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-HT(1/2)receptor, 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.