Effect of Endothelin-Converting Enzyme Inhibitors on big Endothelin-1 Induced Contraction of Rabbit Basilar Artery
In 1988, a novel family of endothelium derived extremely potent vasoconstrictor peptides, named endothelins, were isolated from cultured porcine endothelial cells. ET-1, a 21-amino acid peptide, is synthesized by vascular endothelial or smooth muscle cell
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Effect of Endothelin-Converting Enzyme Inhibitors on big Endothelin-l Induced Contraction of Rabbit Basilar Artery M. Zimmermann!, C. Jung!, A. Raabe!, O. Spanehl 2 , and V. Seifert! 1 Neurosurgical
2 Neurological
Clinic, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany Clinic, University of Leipzig, University of Leibzig, Germany
Introduction
Material and Methods
In 1988, a novel family of endothelium derived extremely potent vasoconstrictor peptides, named endothelins, were isolated from cultured porcine endothelial cells. ET-l, a 21-amino acid peptide, is synthesized by vascular endothelial or smooth muscle cells by specific proteolytic cleavage at Trp-21-Val-22 of a precursor 38 amino-acid peptide, big ET-I [6]. When applied to the adventitial side of blood vessels, endothelins cause a dose dependent, long lasting vasoconstriction, similar to cerebral vasospasm following aneurysmal SAH. Increased levels of big ET-1, ET-l and ET-3 were detected in the cerebrospinal fluid and plasma of patients after aneurysmal SAH [5]. In cerebral vessels, endothelins bind to two different receptor subtypes. The ETA receptor is present in vascular smooth muscle cells and mediates vasoconstriction. The ET B receptor is present in brain, endothelium, and smooth muscle cells and mediates endothelium dependent vasodilatation, but can also cause vasoconstriction. The protease that catalyzes the conversion is the so called endothelin-converting-enzyme (ECE), a membrane bound, neutral zinc metallo-endopeptidase like angiotensin-converting enzyme (ACE) and E-24.11 [4, 7]. Blocking the ECE activity may be one way to suppress or even stop the transformation of big ET-I to vasoactive ET-l. Therefore the effects of two different putative ECE inhibitors were investigated in this experimental study.
Thirty rabbits (Chinchilla-Bastard) with a body weight ranging from 2500 to 3500 g were used in this laboratory experiment. Eight animals each were assigned to the control group (2* 10-6 M big ET-I and phyiologic saline solution), to the captopril treatment group (2*10- 4 M captopril and 2*10- 6 M big ET-l), and to the [D-VaJ22] big ET-l [16-38] treatment group (2*10- 5 M [D_VaI 22 ] big ET-l [16-38] and 2*10- 6 M big ET-I). Three animals each were used as therapeutic controls for captopril (2*10- 4 M captopril) and [DVa1 22 ] big ET-l [16-38] (2*10- 5 M), in order to exclude any constrictive effects of these drugs to the basilar artery. Anesthesia was induced by intramuscular injection of 0.186 mg/kg dormitor and 26.25 mg/kg ketamine. After an intramuscular injection of 0.1 mgt kg atropine trachotomy was performed. The animals were ventilated with a 40% O2 concentration using an ADS 1000 veterinary anaesthesia delivery system (Engler Engineering Corporation, Germany). Anesthesia was maintained with an intravenous infusion ofO.IS mgt kg/hr dormitor and 21,0 mg/ml/hr ketamine. After achieving normal vital parameters, the left femoral artery was dissected and a 16 G vygon catheter (Vygon, Aachen, Germany) was inserted. The catheter
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