Prostacyclin antagonists

The vascular endothelium produces a number of substances that are released basally into the blood vessel wall to alter vascular smooth muscle tone. One such substance is endothelin (ET-1). Endothelin exerts its effects throughout the body, causing vasoconstriction as well as positive inotropic and chronotropic effects on the heart. The resulting increases in TPR and CO contribute to an increase in MAP. Synthesis of endothelin appears to be enhanced by many stimuli, including Ag II, vasopressin, and the mechanical stress of blood flow on the endothelium. Synthesis is inhibited by vasodilator substances such as prostacyclin, nitric oxide, and atrial natriuretic peptide. There is evidence that endothelin is involved with the pathophysiology of many cardiovascular diseases, including hypertension, heart failure, and myocardial infarction. Endothelin receptor antagonists are currently available for research use only. 

Mechanisms of action. The tonus of vascular smooth muscle can be decreased by various means. ACE inhibitors, antagonists at ATI-receptors and antagonists at a-adrenoceptors protect against the effects of excitatory mediators such as angiotensin 11 and norepinephrine, respectively. Prostacyclin an-Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

Hall and Wolf [217] have proposed a hypothesis, concerning the pathogenesis of post-traumatic central nervous system ischaemia, which integrates an injury-induced rise in intracellular Ca2+, the increased synthesis of vasoactive prostanoids and progressive microvascular lipid peroxidation. The model used anaesthetised cats with a contusion injury to the lumbar spinal cord. Antioxidants, vitamin E and selenium, were compared with various Ca2 + antagonists, cyclo-oxygenase inhibitors, a thromboxane synthetase inhibitor and the stable prostacyclin analogue. The most impressive preservation of post-traumatic spinal cord blood flow was provided by the antioxidants. 

Prostacyclin is produced in vascular endothelium and plays a role in the regulation of blood flow. It elicits vasodilation and prevents aggregation of platelets (functional antagonist of thromboxane). 

Cox-1 is constitutively expressed and responsible for most of the housekeeping functions of eicosanoids, including processes such as calcium metabolism in the bone, and stomach mucous membrane maintenance. It is also responsible for synthesis of thromboxanes in thrombocytes and of prostacyclin (PGI) in endothelial cells, which have antagonistic function in thrombocyte aggregation and activation (see later). 

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