Vasoconstrictors secreted by the Endothelium

By: Pharma Tips | Views: 4647 | Date: 01-May-2011

Endothelin contains 21 amino acids peptide is an extremely powerful vasoconstrictor. There are three isoforms of endothelin, but isoform 1 (ET1) only, is released from human endothelial cells. The production of endothelin-1 from big-endothelin is catalysed by endothelin-converting enzyme (ECE); it is released in response to hypoxia and noradrenalin. The biological actions of endothelin are mediated by two distinct G-protein-coupled receptor subtypes (ETA and ETB), located in smooth muscle cells.

1)  Endothelin

                     Endothelin contains 21 amino acids peptide is an extremely powerful vasoconstrictor. There are three isoforms of endothelin, but isoform 1 (ET1) only, is released from human endothelial cells. The production of endothelin-1 from big-endothelin is catalysed by endothelin-converting enzyme (ECE); it is released in response to hypoxia and noradrenalin. The biological actions of endothelin are mediated by two distinct G-protein-coupled receptor subtypes (ETA and ETB), located in smooth muscle cells. Such activation causes an increase in intracellular calcium leading to contraction. ET1 can also interact with ETB receptors on endothelial cells, triggering the release of vasodilators (NO, PGI2). ET1 has a short half life and is present in healthy subjects at low concentrations. ET1 is involved in counter-regulation for preserving peripheral resistance.

2)  Endothelium-derived contracting factors (EDCFs)

                    The endothelium also synthesizes and releases EDCFs, causing endotheliumdependent contractions. These EDCFs include vasoconstrictor prostanoids such as prostaglandin H2 and thromboxane A2, which activate specific receptors on the vascular smooth muscle. Superoxide anions may act as contracting factor by scavenging NO. The stimuli for EDCFs production are hypoxia, blood pressure, and variety of neurohumoral mediators.

3)  Stimuli

A)  Neurohumoral factors

                      The neurohumoral mediators (acetylcholine, bradykinin and histamine), hormones (catecholamines, vasopressin), and substances derived from platelets (adenosine diphosphate and serotonin) and thrombin (T) cause the release of endothelium-derived relaxing or contracting factors by activating specific endothelial receptors, inducing changes in the vascular tone.Vasodilators and vasoconstrictors secreted by the endothelium. NO: nitric oxide, NOS: nitric oxide synthase, ET1: endothelin-1, ECE: endothelin-converting enzyme, PGI2: prostacyclin, COX: cyclooxygenase, L-Arg: L-arginine, EDHF: endothelium-derived hyperpolarizing factor, X?: unknown, cGMP: cyclic guanosine monophosphate, cAMP: cyclic adenosine monophosphate, PGH2: prostaglandin.H2, TXA2: thromboxane A2, AT-I: angiotensin I, AT-II: angiotensin II, ACE: angiotensin-converting enzyme, Ca: calcium, K: potassium, AC: adenylate cyclase, GC: guanylate cyclase. protein G, enzyme, receptor (ET: endothelin, TX: thromboxane, PG: prostaglandins).(30)  In healthy subjects, the muscarinic receptors on the endothelium are activated by acetylcholine (Ach), a neurotransmitter which sets off nitric oxide production. Platelets release substances such as adenosine diphosphate (ADP), adenosine triphosphate (ATP) and 5-hydroxytryptamine (serotonin: 5-HT) which trigger the release of NO and prostacyclin from the endothelium. Thrombin, the major enzyme of the coagulation cascade, also activates the formation of NO by endothelium. The endothelium is also stimulated by substances such as histamine, catecholamines (adrenaline, noradrenaline), substance P (neurotransmitter and neuromodulator from the central nervous system), Calcium gene-related peptide. Bradykinin can also stimulate the production of EDHF by the endothelial cells. Hence, when platelets and the coagulation cascade are activated, intact endothelial cells release NO which acts as a negative feed-back by causing vasodilation and thus preventing vasoconstriction, but also by inhibiting platelet activation to prevent thrombus formation. In contrast, the production of EDCFs can be increased by vasopressin (VP) and thrombin (T) through activation of their specific endothelial receptors. In particular, the effects of ET1 produced by endothelial cells can be amplified by the components of the reninangiotensin system, after transformation of angiotensin I (AT-I) to angiotensin II (AT-II) by angiotensin-converting enzyme (ACE). Activation of the endothelial receptors, such as serotoninergic receptors, can stimulate the enzyme COX in certain blood vessels, with the production of PGH2 and TXA2, leading to contraction.(30)


B)  Wall shear stress
                In addition to receptor-biochemical mechanisms, mechanical factors cause endothelium-dependent vasodilation.
   The blood flow exerts a physical force on the vessel wall which can be resolved into two principal vectors; 1) shear stress, which is parallel to the vessel wall and represents the friction between the flowing blood and the endothelial surface of the vessel wall, 2) tensile stress, which is perpendicular to the vessel wall and is due to the dilating force of blood pressure. The whole vessel wall, including the endothelium, smooth muscle cells and the extracellular matrix is exposed to it. In contrast, only the inner surface of the vessel wall composed of the endothelial cell is exposed to the frictional force of shear stress. This force passed to the vascular wall and moves the endothelium and subintimal layer towards the underlying layers in the direction of the blood flow, so explaining the minimal change in blood vessel diameter, related to the activation of mecanoreceptors by shear stress. There are two broad mechanisms underlying the interaction between blood flow and the endothelium. One is activation of a calcium/ calmodulin complex dependent receptor (shear stress receptor), leading to a rapid post-translational activation of eNOS. This signal is based on potassium channels and G-protein coupling.  The other is the release of NO by an as-yet-unknown direct effect on the endothelial cells. This action is independent of intracellular calcium, but is probably due to phosphorylation of MAP kinases and/or tyrosine kinase activity.

C)  Stretch force
                      The shear stress effect, the stretch force applied on the endothelium can modulate the production of vasoactive substances by endothelial cells, particularly vasoconstrictors factors, by activating the ionic channels-mecanoreceptor pathway (stretch activated channels).

4)  Hypoxia and ischemia
                      They can stimulate the production of NO and secretion of prostacyclins and cause endotheliumdependent vasodilation. Selective luminal hypoxia can cause a 11% dilatation in segments of femoral artery or aorta from rabbits. This hypoxia-induced dilation of intact segments is significantly inhibited by nitric oxide inhibitors. But hypoxia is associated with increases in plasma endothelin-1 or other EDCR factors, particularly at high altitudes, and can cause endothelium-dependent contraction

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