells.

Isoforms

There are three isoforms of the peptide (identified as ET-1, ET-2, ET-3), each encoded by a separate gene, with varying regions of expression and binding to at least four known endothelin receptors, ETA, ETB1, ETB2, and ETC. The human genes for ET-1 (endothelin-1), ET-1 (endothelin-2), and ET-3 (endothelin-3) are located on chromosomes 6, 1, and 20, respectively.

Intracellular Mechanisms and Function

Once ET-1 is released by the endothelial cell, therefore, it binds to receptors on the target tissue for example such as adjacent vascular smooth muscle.
There are two basic types of ET-1 receptors (endothelin 1 receptor): ETA and ETB. Both of these receptors are coupled to a Gq-protein and therefore the formation of IP3. Increased IP3 causes calcium release by the sarcoplasmic reticulum, that causes smooth muscle contraction. In blood vessels, the ETA receptor is dominant under the general conditions in terms of ET-1 (Endothelin 1) effects on contraction.

In addition to ETA and ETB receptors on the smooth muscle, therefore, ETB receptors are also found on the endothelium. When ET-1 binds to these endothelial ETB receptors, therefore, the formation of NO (nitric oxide) is stimulated. thus, In the absence of smooth muscle endothelin receptor stimulation, this NO (nitric-oxide)causes vasodilation.

ET-1 receptors in the heart also are connected to the Gq-protein and IP3 signal transduction pathways. Therefore, ET-1 in the heart causes the release of calcium (Ca) by the sarcoplasmic reticulum, which will increase contractility and heart rate.

Diseases and Conditions Associated with Elevated Endothelin

Therefore, its powerful vasoconstrictor properties, and its effects on intracellular calcium, ET-1 has been implicated in the pathogenesis of hypertension, heart failure, and coronary vasospasm. within the latter condition, ET-1 is released by the failing myocardium wherever it will contribute to hypertrophy and calcium overload. furthermore, Endothelin receptor antagonists have been shown to decrease mortality and it improves hemodynamics in experimental models of heart failure. Therefore, a number of studies suggest a role for ET-1 in pulmonary hypertension, as well as in systemic hypertension. A non-selective ET-1 receptor antagonist is currently utilized in the treatment of pulmonary hypertension.

Cardiovascular Effects of Endothelin

The distribution of endothelial and smooth muscle receptors helps to clarify the phenomenon that systemic administration of ET-1 causes transient vasodilation and hypotension, followed by prolonging vasoconstriction and hypertension (i.e.smooth muscle ETA and ETB activation). Direct effects of ET-1 on the heart are changed by baroreceptor reflexes in response to changes in arterial pressure following systemic administration of ET-1.

ET-1 has a number of other actions besides vasoconstriction and cardiac stimulation which will indirectly have an effect on cardiovascular function. ET-1 stimulates aldosterone secretion, decreases renal blood flow, and releases atrial natriuretic peptide (ANP) and glomerular filtration rate.

Specific Drugs

Bosentan, a non-selective ET-1 receptor antagonist (blocks ETA and ETB receptors) is presently utilized in the treatment of pulmonary hypertension. Another medicines also used for pulmonary hypertension is ambrisentan, furthermore, which is a selective ETA receptor antagonist. (For more detailed information on bosentan, visit www.rxlist.com )

Side Effects and Contraindications

Some of the endothelin antagonist side effects are common to most vasodilators, headache, namely, edema formation, and cutaneous flushing. This class of drugs could cause birth defects and so is contraindicated in pregnancy. These drugs also can cause liver injury.

Endothelin Receptor

Endothelins are known to regulate vascular function through interaction with G protein-coupled receptors. Three(3) distinct genes encoding for three ET (Endothelins) isopeptides: ET-1, ET-2, and ET-3 were identified. Therefore, ET1 is released constitutively from endothelial cells and regulates vascular function. Therefore, these three isopeptides (ET 1, ET 2, and ET 3) mediate their biological functions by ETα and ETβ receptor subtypes. Furthermore, the ETα is located on vascular smooth muscle cells and ETβ on vascular endothelial cells. Therefore, the receptors function in opposition. While ETα mediates vasoconstriction, and ETβ produces vasodilatation (through prostaglandin and nitric oxide release). Thus, Both ET α and ETβ are present in human iris, ciliary processes, and ciliary muscles.

Physiological Effects

Endothelins are the most potent vasoconstrictors best-known. Therefore, the overproduction of endothelin in the lungs might cause pulmonary hypertension, that was treatable in preliminary research by bosentan, ambrisentan, or sitaxentan.

Furthermore, The endothelins have involvement in the cardiovascular function, fluid-electrolyte homeostasis, and neuronal mechanisms across diverse cell types. Therefore, Endothelin receptors, which are present in the 3 pituitary lobes that show the increased metabolic activity when exposed to ET-1 in the ventricular system or in the blood.

ET-1 contributes to the vascular dysfunction associated with particularly cardiovascular disease, atherosclerosis, and hypertension. furthermore, the ETA receptor for ET-1 is primarily located on vascular smooth muscle cells, mediating vasoconstriction, whereas the ETB receptor for ET-1 is primarily located on endothelial cells, causing vasodilation due to nitric oxide release.

Therefore, The binding of platelets to the endothelial cell receptor LOX-1 that causes a release of endothelin, which induces endothelial dysfunction.

Clinical Significance

The ubiquitous distribution of thee endothelin peptides and receptors implicates the involvement in a wide variety of physiological processes and pathological among the different organ systems. Therefore, among numerous diseases potentially occurring from the endothelin dysregulation are:

• Dengue hemorrhagic fever
• arterial hypertension, pulmonary hypertension, and other cardiovascular disorders
• pain mediation
• several types of cancer
• cardiac hypertrophy and heart failure
• cerebral vasospasm following subarachnoid hemorrhage
• Type II diabetes
• some cases of Hirschsprung disease

Therefore, in insulin resistance, the high levels of the blood insulin result in increased activity of ET-1 and production, which promotes vasoconstriction and elevates blood pressure.

Furthermore, ET-1 (endothelin -1)impairs glucose uptake in the skeletal muscles of insulin-resistant subjects, thereby worsening insulin resistance.

In preliminary research, injection of endothelin-1 (ET-1) into a lateral cerebral ventricle was shown to potently stimulate glucose metabolism in the specified inter-connected circuits of the brain, and to induce convulsions, furthermore, it indicating its potential for diverse neural effects in conditions like epilepsy. thus, the receptors for endothelin-1 (ET 1) exist in brain neurons, that’s indicating a potential role in neural functions

REFERENCES

1. Endothelin From Wikipedia https://en.wikipedia.org/wiki/Endothelin
2. Boron WF, Boulpaep EL (2009). Medical physiology a cellular and molecular approach (2nd International ed.). Philadelphia, PA: Saunders/Elsevier. p. 480
3. Cardiovascular Physiology Concepts Richard E. Klabunde, PhD
4. Endothelin Receptor Antagonists, Cardiovascular Pharmacology Concepts Richard E. Klabunde, PhD,
5. Endothelin: Potential Role in Hypertension and Vascular Hypertrophy,
6. Gross PM, Wainman DS, Espinosa FJ (August 1991). “Differentiated metabolic stimulation of rat pituitary lobes by peripheral and central endothelin-1”. Endocrinology. 129 (2): 1110–2