TxA2 receptor activation elicits organ-specific increases in microvascular permeability in the rat.
We investigated whether the stable thromboxane A2 (TxA2) analogue U-46619 had any direct effect on extracellular fluid partition. In anesthetized open-chest rats, U-46619 (1.25 and 20 micrograms/kg iv) dose dependently increased mean pulmonary arterial pressure and hematocrit, whereas mean systemic arterial pressure was raised only at the low dose of agonist. The increase in hematocrit (13.2 +/- 2.9% at 20 micrograms/kg; P < 0.05) still occurred in bilaterally nephrectomized rats and in binephrectomized plus splenectomized rats (11.6 +/- 2.7 and 12.2 +/- 4.6%, respectively; both P = NS vs. U-46619 in control rats), corresponding to a calculated decrease in plasma volume of 22.1 +/- 4.5, 19.6 +/- 4.0, and 19.2 +/- 5.8%, respectively. Plasma protein concentration increased less than hematocrit, and the coefficient of reflection was significantly lower in these groups, suggesting protein extravasation. Additional experiments showed that U-46619 (1.25 and 10 micrograms/kg iv) dose dependently increased the vascular leak of albumin mainly in lung, kidneys, and spleen but not in brain, liver, mesentery, and cardiac and skeletal muscles. Pretreatment with the TxA2 receptor antagonist SQ-29,548 (2.5 mg/kg iv bolus plus 2.5 mg.kg-1.h-1 as maintenance) abolished all effects of U-46619, including the increase in mean pulmonary arterial pressure, hematocrit, plasma protein concentration, and albumin extravasation and the decrease in mean systemic arterial pressure, plasma volume, and coefficient of reflection.(ABSTRACT TRUNCATED AT 250 WORDS)
Bertolino
F
F
Division of Cardiovascular Diseases II, Centre de Recherche Pierre Fabre, Castres, France.
Valentin
J P
JP
Maffre
M
M
Bessac
A M
AM
John
G W
GW
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002199:Capillary Permeability; D005231:Fatty Acids, Unsaturated; D006400:Hematocrit; D006439:Hemodynamics / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D008833:Microcirculation; D009392:Nephrectomy; D009994:Osmolar Concentration; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D012709:Serum Albumin / Q000378:metabolism; D013156:Splenectomy; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology
D001798:Blood Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D012709:Serum Albumin; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548