Effects of neurokinin A (NKA) and substance P (SP) on coronary resistance vessels were studied in isolated guinea pig hearts perfused with isotonic buffer containing 20 mM KCl. Injections of NKA and SP caused dose-dependent reductions in perfusion pressure with ED50 values of 14.0 and 0.326 pmol, respectively. Blockade of nitric oxide synthesis or removal of the endothelium inhibited vasodilator responses to neurokinins. Infusions of NKA or SP caused tachyphylaxis and cross-desensitization to the other neurokinin but not to acetylcholine. Injections of 2.5 nmol NKA increased perfusion pressure by 31 ± 8% when given after tachyphylaxis developed to infused SP (2.5 nmol/100 μl/min). It was concluded that 1) neurokinins cause an endothelium-dependent relaxation of coronary resistance vessels by stimulating NK-1 receptors on endothelial cells, and 2) desensitization of the receptor mediating vasodilation unmasks a vasoconstrictor response to NKA.