Monocrotaline Pyrrole-Induced Pulmonary Hypertension in Fawn-Hooded Rats with Platelet Storage Pool Deficiency: 5-Hydroxytryptamine Uptake by Isolated, Perfused Lungs

Abstract

SummaryPlatelets are believed to be involved in the development of monocrotaline pyrrole (MCTP)-induced pulmonary hypertension. To help identify the role of the platelet, the cardiopulmonary toxicity of MCTP was examined in fawn-hooded (FH) rats, a strain with a platelet function defect. Both Sprague-Dawley (SD) and FH rats developed right ventricular hypertrophy and increased lung weights and exhibited decreased biogenic amine removal by isolated, perfused lung preparations after MCTP treatment. The responses of the FH rats were not significantly different from those of the SD rats, suggesting that platelet uptake and release of 5-hydroxytryptamine (5HT) are not the platelet functions involved in MCTP-induced pulmonary hypertension. The FH rats had an interesting strain-related difference from SD rats; isolated lungs from FH rats removed and metabolized a greater proportion of perfused 5HT than the SD rats.

Role of serotonin in the pathogenesis of acute and chronic pulmonary hypertension

“…An experimental model of platelet storage pool disease exists in the fawn hooded rat, an animal which is studied for its propensity to develop pulmonary hypertension 154. In this species pulmonary vascular smooth muscle proliferates more rapidly in response to epidermal growth factor than in normotensive rats,155 there is increased vasoconstrictor sensitivity to serotonin,156 and decreased biogenic amine removal by lung tissue 157. These rats also appear to have a genetic propensity to overproduce endothelin-1, another mitogen and vasoconstrictor 158…”

Protection by oestradiol against the development of cardiovascular changes associated with monocrotaline pulmonary hypertension in rats

“…Endothelial damage is not caused directly by monocrotaline I but by its metabolic products. Monocrotaline is converted to reactive pyrroles by the mixed function oxidase system of the liver (Hilliker et al, 1983). Oestradiol may have a direct inhibitory effect on the conversion of monocrotaline to its toxic metabolite, monocrotaline pyrrole.…”

Prostanoid production in endothelial and Kupffer liver cells from monocrotaline intoxicated rats

“…Hilliken et al 21 demonstrated that MCT is converted to reactive pyrrols by the mixed functions oxidase system of the liver, that can be the putative producers of the hepatic damage. Ono and Voelkel 22 as well as Ito et al 3 suggested that these metabolites may be not directly toxic but may trigger some other mechanisms, perhaps through the production and release some endogenous in¯ammatory mediators, such as leukotrienes and cytokines or inhibit the production of NO and/or, some cytoprotective substances like prostacyclin.…”