Antagonistic effect of yangambin on platelet-activating factor (PAF)-induced cardiovascular collapse.

The cardiovascular protective effects of yangambin, a novel and specific naturally-occurring platelet activating factor (PAF) receptor antagonist, were investigated in the pentobarbital anesthetized and artificially ventilated rat. Yangambin (3-30 mg kg(-1)) as well as the reference PAF antagonist WEB 2086 (0.1-1.0 mg kg(-1)) prevented the circulatory collapse elicited by the intravenous administration of PAF (0.5 µg kg(-1)), in a dose-dependent manner. Yangambin did not interfere with the hypotensive effect of several endogenous vasoactive mediators such as acetylcholine, bradykinin, histamine and serotonin. Moreover, when adminstered as a post-treatment the antagonist showed the ability to reverse the cardiovascular effects induced by PAF (1.0 µg kg(-1)). The protective effect of yangambin showed to have a duration of action of more than 2 hours. It is concluded that yangambin is a selective antagonist of the cardiovascular effects of PAF and therefore constitutes a potential therapeutic agent in different shock states where abnormal PAF release is supposed to play an important role.

Protective effects of Yangambin - a naturally occurring platelet-activating factor (PAF) receptor antagonist - on anaphylactic shock in rats.

The purpose of this study was to investigate the ability of yangambin to inhibit cardiovascular collapse and to reduce the mortality due to systemic anaphylaxis induced by antigen challenge in actively sensitized rats. The i.v. injection of the antigen (ovalbumin, 250 or 500 µg/kg), induced a systemic anaphylactic reaction mainly characterized by sudden and marked arterial hypotension and high mortality rates. Yangambin, a PAF receptor antagonist isolated from the Brazilian plant Ocotea duckei Vattimo (Lauraceae), as well as the reference PAF receptor antagonist SR 27417, significantly prevented and partially reversed the circulatory collapse elicited by antigen challenge. Moreover, yangambin and SR 27417, when administered 5 min before re-exposure of the animals to the antigen, markedly improved the survival rate at 120 min. These results confirm that PAF plays an important role in the pathophysiology of anaphylactic shock and show that yangambin presents good therapeutic potential in the treatment of the cardiovascular alterations observed during immediate hypersensitivity reactions.

Systemic neutrophilia observed during anaphylactic shock in rats is inhibited by dopaminergic antagonists.

The involvement of the sympathetic and dopaminergic systems on blood neutrophilic leucocytosis observed during anaphylaxis was investigated. Blood neutrophil counts impressively increased 1 h after intravenous injection of ovalbumin (OVA, 250 micrograms/kg) into OVA-immunized rats. The increase in neutrophil counts induced by OVA was abrogated after catecholamine depletion by reserpine. Either adrenalectomy or the alpha- and beta-adrenoceptor antagonists phentolamine and propranolol, respectively, had only minor inhibitory effects on neutrophilia induced by antigen. On the other hand, pretreatment with the dopaminergic antagonists chlorpromazine and pimozide significantly inhibited the neutrophilia. The intravenous injection of apomorphine, a dopaminergic agonist, increased neutrophil counts in naive animals, while chlorpromazine completely inhibited this phenomenon. These results suggest that dopaminergic mechanisms play a role in the systemic neutrophilia observed during anaphylactic shock.

Yangambin: a new naturally-occurring platelet-activating factor receptor antagonist: binding and in vitro functional studies.

The effects of the furofuran lignan yangambin on rabbit platelet aggregation and binding of [3H]-PAF to rabbit platelet plasma membranes were studied. Log concentration-response curves to PAF were obtained in the presence or absence of increasing concentrations of yangambin. This lignan dose-dependently inhibited PAF-induced platelet aggregation in platelet-rich plasma (PRP) and shifted PAF curves to the right without decreasing the maximal response. The Schild plot constructed from these data showed a slope of 1.17 and a pA2 of 6.45. Moreover, yangambin at 10(-5) M did not inhibit the platelet aggregation induced by ADP (5 x 10(-7) M), collagen (0.1 microgram ml-1), or thrombin (0.05 U ml-1). Biochemical studies showed that [3H]-PAF labelled in a saturable manner a single class of binding sites on platelet membranes with a Kd of 1.25 +/- 0.24 nM and a maximal binding capacity (Bmax) of 14.9 +/- 2.4 pmol mg protein-1. Both unlabelled PAF and yangambin competitively displaced [3H]-PAF binding with an IC50 of 1.54 +/- 0.37 nM and 1.93 +/- 0.53 microM, respectively. The incubation of rabbit blood neutrophils with yangambin at 10(-5) M did not prevent PAF-induced in vitro chemotaxis in conditions where the PAF antagonist SR 27417 at 10(-5) M abolished the phenomenon. These results indicate that yangambin is an antagonist that selectively blocks PAF receptors on platelets.

Yangambin: a new naturally-occurring platelet-activating factor receptor antagonist: in vivo pharmacological studies.

The pharmacological profile of a novel specific platelet-activating factor (PAF) receptor antagonist-yangambin-isolated from the Brazilian plant Ocotea duckei Vattimo (Lauraceae), was investigated in the pentobarbitone-anaesthetized rabbit. The i.v. administration of PAF (0.03-3.0 microgram kg-1) induced marked but reversible hypotensive effects and mild reductions in the heart rate. Both effects are independent of the respiratory conditions imposed on the animals. Moreover, PAF (3.0 microgram kg-1, i.v.) induced a reversible decrease of the circulating levels of platelets and of polymorphonuclear leukocytes. Pretreatment with yangambin (10 and 20 mg kg-1, i.v.) dose-dependently attenuated PAF-induced cardiovascular changes and thrombocytopaenia. Nevertheless, the neutropenic leukopaenia elicited by PAF (3.0 microgram kg-1, i.v.) was not prevented by yangambin whereas the reference PAF antagonists WEB 2086 (2 mg kg-1, i.v.) and SR 27417 (1 mg kg-1, i.v.) significantly inhibited the phenomenon. The hypotensive effects of acetylcholine, histamine, and 5-hydroxytryptamine were not affected by prior administration of yangambin. It is concluded that yangambin is a selective antagonist of the cardiovascular effects of PAF which could be useful in pathological states characterized by abnormal PAF release, such as anaphylactic and septic shocks. Furthermore, yangambin might discriminate a PAF receptor subtype present in the cardiovascular system and platelets from the one existing in polymorphonuclear leukocytes in the rabbit.

Adrenergic modulation of the blood neutrophilia induced by platelet activating factor in rats.

The involvement of catecholamines in blood neutrophilia observed after administration of platelet activating factor (PAF) to rats was studied. Intravenous (i.v.) injection of PAF (4 micrograms/kg) into naive rats more than doubled the number of neutrophils after 1 h. In contrast, PAF failed to induce neutrophilia in both adrenalectomized rats and those which had their catecholamine stores depleted by reserpine. PAF-induced neutrophilia was not inhibited by the selective antagonism of alpha 1- and alpha 2-adrenoceptors with prazosin and yohimbine, respectively. However, pretreatment with the beta-adrenoceptor antagonist, propranolol, significantly inhibited the phenomenon. Increase in the blood neutrophil counts was also achieved following the i.v. injection of the beta-agonist, salbutamol (1 mg/kg, i.v.). This response was clearly sensitive to propranolol but was not modified in rats submitted to adrenalectomy or reserpine pretreatment. The results suggest that the blood neutrophilia induced by the i.v. administration of PAF in rats is dependent on the stimulation of beta-adrenoceptors by catecholamines released from adrenal glands.