The competitive antagonistic effect of compounds from Mandevilla velutina on kinin‐induced contractions of rat uterus and guinea‐pig ileum in vitro

Abstract

1 Pure non-peptide compounds obtained in crystal form from the crude extract of the plant Mandevilla velutina (Apocynaceae) were analysed for their antagonistic effects on rat uterine and guineapig smooth muscle contractions induced by bradykinin (Bk), lisyl-bradykinin (L-Bk), acetylcholine (ACh), oxytocin and histamine, in vitro. 3 In the guinea-pig ileum, both MV 8608 and MV 8612 (5 to 20 pgml-1), produced concentration-dependent rightward displacements of the concentration-response curve to Bk (0.1 to 1000 nM) when the experiments were performed in the presence but not in the absence of atropine (2.5 pM). However, in contrast to the result obtained in the rat uterus, compound MV 8608 also caused a significant reduction of the maximal response to Bk. The Schild plot for compound MV 8612 was linear (correlation close to unity) and furnished a nominal pA2 value (g ml 1) of 5.3 and a slope not different from unity.4 In rat uterine muscle, compounds MV 8608 and MV 8612 at concentrations producing marked rightward displacements of the kinin concentration-response curves (10 and 20Ygml 1), did not influence the uterine contractile response to oxytocin or ACh, indicating some selectivity towards kinin receptors. Similarly, compound MV 8612 (10 and 20 ygml 1) did not interfere with the sensitivities or the maximal responses to ACh and histamine in the guinea-pig ileum, whereas compound MV 8608 (10 and 20ug ml-1) caused a slight reduction of ACh-and histamine-induced maximal contractions, allied to decrease of the sensitivity to histamine at concentrations of 20pgml-1 or more.5 These results extend our previous data, indicating the existence of several non-peptide compounds in the crude extract of Mandevilla velutina that act as simple, competitive, selective and reversible kinin receptor antagonists in the rat isolated uterus and guinea-pig ileum smooth muscle.

Action of compounds from Mandevilla velutina on croton oil‐induced ear oedema in mice. A comparative study with steroidal and nonsteroidal antiinflammatory drugs

“…These findings agree well with our previous observations and indicate that although M. uelutina rhizome presents five pregnane antibradykinin compounds as revealed in the isolated tissues (Calixto et al, 1988), compound MV8612, in spite of being the most selective in antagonizing kinin action, is certainly the main substance responsible for the antiinflammatory activity previously observed for the CE of M. uelutina (Calixto et al, 1990a, b;Henriques et al, 1991). In addition, compound MV8612 was markedly more effective than compounds MV8608 and MV8610 (both given topically and systemically) in antagonizing arachidonic acidinduced mouse ear oedema as well as bradykinin and carrageenan-induced rat paw oedema (Calixto et at.…”

“…We have previously demonstrated that the crude aqueous/alcoholic extract (CE) and some natural pregnane compounds isolated from Mandeuiffa uelutina antagonize bradykinin and related kinin responses in smooth muscle preparations (Calixto et al, 1985(Calixto et al, , 1987(Calixto et al, , 1988Calixto and Yunes, 1986). The CE from the plant was also found to be effective in inhibiting both rat paw oedema and pleurisy induced by a great variety of phlogistic agents, including bradykinin, cellulose sulphate, Paf-acether and carrageenan amongst others, as well as the increase of cutaneous vascular permeability in rats (Henriques et al, 1991; for review see Calixto et al, 1991).…”

Evidence for participation of B1 and B2 kinin receptors in formalin‐induced nociceptive response in the mouse

“…To avoid the influences of pharmacokinetics in the action of the drugs studied, different groups of animals were used to analyse each phase of formalin-induced pain. The animals were treated topically (in association with formalin) or by the s.c. route (0.1 ml 10 g ' weight) with several selective B, and B2 antagonists, or with functional BK antagonists isolated from the rhizome of the plant Mandevilla velutina (Calixto et al, 1988). For the purpose of comparison in a separate set of experiments, the animals were treated with morphine (2.6-13 ltmol kg-, s.c.) or with indomethacin (2.7-27 j.mol/paw, i.p.…”

“…The Mandevilla velutina compounds (MV 8608, molecular weight of 326 and MV8612, molecular weight of 1182) were obtained in our laboratory as described previously (Calixto et al, 1988). The stock solution for all peptides used was prepared in PBS (1-10 mM) and kept in siliconized plastic tubes, maintained in a freezer at -18°C.…”

Pharmacological evidence for a single bradykinin B2 receptor in the guinea‐pig

“…Segments of ileum, lung parenchymal strips, 25 mm in length, and transverse strips of trachea as well as two to three rings of jugular vein, 4 mm in length, were prepared and suspended in 8 ml jacketed organ baths containing normal Krebs solution and maintained at 370C. In accordance with previous work, the resting tension was set up at 0.5 g for the jugular vein and the lung parenchyma (Fleisch et al, 1982;Gupta, 1992), 1 g for the ileum (Calixto et al, 1988) and 2 g for the trachea ). An initial load of 200 mg was applied to tracheal preparations and tissues were washed three times at 15 to 20 min intervals.…”