Bronchoconstrictor Action and Antagonism of a Slow‐reacting Substance From Anaphylaxis of Guinea‐pig Isolated Lung

1. Nine non-steroidal anti-inflammatory drugs were tested for antagonism of bradykinin-induced bronchoconstriction in guinea-pig lungs in vivo. Only one, benzydamine, was inactive. 2. The descending order of potency of the active anti-inflammatory drugs was meclofenamate=Scha 306>Scha 87/2>indoxole>Mi85>indomethacin> glafenine>ibufenac. 3. Of eight other drugs tested, chlorpromazine, phenoxybenzamine and four others were inactive, whereas phenelzine and mebanazine possessed activity. 4. In tests at two dose-levels of meclofenamate, the dose-ratio of bradykinin increased proportionately with the dose of meclofenamate. 5. The anti-bradykinin effect of meclofenamate was still observed after destruction of the brain and spinal cord, after bilateral adrenalectomy or after blockade of s-receptors for adrenaline. 6. Meclofenamate did not release catecholamines from the adrenal medulla or prevent such a release by bradykinin given intra-arterially. 7. The fenamates and like-acting drugs reduced the intensity of anaphylactic bronchoconstriction in guinea-pigs treated with mepyramine or propranolol. The descending order of potency was meclofenamate>flufenamate>mefena-mate.8. Dose/response curves for the antagonism of anaphylactic bronchoconstriction by the fenamates, in the presence of propranolol, turned downwards at high doses.9. These findings suggest that the fenamates may find a useful place in the treatment of bronchial asthma or other conditions involving allergic ventilatory impairment.

Section: Discussionsupporting

confidence: 78%

Antagonism by fenamates and like‐acting drugs of bronchoconstriction induced by bradykinin or antigen in the guinea‐pig

Collier¹,

James²,

Piper³

1968

“…Sodium meclofenamate inhibits certain actions of kinin, SRS-A, prostaglandin F2a and anaphylactic bronchoconstriction in the guinea-pig (Collier & Shorley, 1963;Berry & Collier, 1964;Collier & Sweatman, 1968). At low concentrations, neither antagonist had any inhibitory activity against exogenous agonists.…”

Section: Discussionmentioning

confidence: 99%

The Pharmacology of Anaphylaxis in the Chicken Intestine

Chand

Eyre

1976

“…The possibility that leukotrienes may contribute to the effects of Paf-acether could not be ruled out since their bronchial effects are also inhibited by aspirin in the guinea-pig (Berry & Collier, 1964;Engineer et al, 1977;Omini et al, 1981;Piper, 1983). However, the ability of the leukotriene antagonist FPL 55712 to suppress the release of TXA2 induced by LTC4 but not Paf-acether, Bk and AA, excluded LTC4 and LTD4 as possible mediators of the Paf-acether response but not LTB4 whose myotropic effects are not inhibited by FPL 55712 but are suppressed by aspirin and mepacrine (Sirois et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

The platelet‐independent release of thromboxane A₂ by Paf‐acether from guinea‐pig lungs involves mechanisms distinct from those for leukotriene

Lefort

Rotilio

Vargaftig

1984

129

1 Intra-arterial injections of platelet-activating factor (Paf-acether, 10-300 ng) to the perfused guinea-pig lung induced a dose-related bronchoconstriction, followed by contraction of the rat aorta superfused with the lung effluent, indicating the release of thromboxane A2 (TXA2) activity. These effects were matched with injections of bradykinin (Bk) at 100-1000 ng, leukotriene C4 (LTC4) at 10-300 ng or arachidonic acid (AA) at 30-300 jLg. 2 Repeated doses of Paf-acether led to a specific desensitization of the release of TXA2, under conditions where Bk, LTC4 and arachidonic acid retained their ability to release TXA2. 3 Bronchoconstriction and the release of TXA2 induced by Paf-acether were suppressed when the lungs were perfused with acetylsalicylic acid, but not with salicylic acid. 4 The phospholipase A2 inhibitor, p-bromophenacyl bromide suppressed the release of TXA2 by Bk, but did not interfere with its formation from AA, nor with its release with Paf-acether and LTC4. The lipoxygenase inhibitor, nordihydroguaiaretic acid, inhibited to a similar extent the release of TXA2 by Bk, LTC4 and Paf-acether but also reduced directly the formation of TXA2 from arachidonic acid, invalidating its use as a specific antilipoxygenase agent.5 The leukotriene C4/D4 antagonist, FPL 55712, suppressed the TXA2 releasing effects of LTC4, and was completely inactive against Paf-acether, Bk or arachidonic acid. 6 The aerosol of Paf-acether was tested in the anaesthetized guinea-pig and resulted in bronchoconstriction, unaccompanied by thrombocytopenia. Unlike bronchoconstriction induced by intravenous Paf-acether, which is refractory to cyclo-oxygenase inhibitors, the effects of the aerosol were suppressed by aspirin. Platelet depletion, which blocks the intravenous effects of Paf-acether, failed to interfere with those of the aerosol. 7 Paf-acether induced a marked contraction of the superfused guinea-pig isolated parenchyma lung strip, which was followed by total and irreversible desensitization to itself. The contractile effect was not inhibited by aspirin or indomethacin, atropine, mepyramine, methysergide, phenoxybenzamine or propranolol, indicating that cyclo-oxygenase products, cholinergic stimuli, histamine, 5-hydroxytryptamine and catecholamine mechanisms are not involved. 8 Our results indicate that Paf-acether interacts with pulmonary sites distinct from those for Bk, LTC4 or AA, since no cross-desensitization between Paf-acether and the other agonists was noted, p-bromophenacyl bromide inhibited Bk only and FPL 55712 inhibited only LTC4. The phospholipase A2 involved with the release of the arachidonate needed for the formation of TXA2 by Paf-acether or LTC4-stimulated lungs may differ from the enzyme accounting for its formation by Bk. The cellular sites with which Paf-acether interacts may also be distinct and less readily accessible to p-bromophenacyl bromide.