Gestational resistance to the pulmonary vasoconstrictor effect of the TxA2 mimetic U-46619: possible mechanism.
Pregnancy is associated with the reduction of vascular sensitivity to vasoconstrictor compounds. We have examined whether pregnancy in rabbits induces hyposensitivity of the pulmonary vascular system to U-46619. Anesthetized, mechanically ventilated nonpregnant (NP; n = 7) and late-pregnant (P; n = 7) rabbits were studied. The intravenous injection of 0.03, 0.1, and 0.3 microgram/kg U-46619 led to a dose-dependent elevation of mean pulmonary arterial pressure (MPAP) in NP rabbits from a baseline value of 15 +/- 1 to 22 +/- 1 mgHg. There was no significant MPAP response to intravenous administration of U-46619 in P rabbits. The pulmonary arterial pressure response of isolated, ventilated, and buffer-perfused lungs of P rabbits was also blunted (P < 0.001 vs. NP). Pulmonary arterial membrane binding of [125I]BOP, another thromboxane (Tx)A2 analog, indicated 48 +/- 16 fmol receptors/mg protein in P rabbits and 193 +/- 48 fmol receptors/mg protein in NP samples (P < 0.025). Receptor affinity [1/dissociation constant (KD)] was also lower in the tissue of P rabbits (P < 0.01 vs. NP). The urinary excretion of the stable TxA2 metabolite 11-dehydro-TxB2 was lower in P than in NP rabbits (P < 0.02), which made homologous desensitization an unlikely explanation for the changes of vascular TxA2 receptors. These results show that, in late gestation, rabbit pulmonary vascular sensitivity to U-46619 is reduced simultaneously with, and as a possible consequence of, downregulation of specific receptors.
Losonczy
G
G
Department of Medicine, State University of New York at Buffalo 14215, USA.
Brown
G
G
Mucha
I
I
Klocke
R
R
Muller
V
V
Merkely
B
B
Tornoci
L
L
Rosivall
L
L
Venuto
R
R
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001158:Arteries / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects*; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000378:metabolism; D012016:Reference Values; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D014556:Urine / Q000737:chemistry; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D011450:Prostaglandin Endoperoxides, Synthetic; D011956:Receptors, Cell Surface; D014662:Vasoconstrictor Agents; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid