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


METHODS
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).


RESULTS
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).


CONCLUSIONS
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.
Mandelbaum
A
A
Department of Nephrology, Meir Hospital, Kfar Saba and Sackler School of Medicine, Tel Aviv University, Israel.
Podjarny
E
E
Bernheim
J
J
Green
J
J
Rathaus
M
M
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D066298:In Vitro Techniques; D007674:Kidney Diseases / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology; D010648:Phenylacetates / Q000494:pharmacology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology; D013931:Thromboxanes / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology
D010648:Phenylacetates; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013931:Thromboxanes; D014662:Vasoconstrictor Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D004317:Doxorubicin; C051762:daltroban; D009638:Norepinephrine