Protease-activated receptor (PAR)-mediated vascular relaxations have been compared in coronary arteries of different diameters isolated from both humans and pigs. Thrombin, trypsin, and the PAR1-activating peptide, TFLLR, all caused concentration-dependent relaxation of both large (epicardial; approximately 2 mm internal diameter) and small (intramyocardial; approximately 200 microm internal diameter) human coronary arteries. EC(50) values for thrombin (0.006 u ml(-1) in epicardial, 1.69 u ml(-1) in intramyocardial) and trypsin (0.02 u ml(-1) in epicardial, 1.05 u ml(-1) in intramyocardial) were significantly (P<0.01) greater in intramyocardial arteries. By contrast, EC(50) values for TFLLR were not different between epicardial (0.35 microM) and intramyocardial (0.43 microM) arteries. In porcine coronary arteries, EC(50) values for relaxations to thrombin (0.03 u ml(-1) in epicardial 0.17 u ml(-1) in intramyocardial) were also significantly (P<0.01) greater in the smaller arteries. EC(50) values for both TFLLR and the PAR2-activating peptide, SLIGKV, were not different between the two different-sized pig coronary arteries. PAR1-immunoreactivity was localized to the endothelium of human epicardial and intramyocardial arteries and both PAR1- and PAR2-immunoreactivity was observed in endothelial cells of equivalent porcine arteries. These findings indicate that enzymatic activation of endothelial cell PARs in human (PAR1) and porcine (PAR1 and PAR2) coronary arteries is markedly reduced in intramyocardial arteries when compared with epicardial arteries, suggesting increased regulation of PAR-mediated vascular responses in resistance-type arteries.