Pneumotoxicity and thrombocytopenia after single injection of monocrotaline

Abstract

Adult Sprague-Dawley rats were treated once with 105 mg/kg monocrotaline (MCT) subcutaneously or an equivalent volume of isotonic saline and examined 2, 5, 10, and 14 days later. The earliest changes observed were in the platelet count, which was decreased in the MCT animals at 2, 5, and 10 days postinjection. Clearance of perfused 5-hydroxytryptamine, a function of pulmonary vascular endothelium, was unaltered in isolated lungs of treated rats until 5 days after dosing but decreased progressively thereafter in the MCT animals and was 24% less than controls by 14 days. The magnitude of this effect was dose related. Inflow perfusion pressure was elevated in perfused lungs of MCT-treated animals at day 14. Right heart hypertrophy, measured as an increase in the ratio of right ventricle to left ventricle plus septum weights, was not evident until 14 days after treatment. A larger dose of MCT (130 mg/kg) resulted in significant mortality, whereas a lower dose (60 mg/kg) did not result in right ventricular hypertrophy 2 wk after treatment. The treatment regimen described has advantages over administration of MCT by ingestion and may prove suitable for investigations of the mechanism by which MCT results in pulmonary hypertension.

Tadalafil, a Long-Acting Inhibitor of PDE5, Improves Pulmonary Hemodynamics and Survival Rate of Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

“…MCT is metabolized in the liver and changed to the active form (monocrotaline pyrrole) which, after a single subcutaneous injection, injures vascular endothelium of pulmonary vessels within several hours (26), activates platelets within 1 week (27,28), and causes enhanced reactivity of pulmonary vessels to vasoconstrictive substances (29) and muscular hypertrophy of the media of pulmonary vessels (30). Mortality due to right cardiac failure begins 3 to 4 weeks after the injection and the survival decreases to about 30% by 6 weeks after the injection.…”

Changes in Sequestered Leukocytes and Platelets in the Pulmonary Microvasculature of Rats with Monocrotaline-lnduced Pulmonary Hypertension

“…The inflammatory lesions of pulmonary capillaries, arterioles and arteries induced by MCT con tain WBCs, and a large number of WBCs and elevation of eieosanoids are also seen in bronchoalveolar lavage fluid [9J. H ¡Hiker et al [7,8] studied MCT rats and found data that strongly pointed to a role of PLTs in the development of pulmonary hypertension. The purpose of the present study was to investigate the sequestration ofWBCs and PLTs in pulmonary' capillaries during the development of Sequestered Leukocytes and Platelets in Monocrotaline Pulmonary Hypertension pulmonary' hypertension and RV hypertrophy.…”

“…When pulmonary inflammation peaked 14-28 days after MCT injection, sequestered PLTs in the alveo lar capillaries decreased progressively. Ono and Voelkel [21] have reported that lung tissue PLT-activating factor levels were elevated in MCT rats during the early injury phase; Hilliker et al [7,8] also strongly suggested that PLTs were involved in the development of pulmonary hypertension in MCT rats. Stenmark et al [9] found that inhibition of WBC leukotriene synthesis by administra tion of diethylcarbamazine to rats with MCT-induced pulmonary hypertension lessened the pulmonary hyper tension and RV hypertrophy that characterized the late phase of the MCT lung disease.…”

“…A progressive rise in pulmo nary artery pressure and the development of right ventric ular (RV) hypertrophy appear to correlate with these pul monary vascular changes [4][5][6], Therefore, the type of pulmonary hypertension for which MCT-induced pulmo nary hypertension is used as a model need to be specified. In addition, time course studies in this MCT rat model have indicated that chronic lung inflammation precedes pulmonary hypertension and RV hypertrophy [7][8][9], In the present study, the sequestration of leukocytes (WBCs) and platelets (PLTs) in the pulmonary microvas culature was investigated by real-time confocal laser mi croscopy [10][11][12][13] tion of these cells to the development of cardiopulmonary changes in rats with MCT-induced pulmonary hyperten sion.…”

Orally Administered Beraprost Sodium Inhibits Pulmonary Hypertension Induced by Monocrotaline in Rats.

“…It has been known that platelets are responsible for the development of pulmonary arterial injury in this model. MCT induces pulmonary sequestration of platelets and thrombocytopenia (Hilliker et al 1982(Hilliker et al , 1984. A single intravenous injection of prostacyclin (PGI2) at the time of MCT administration inhibits MCT-induced immediate pulmonary hypertension (Czer et al 1986).…”