Molecular Pharmacology, Vol 14, 1189-1203, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

The Effect of a Pyrrolizidine Alkaloid, Monocrotaline, and a Pyrrole, Dehydroretronecine, on the Biochemical Functions of the Pulmonary Endothelium

¹ University of Arizona Health Sciences Center, Department of Pharmacology, Tucson, Arizona 85724

Monocrotaline was placed in the drinking water of rats at a concentration of 20 mg per liter for periods of up to three weeks. This method of administration produced pulmonary arterial hypertension and right ventricular hypertrophy without inflammatory changes. No changes were noted in liver weight or RNA or protein synthesis in the liver. Isolated, perfused lungs from treated rats were examined for changes in four endothelial cell functions: angiotensin converting enzyme (E.C.3.4.99.3), 5'-nucleotidase (E.C.3.1.3.5), serotonin uptake and metabolism, and norepinephrine uptake and metabolism. Monoamine oxidase (E.C.1.4.3.4) is involved in the metabolism of both transmitters. The activities per lung of the 3 enzymes were unaltered. Norepinephrine transport was also unaffected. Serotonin transport was specifically and markedly impaired. Extraction of serotonin from the perfusate was reduced to 33% of control.

Dehydroretronecine, a metabolite of monocrotaline, produced right ventricular hypertrophy following daily subcutaneous administration for 2 weeks at a dose of 4 mg/kg. Acid-fast activity remained in lungs following perfusion with [³H]dehydroretronecine. Dehydroretronecine, coperfused through isolated lungs at 1 mM concentration, or injected subcutaneously 24 hours before sacrifice at a dose of 100 mg/kg, did not affect the activities of 5'-nucleotidase or angiotensin converting enzyme. However, the retention of serotonin by the lungs was decreased, and the release of metabolites was increased. The different effects observed between monocrotaline and dehydroretronecine may indicate that the pulmonary toxicity of monocrotaline is not mediated through dehydroretronecine. Alternatively, the differences may be due to increased permeability of the endothelial cell caused by the high doses of dehydroretronecine used relative to the levels of monocrotaline. Dehydroretronecine dosages were chosen to be consonant with work by others on this metabolite.

These data indicate that the slow release of metabolites from the liver into the circulation following low-level exposure to monocrotaline results in a specific inhibition of an endothelial cell function in the lung. As well as providing insight into the molecular mechanism of action of pyrrolizidine in the lung, this information suggests that human populations exposed to low levels of pyrrolizidines may have impaired ability to regulate circulating vasoactive substances.

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ACKNOWLEDGMENTS We thank W. R. Langford (USDA Agricultural Research Service) for a gift of Crotalaria spectabilis seeds, and A. Chen and J. Laugharn for excellent technical assistance. We thank A. R. Mattocks (MRC, Carshalton, England) for information on the chemistry of dehydroretronecine.