The significance of liberated cyclooxygenase products for the pulmonary and cardiovascular actions of leukotriene C4in the guinea pig depends upon the route of administration

Abstract

Leukotriene C4 (LTC4), given as an aerosol or i.v., was at least 100 tiems more potent than histamine in causing an increase of the tracheal insufflation pressure in pentobarbital anesthetized artificially ventilated guinea pigs. Indomethacin [INDO] or meclofenamate enhanced the longlasting bronchoconstriction elicited with aerosols of LTC4, but antagonized the relatively short lived airway response to i.v. LTC4. By increasing the injected dose of LTC4, a slowly developing but maximal bronchoconstriction could be obtained in the presence of Indo. Indo did not affect the airway response to histamine, administered by either route. Injection of LTC4 i.v. had little effect on the heart rate, but evoked a biphasic change of the systemic arterial blood pressure. An initial pressor response, which was attenuated but not abolished by INDO, was followed by a longlasting reduction of blood pressure. The hypotensive period evoked with higher doses of LTC4 occurred earlier and was of greater magnitude in INDO treated animals. Thus, LTC4 has a potent cyclooxygenase-independent bronchoconstrictor action in the intact guinea pig, which supports the possibility that LTC4 and its metabolites are important mediators of airway anaphylaxis in this animal. Depending upon the route of administration, secondarily released prostaglandins and/or thromboxanes may amplify or reduce the direct pulmonary effects of LTC4.