Role of thromboxane in the altered vascular reactivity of pregnant rats with adriamycin nephropathy.

Abstract

Pregnant rats with adriamycin nephropathy (ADRP rats) develop hypertension and have an increased vascular reactivity to noradrenaline in the isolated mesenteric bed in vitro. We have shown previously that the administration of daltroban, a specific thromboxane receptor antagonist, prevented hypertension in ADRP rats. We measured the effect of daltroban (10(-5) mol/l) on the vasoconstrictory response to noradrenaline (1-10 micromol/l) in the isolated mesenteric bed of ADRP rats at the end of pregnancy, as compared with normal pregnant and adriamycin-treated virgin rats. In further experiments, we measured the changes of flow induced by increasing concentrations of the thromboxane analogue, U46619 (10(-7)-10(-6) mol/l). Finally, changes of flow were assessed in arteries maximally constricted with U46619 (10(-6) mol/l), during perfusion in the presence of increasing concentrations of daltroban (10(-7)-10(-5) mol/l). Daltroban diminished the response to noradrenaline in all groups, shifting the concentration-effect curve to the right. However, at maximal concentrations of noradrenaline, daltroban was ineffective in all rats, except in ADRP animals. The vasoconstrictory response to U46619 was significantly reduced in all pregnant rats, both normal and adriamycin-treated. Daltroban progressively released the vasoconstriction induced by U46619 in all groups. However, this vasodilator response was attenuated in the adriamycin-treated rats, the slopes of their curves being smaller than those of the respective untreated groups (0.038 +/- 0.006 in virgin rats vs 0.063 +/- 0.011 in controls, P < 0.05; and 0.015 +/- 0.005 in ADRP vs 0.028 +/- 0.008 in normal pregnancy, P < 0.05). The findings could be explained by enhanced occupancy of thromboxane receptors by an endogenous agonist, possibly PGH2, as a consequence of either increased levels of the autacoid or increased number of affinity receptors.