© 1992 Oxford University Press
research-article |
Respiratory and Cardiovascular Changes Associated with Toxic Doses of a Peptide Antagonist of Vasopressin in the Rat
Department of Investigative Toxicology, SmithKline Beecham Pharmaceuticals King of Prussia, Pennsylvania
Received April 17, 1991; accepted September 12, 1991
SK&F 101926 is a synthetic octapeptide which was designed to promote free water excretion by antagonizing the action of anti-diuretic hormone. The clinical and pathologic changes in rats resulting from lethal doses of SK&F 101926 have suggested that death is associated with respiratory failure and/or cardiovascular collapse. To define the relationships between respiratory failure, cardiovascular collapse, and death, respiratory and cardiovascular parameters were monitored in anesthetized rats following the intravenous administration of SK&F 101926 at a dosage (3 mg/kg) which resulted in 70% mortality. Within 5 min after receiving this dosage, mean arterial blood pressure was reduced to values between 30 and 40 mm Hg in all rats. This degree of hypotension was well tolerated by some rats and, consequently, was not considered to be the cause of death. Deaths occurred between 9 and 58 min after dosing and were preceded by respiratory depression involving marked reductions in respiratory rate and the lack of compensatory increases in tidal volume. At the time of respiratory arrest, heart rates remained above 200 beats/min, mean arterial blood pressure remained between 30 and 40 mm Hg, and there were no consistent changes in dynamic lung compliance or total pulmonary resistance. Pretreatment of rats with a mast cell stabilizing agent (disodium cromoglycate), a mast cell degranulatung agent (compound 48/80), or a histamine/5-hydroxytryptamine blocking agent (cyproheptadine) prevented the reductions in respiratory rate and death caused by SK&F 101926. These pretreatments also reduced the effect of SK&F 101926 on blood pressure, but were not able to completely prevent the hypotension. In conclusion, administration of SK&F 101926 can produce marked changes in respiratory and cardio vascular functions, with death appearing to be more closely asso dated with respiratory failure than with cardiovascular collapse. Furthermore, respiratory failure was not related to changes in the mechanical properties of the lung, and both the respiratory and cardiovascular changes which occurred following the administration of SK&F 101926 appear to be dependent on the release of mast cell mediators.