The purpose of this study was to determine whether protein tyrosine kinase, a ubiquitous family of intracellular signaling enzymes that regulates endothelial cell function, modulates bradykinin- and substance P-induced increase in macromolecular efflux from the intact hamster cheek pouch microcirculation. Using intravital microscopy, we found that suffusion of bradykinin or substance P (each, 0.5 & 1.0 µM) onto the cheek pouch elicited significant, concentration-dependent leaky site formation and increase in clearance of fluorescein thioisocyanate-dextran (FITC- dextran; mol mass, 70 kDa; p0.05). These responses were significantly attenuated by suffusion of genistein (1.0 µM) or tyrphostin 25 (10 µM), two structurally unrelated, nonspecific protein tyrosine kinase inhibitors (p0.05). Conceivably, the kinase(s) involved in this process could be agonist-specific because genistein was more effective than tyrphostin 25 in attenuating bradykinin-induced responses while the opposite was observed with substance P. Both inhibitors had no significant effects on adenosine (0.5 M)-induced responses (p0.5). Collectively, these data suggest that the protein tyrosine kinase metabolic pathway modulates, in part, the edemagenic effects of bradykinin and substance P in the intact hamster cheek pouch microcirculation in a specific fashion.