Endothelin mechanisms in the central nervous system: A target for drug development

Abstract

Endothelin (ET), a vasoconstrictor peptide, was isolated and characterized in 1988. Since then extensive studies have been done in different animal species to identify its receptors in central nervous system (CNS) and peripheral tissues. Three forms of ETs have been identified: ET‐1, ET‐2, and ET‐3. Their distribution pattern and pharmacological functions have been defined. ET‐1 and ET‐2 are mainly distributed in the CNS, including spinal cord and the peripheral tissues, while ET‐3 although present in other tissues is mainly concentrated in the pituitary. ET receptors have been found to be coupled to intracellular pathways involving stimulation of Ca++ fluxes, through phospholipase C and inhibition of adenyl cyclase. The literature concerning central actions of ET has been reviewed. The bulk of the evidence shows that it may be a regulator of regional cerebral blood flow, and a modulator of the release of posterior pituitary hormones (oxytocin and vasopressin). It may also regulate the release of prolactin, growth, thyroid stimulating, or luteinizing hormones. The regulatory role of ET on cardiovascular system can be exerted by central as well as peripheral actions. Besides direct regulation, ET modulates the release of endothelium derived relaxing factor/nitric oxide (EDRF/NO) and increases the sensitivity of peripheral α‐adreno‐ceptors. Thus ET appears to establish a balance between vasodilatation induced by EDRF/NO release and vasoconstriction due to increased sensitivity of vascular a‐adrenoceptors. The level of ET was found to be raised in several pathological conditions like subarachnoid hemorrhage, myocardial infarction, cardiogenic and septic shock, Raynaud's disease, and pulmonary hypertension. Its level was also raised in patients undergoing chronic hemodialysis. On the other hand, the level of ET was significantly lower in the cerebrospinal fluid (CSF) of patients of depression. The available data suggest that ET has a neuromodulatory role in the CNS and may be involved in the pathophysiological processes of several diseases. ET mechanisms in the CNS could provide potential targets for the development of newer drugs. © 1992 Wiley‐Liss, Inc.

Altered Endothelin 1 Concentration in Brain and Peripheral Regions during Thyroid Dysfunction

“…The role of ET in the regulation and secre tion of several endocrine hormones is being increasingly implicated [23], The present study provides further evidence in support of studies conducted earlier indicating that ET mechanisms are involved in the thyroid dysfunction. Studies conducted earlier had shown that ET receptors are down-regulated in the pituitary, and plasma ET-1 concentra tion was increased in hyperthyroid rats [20], The present study showed that the concentra-…”

Changes in the Concentration of Endothelin-1 during Development of Hypertensive Rats

“…ET binding sites have been identified in the heart [2], blood vessels and central nervous system (CNS) [1,3]. The ma jor biological action of ET is vasoconstriction [4], However, in addition, ET has several important cardiovascular, renal and endo crine functions [1,5], Studies indicate that both central and peripheral ET mechanisms are involved in blood pressure regulation. Intracerebroventricular injection of ET in con scious normotensive Wistar-Kyoto (WKY) rats increased blood pressure in a dose-related manner [6].…”

“…Widely distributed throughout many tis sues, endothelin (ET) exerts its biological ac tions by acting on specific receptors on cell membranes [1]. ET binding sites have been identified in the heart [2], blood vessels and central nervous system (CNS) [1,3].…”

Evidence that Morphine Tolerance May Be Regulated by Endothelin in the Neonatal Rat

“…The mechanisms involved in tolerance after chronic administration of opiates are extremely complex, involving changes in opiate signal transduction and interactions between opiate and non-opiate systems [9]. The ET system in the central nervous system (CNS) has been shown to be a potent regulatory system for the sympathetic nervous system [27,31]. ET antagonists have also been shown to block sympathetic nervous systemmediated responses of clonidine and propranolol [32,33].…”