SYNERGISM BETWEEN THE CONTRACTILE EFFECT OF EPIDERMAL GROWTH-FACTOR AND THAT OF DES-ARG9-BRADYKININ OR OF ALPHA-THROMBIN IN RABBIT AORTIC RINGS

1 Rabbit aortic rings were used to test the possible contractile effec ts of growth factors and their interaction with other stimuli. A rapid potentiation of kinin-induced contraction by epidermal growth factor (EGF) has been previously observed in this preparation. 2 EGF (5-1500 ng ml-1) and the isoform BB of platelet-derived growth factor (PDGF-BB ; 1-126 ng ml-1) exerted modest but sustained contractile effects in r abbit aortic rings. 3 EGF pretreatment (100 ng ml-1) potentiated the c ontractile responses to des-Arg9-bradykinin (des-Arg9-BK), an agonist of the B1 receptors for kinin found in this preparation, and to human alpha-thrombin but not to several other contractile stimuli. The inter action appeared also relatively selective for the growth factor, becau se PDGF-BB pretreatment potentiated neither des-Arg9-BK nor alpha-thro mbin-induced contraction. 4 EGF, applied on a contraction plateau indu ced by des-Arg9-BK or alpha-thrombin, exerted a synergistic contractil e effect, with a time course and a half-maximal concentration for EGF- induced contraction similar to the ones recorded in resting tissues (b etween 67 and 220 ng ml-1, depending on the series of experiments). 5 The direct or synergistic contractile effects of EGF were not modified by the removal of the endothelium or by treatment with indomethacin. However, the tyrosine kinase inhibitors, erbstatin or genistein, inhib ited the synergistic effect of EGF with des-Arg9-BK. The small direct contractile effect of EGF was significantly reduced by genistein. The synergistic effect of EGF with alpha-thrombin was comparatively more r esistant to the tested tyrosine kinase inhibitors. 6 An inhibitor of t he catalytic activity of alpha-thrombin, D-Phe-Pro-Arg-CH2Cl, prevente d the contractile effect of alpha-thrombin in the aortic rings. In thi s system, a tetradecapeptide derived from a recently cloned alpha-thro mbin receptor was a contractile stimulus at and above 10-mu-M. Consist ent with the hypothesis that this peptide could behave as an alpha-thr ombin receptor agonist, its contractile effect was potentiated by EGF pretreatment. Pharmacological evidence was provided to show that the r eceptors for alpha-thrombin were distinct from the B1 receptors for ki nins. Together, these findings suggest that a model of a cleavable rec eptor recently elaborated to account for alpha-thrombin effects on hum an platelets is valid in blood-free vascular smooth muscle preparation s such as the rabbit isolated aorta. 7 The synergism between EGF and k inin- or alpha-thrombin-induced contractions constitutes a novel mode of myotropic action for growth factors. The synergism is probably depe ndent on the tyrosine kinase activity of receptors for EGF. These comb inations of stimuli could occur in various types of vascular disease a nd account for abnormal vascular reactivity often associated with athe roma lesions or vascular wound healing.