THE ability of bradykinin to induce vasodilatation, JL increased vascular permeability and leucocytic diapedesis has directed attention to its possible function as a mediator of the early vascular events in inflammation1. As a permeability factor, bradykinin has outstanding activity in the guinea-pig, being about 80 times more potent in this species than histamine2'3. In the rat, on the other hand, bradykinin and histamine both have relatively low potency2, whereas histamine has high activity in the rabbit, comparable to that in the guinea-pig4. To our knowledge, however, bradykinin has not been tested in the rabbit. Bradykinin is a nonapeptide5'6 (Fig. 1) to which kallidin is closely related6; it differs only in possessing an N-terminal lysine group7, thus making kallidin a decapeptide. Although kallidin has pharmacological properties similar to those of bradykinin, there is little evidence concerning the relative potency of the two preparations as permeability factors. Serum kallikrein has a similar potency to bradykinin in the guinea-pig8, but the permeability effects of kallikrein may be mainly due to the production of bradykinin9.In the present work, the permeability-increasing potency of synthetic bradykinin, kallidin and eledoisin has been compared in the skin of guinea-pigs, rats and rabbits. This was done to assess the permeability effects of bradykinin in the rabbit, relative to its known activity in the guinea-pig and rat, to determine the relative potency of bradykinin and kallidin in all three species, and to compare the potency of an unrelated pep tide, eledoisin, since the pharmacological activity of polypeptides appears to be affected both by the internal arrangements of their amino-acid residues10 and their chain-length11'12. Eledoisin is a peptide13 containing eleven amino-acid residues (Fig. 1) obtained from the posterior salivary gland of the Eledone, a close relative of the genus Octopus. The test preparations were injected intradermally in guinea-pigs, rats and rabbits with Evans blue circulating in their blood, according to the technique of Miles and Miles14 and Wilhelm et al.15. Twenty min after completing the injections, the animals were killed and the lesions at the test sites were measured on both the upper and under surfaces of the skin. The sites were then excised and their content of exuded dye was determined by homogenizing the skin and extracting the dye by the technique of Clausen and Lifson3-16. The results are recorded in Fig. 2.Fig. 1. Structure of bradykinin, kallidin and etedoisin Previous work3 in the guinea-pig has indicated that the potency of various permeability factors differs considerably when lesion-diameter is measured on the upper or lower surface of the skin. The procedure of dye extraction is rather tedious as a routine technique, but the results agree more closely with those obtained by measuring lesion diameter on the under rather than the upper surface of the skin3.Although the three polypeptides which were tested each evoke satisfactory responses on both the upper and under surface of rats' skin, the amounts of extracted dye are much less than in the guinea-pig, and the dosage response lines correspondingly unsatisfactory for the evaluation of relative potency. Nevertheless, our dye extraction results for the rat agree with those of other workers19'20 using trypan blue as a marker substance in the investigation of the permeability effects of histamine and kallikrein. In the rabbit, on the other hand, the lesions are not estimable on the upper surface of the skin. The exudation of the dye is confined to the upper layers of the skin and does not extend down to the panniculus carnosus, which in turn is too opaque for the pale overlying lesions to be viewed from the under surface. That the amount of exuded dye is relatively small in the rabbit is confirmed by the dye extraction results (Fig. 2).As Fig. 2 also illustrates, the amount of exuded dye in the rabbit was even less than in the rat, and the corresponding dosage-response lines were unsatisfactory for the estimation of relative potency of permeability factors. The foregoing disadvantages in the rat and rabbit were unexpected, particularly in the latter, and hence the interspecies comparison of the three test peptides had to be confined to the results from the upper-surface readings. The outstanding activity of bradykinin in the guinea-pig and its lower activity in the rat are confirmed. In the rabbit, bradykinin has high activity, of the same order as in the guinea-pig. Relative to histamine, bradykinin has a potency of 86 in the guinea-pig and 63 in the rabbit; and relative to 5-hydroxytryptamine, a potency of 0-6 in the rat.In all three species, kallidin. has slightly less activity than bradykinin, but the relative factor is only about 1-3 in the guinea-pig, 2 in the rat, and 3 in the rabbit. The results for eledoisin are surprising in that this peptide has high potency in both the guinea-pig and rat, but negligible activity in the rabbit. In the guinea-pig, the activity of eledoisin is comparable to that of both bradykinin and kallidin, but in the rat it far outstrips any factor we have tested, being 18 times more active than bradykinin and 10 times more active than 5-hydroxy~ tryptamine.Our results, therefore, indicate that bradykinin has high permeability-increasing activity in the rabbit, as in the guinea-pig and rat, and that in all three species its activity slightly but consistently exceeds that of kallidin. On the other hand, eledoisin, an unrelated peptide of similar chain-length, has comparable activity in the guinea-pig, outstanding effects in the rat, but negligible and the mean amounts of Evans blue extracted from the same lesions potency in the rabbit. Whatever the explanation of this unexpected result with eledoisin, it seems noteworthy that this is still another example of a biological substance exhibiting wide variations in permeability effects according to the species of test animal3. Fig 2 Permeability-increasing potency of bradykinin (J5), kallidin (K) and eledoisin (E), relative to histamine (H), in guinea-pigs and rabbits, and to 5-hydroxytryptamine () in rats. The response lines record the mean lesion diameters on the upper and under surfaces of the skin, and the mean amounts of Evans blue extracted form the same lesions We thank Sandoz, Ltd., for supplies of the synthetic peptides, and the Bushells Trust for financial support to one of the authors (J. C.).