Few studies have reported on the association of viscosity with coronary circulation. We evaluated the change in coronary flow after dextran was added to a perfusion solution to increase viscosity in isolated rat hearts. We also measured NOx- production induced by the change in shear stress in the coronary effluent, as a marker of NO synthesis. The baseline coronary flow was not influenced by the presence of either the cyclooxygenase inhibitor indomethacin, the thromboxane A2 (TXA2)-prostaglandin H2 (PGH2) receptor antagonist ONO-3708, or the TXA2 synthase inhibitor OKY-046. After exposure to solution containing 0.5% dextran, the coronary flow first decreased and then gradually increased until 10 min. The initial decrease in coronary flow was inhibited by indomethacin, ONO-3708, and OKY-046 individually. The gradual increase was completely inhibited by the NO inhibitor L-NAME, but not by indomethacin or ONO-3708. OKY-046 partially inhibited the increase. NOx- levels in the effluent were higher after the dextran solution was administered, and the increased NOx- levels were inhibited by L-NAME. The increased NOx- levels were not inhibited by inhibitors of the cyclooxygenase pathway. It appears that a higher viscosity of perfusion solution induced a gradual increase in NO production and was associated with increased production of indomethacin-sensitive contracting factor.