Low dose monocrotaline causes a selective pulmonary vascular lesion in male and female pneumonectomized rats

ABSTRACT

Purpose/Aim: Low doses (30–80 mg/kg) of monocrotaline are commonly used to create experimental models of pulmonary hypertension in rats. At these doses, monocrotaline causes pulmonary endothelial apoptosis and acute lung injury which ultimately results in pulmonary vascular disease. Higher doses of monocrotaline (300 mg/kg) are known to create severe liver injury, but previous investigations with lower doses have not reported histology in other organs to determine whether the vascular injury with monocrotaline is pulmonary-selective or generalized. Materials and Methods: We therefore sought to determine whether monocrotaline caused extra-pulmonary injury at doses commonly used in pulmonary hypertension studies. We performed left pneumonectomy on young male and female rats before administering 50–60 mg/kg monocrotaline 7 days later. We monitored serum chemistry and urine dipsticks during the first 3 weeks while the animals developed pulmonary hypertension. After 3 weeks, we sacrificed animals and stained the lungs and highly vascular visceral organs (kidney, liver, and spleen) for elastin to evaluate the degree of vascular injury and remodeling. Results: We did not observe proteinuria or significant transaminitis over the 3 weeks following monocrotaline. As previously published, monocrotaline caused severe pulmonary vascular disease with neointimal lesions and medial hypertrophy. We did not identify significant large or small arterial damage in the kidneys, liver, or spleen. Two external veterinary pathologists did not identify histopathology in the kidneys, liver, or spleen of these rats. Conclusions: We conclude that 50–60 mg/kg of monocrotaline causes a selective pulmonary vascular lesion and that male and female rats have little non-pulmonary damage over 3 weeks at these doses of monocrotaline.

KEYWORDS:

• endothelium
• kidney
• liver
• monocrotaline
• pulmonary hypertension

Acknowledgments

The authors are grateful to Dara Kallop, Christine Miller, and Jennifer Harvey who provided technical assistance with aspects of this work, and Dr. Shari Hamilton and Dr. Cindy Besch-Williford from IDEXX BioResearch who evaluated our tissue samples.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Funding

Funding was provided by American Heart Association Scientific Development Grant (RJW), Parker B. Francis Fellowship (RJW), and the National Institutes of Health training grant T-32HL066988-1 (DJL).

Additional information

Funding

Funding was provided by American Heart Association Scientific Development Grant (RJW), Parker B. Francis Fellowship (RJW), and the National Institutes of Health training grant T-32HL066988-1 (DJL).