Early manifestations of kidney disease occur in atherosclerosis and activation of TP (thromboxane A₂)-receptors is implicated in atherosclerotic, diabetes and renal diseases. The purpose of the present study was to analyze in isolated perfused mouse kidneys, the participation of TP-receptors in renal vasoconstrictions and vasodilatations. In kidneys, taken from wild-type C57BL6, apolipoprotein E-deficient (ApoE-KO) and diabetic ApoE KO mice, changes in perfusion pressure were recorded. Constrictions to TP-receptor ligands, U 46619, arachidonic acid, PGH₂ and 8iso-PGF₂, but not those to angiotensin II, endothelin or norepinephrine, were inhibited by the selective TP-receptor antagonist Triplion® (S 18886, 10 nM). Acetylcholine and prostacyclin evoked biphasic responses during methoxamine constrictions; the constrictor part was blocked by Triplion®. In ApoE-KO mouse kidneys, when compared to C57BL6, a specific decrease in norepinephrine response and no modification in dilator responses, were observed. In diabetic ApoE-KO mouse kidneys, constrictions to U 46619 and those to 8iso-PGF₂ were significantly and selectively augmented, without modification in the expression of the TP-receptor, and again without any significant change in vasodilator activity. Thus, TP-receptors are functional and their activation is not involved in norepinephrine, endothelin and angiotensin II vasoconstrictions but is implicated in the unusual vasoconstrictions to acetylcholine and prostacyclin. Increased responsiveness of TP-receptor occurs in diabetic ApoE-KO mouse kidneys. Thus, early changes in TP-receptor mediated vasoconstrictor activity may participate to the development of kidney disease in atherosclerosis and diabetes.