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Evaluation of the Serotonin Receptor Blocker Methiothepin in Broilers Injected Intravenously with Lipopolysaccharide and Microparticles¹

Department of Poultry Science, University of Arkansas, Fayetteville 72701

² Corresponding author: mchapman{at}uark.edu

There has been considerable interest in the role of serotonin (5-hydroxytryptamine, 5-HT) in the pathogenesis of pulmonary hypertension due to episodes of primary pulmonary hypertension in humans linked to serotoninergic appetite-suppressant drugs. In this study, we investigated the effect of 5-HT on the development of pulmonary hypertension induced by injecting bacterial lipopolysaccharide (LPS; endotoxin) and cellulose microparticles intravenously, using the nonselective 5-HTreceptor, antagonist methiothepin. In Experiment 1, broilers selected for ascites susceptibility or resistance under conditions of hypobaric hypoxia were treated with methiothepin or saline, followed by injection of LPS, while recording pulmonary arterial pressure (PAP). In Experiment 2 ascites-susceptible broilers were treated with methiothepin or saline, followed by injection of cellulose microparticles, while recording PAP. In Experiment 3, an i.v. microparticle injection dose shown to cause 50% mortality was injected into ascites-susceptible and ascites-resistant broilers after methiothepin or saline treatment. Injecting methiothepin reduced PAP below baseline values in ascites-susceptible and ascites-resistant broilers, suggesting a role for 5-HT in maintaining the basal tone of the pulmonary vasculature in broilers. Injecting microparticles into the wing vein had no affect on the PAP in the broilers treated with methiothepin, suggesting that 5-HT is an important mediator in the pulmonary hypertensive response of broilers to microparticles. Furthermore, injecting an 50% lethal dose of microparticles into ascites-susceptible and ascites-resistant broilers pretreated with methiothepin resulted in reduced mortality. Serotonin appears to play a less prominent role in the pulmonary hypertensive response of broilers to intravenously injected LPS, indicating that other mediators within the innate response to inflammatory stimuli may also be involved. These results are consistent with our hypothesis that pulmonary hypertension syndrome ensues when vasoconstrictors, such as 5-HT, overwhelm the dilatory effects of vasodilators, such as NO, thereby effectively reducing the pulmonary vascular capacity of pulmonary hypertension syndrome-susceptible broilers.

Key Words: broiler • serotonin • lipopolysaccharide • microparticle • methiothepin

¹ US patent 6,720,473 protects the exclusive rights of the University of Arkansas to all uses of the i.v. microparticle injection technology within the context of evaluating or affecting pulmonary vascular capacity, pulmonary vascular resistance, pulmonary hypertension, cardiopulmonary hemodynamics, and susceptibility to pulmonary hypertension and pulmonary hypertension syndrome (ascites) in domesticated animal species.

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				K. R. Hamal, R. F. Wideman, N. B. Anthony, and G. F. Erf Differential expression of vasoactive mediators in microparticle-challenged lungs of chickens that differ in susceptibility to pulmonary arterial hypertension Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2010; 298(1): R235 - R242. [Abstract] [Full Text] [PDF]

				R. F. Wideman, O. T. Bowen, and G. F. Erf Broiler pulmonary hypertensive responses during lipopolysaccharide-induced tolerance and cyclooxygenase inhibition Poult. Sci., January 1, 2009; 88(1): 72 - 85. [Abstract] [Full Text] [PDF]

				M. E. Chapman, R. L. Taylor, and R F. Wideman Jr. Analysis of Plasma Serotonin Levels and Hemodynamic Responses Following Chronic Serotonin Infusion in Broilers Challenged with Bacterial Lipopolysaccharide and Microparticles Poult. Sci., January 1, 2008; 87(1): 116 - 124. [Abstract] [Full Text] [PDF]

				R. F. Wideman, M. E. Chapman, K. R. Hamal, O. T. Bowen, A. G. Lorenzoni, G. F. Erf, and N. B. Anthony An Inadequate Pulmonary Vascular Capacity and Susceptibility to Pulmonary Arterial Hypertension in Broilers Poult. Sci., May 1, 2007; 86(5): 984 - 998. [Abstract] [Full Text] [PDF]