title: Effect of endothelins on the cardiovascular system.
abstract: Endothelins (ETs) exert a persistent constrictor effect on the vessels via an increase in intracellular Ca2+ concentration due to the activation of Na+/H+ and Na+/Ca2+ exchangers of the vascular smooth muscle fibres. They also produce a transient dilator effect via the activation of endothelial nitric oxide synthase mediated by protein kinase B/Akt. ETA and ETB2 receptors are involved in vasoconstriction, whereas transient vasodilatation depends on the activation of ETB1 receptors. Depending on animal species and experimental conditions, ETs can also play a role in cardiac muscle contraction and induce either an increase or a decrease in contractility. It is likely that only ETA, and not ETB, receptors are involved in the ET-induced increase in myocardial contractility. As in the case of vasoconstriction, this inotropic effect depends on an increase in intracellular Ca2+ concentration induced by Na+/H+ and Na+/Ca2+ exchangers. Activation of the Na+/H+ exchanger is stimulated by protein kinase C, which is activated by diacylglycerol released in response to ET activity. It has also been proposed that the positive inotropic effect can occur without the contribution of the Na+/Ca2+ exchanger, if the cell alkalinisation produced by the Na/H exchanger improves myofibrillar Ca2+ sensitivity. A reduction in contractility has been attributed to the involvement of the Gi protein/protein kinase G pathway or to the activation of protein kinase C without an increase in intracellular Ca2+ concentration or in myofibrillar Ca2+ sensitivity. The chronic effect of ETs on the myocardium results in hypertrophy and prevention of apoptosis, two processes that are together responsible for the contradictory effect of ETs in heart failure.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Penna
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rastaldo
authors.forename: Daniele
authors.initials: D
authors.lastname: Mancardi
authors.forename: Sandra
authors.initials: S
authors.lastname: Cappello
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pagliaro
authors.forename: Nico
authors.initials: N
authors.lastname: Westerhof
authors.forename: Gianni
authors.initials: G
authors.lastname: Losano
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016232:Endothelins / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D006321:Heart / Q000502:physiology; D006801:Humans; D032342:Muscle Cells / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000502:physiology; D017466:Receptors, Endothelin / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D016232:Endothelins; D017466:Receptors, Endothelin; D017923:Sodium-Hydrogen Exchangers; D019001:Nitric Oxide Synthase