In-Vitro Contraction of the Equine Aortic Valve I. Mark Bowen, Celia M. Marr, Adrian H. Chester 1 , Caroline P. D. Wheeler-Jones, Jonathan Elliott The Royal Veterinary College, University of London, Hatfield, Hertfordshire, UK, 1 Heart Science Centre, Harefield Hospital, National Heart and Lung Institute, Imperial College of Science Technology and Medicine, UK The mechanisms that lead to regurgitation and myx- omatous degeneration of the aortic valve remain elu- sive. Vasoactive agents have been shown to induce receptor-mediated contraction of the porcine aortic valve (1), and these responses have been reported to lead to increased regurgitation in vitro (2). The rele- vance of this contractile ability of the valve is of partic- ular interest, since drugs that interact with these receptors (e.g. fenfluramine) have been associated with the development of valvular heart disease (3,4). It is hypothesized that changes in aortic valvular tone, brought about by circulating and locally produced vasoactive agents, lead to regurgitation prior to the development of structural abnormality of the valve. While the porcine aortic valve is often used as a model for studying valve pathology, these studies are limited by tissue collection usually being restricted to young animals as they enter the human food chain. Furthermore, porcine aortic valve disease is a poorly categorized entity, which is most frequently associated with specific bacterial etiologies, rather than being a degenerative, non-inflammatory disease such as occurs in humans. By comparison, aortic valve disease is a common disease of the aging horse, and is charac- terized as a non-inflammatory, myxomatous degenera- tive disease (5), sharing many of the same histological characteristics as human aortic valvular pathology. The disease can occur with variable severity, where regurgitation can be detected using Doppler echocar- diography before structural disease is evident (6,7), or Address for correspondence: Mr. I. M. Bowen, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield AL9 7TA, UK © Copyright by ICR Publishers 2004 Background and aim of the study: The equine aortic valve is subject to non-inflammatory degenerative changes, associated with aortic valvular regurgitation (AR). This disease shares pathological and epidemi- ological features with AR in humans, and may serve as a useful model to study in-vitro functional responses associated with aging and disease. The study aim was to determine the contractile properties of the normal equine aortic valve. Methods: The contractile responses of equine aortic valves to angiotensin II, the thromboxane-mimetic U44069, endothelin-1, 5-hydroxytryptamine and the alpha-adrenoceptor agonists medetomidine, norepi- nephrine and phenylephrine were studied in vitro in organ baths. Selective antagonists were used to con- firm the receptors involved. Results: The order of potency of the agents causing contraction of equine aortic valve segments was angiotensin II > endothelin-1 > U44069 > medetomi- dine > norepinephrine > phenylephrine. 5- Hydroxytryptamine did not cause contraction of the equine aortic valve. The contractile response to angiotensin II was abolished by the AT1 receptor antagonist Sar 1 -Ile 8 -Angiotensin II, and that of U44069 by the thromboxane TXA2 receptor (TP) antagonist SQ29548. The contractile effects of endothelin-1 were blocked by the ETA receptor antagonist BQ123, but not by the ETB receptor antag- onist BQ788. Yohimbine inhibited the contractile effects of phenylephrine, suggesting an alpha-2 adrenoceptor-mediated response. Conclusion: Equine aortic valves contract in response to a number of physiologically important endocrine, paracrine and neuronal mediators. Regulation of valvular tone could therefore be important in the normal functioning of the valve, and further under- standing of these mechanisms may lead to insights into the pathophysiology of naturally occurring equine aortic insufficiency. In this respect, the horse should be considered as a model of the human con- dition. The Journal of Heart Valve Disease 2004;13:593-599