Losartan prevents thromboxane A2/prostanoid (TP) receptor mediated increase in microvascular permeability in the rat.
We explored the putative inhibitory effects of losartan, a potent nonpeptide, AT1 receptor antagonist, against thromboxane A2 (TxA2)/prostanoid (TP) receptor-mediated transcapillary shift of plasma fluid and proteins. The effects of the TP receptor agonist U-46619 (1.25 or 10 microg/kg intravenously) on hematocrit (Hct), albumin extravasation (AE), and mean arterial pressure (MAP) were evaluated in anesthetized Sprague-Dawley rats. U-46619 dose-dependently increased Hct (by 4.5% +/- 0.7% and 7.5% +/- 1.0% at the low and high dose, respectively; both P < .05 v vehicle-infused group) and decreased MAP (by 7.9% +/- 4.1% and 16.8% +/- 5.7% at the low and high dose, respectively; P = NS and P < .05 v vehicle-infused group, respectively). In these experiments, using a quantitative Evans blue technique, we showed that U-46619 dose-dependently increased AE in kidney, lung, spleen, and testis (by approximately 31%, 172%, 52%, and 57% at the highest dose) but not in adipose tissue, brain, liver, mesentery, and skeletal muscle. In the heart, AE was maximally increased by the low dose of U-46619. The U-46619 (10 microg/kg)-induced increases in Hct and AE and decreases in MAP were blocked by pretreatment with the TP receptor antagonist SQ 29,548 (2.5 mg/kg intravenously + 2.5 mg/kg/h) and the high dose of losartan (40 mg/kg intravenously). The low dose of losartan (10 mg/kg intravenously) did not significantly alter the responses to U-46619 except for the AE, which was reduced in some but not all tissues. Furthermore, the U-46619-induced changes in Hct (+6.3% +/- 1.7%), MAP (-13.9% +/- 8.4%) and AE were not affected in rats pretreated with the converting-enzyme inhibitor enalapril. Thus, selective activation of TP receptors by U-46619 induced plasma fluid and protein exudation; these responses were specifically attenuated by the relatively high dose of losartan, suggesting that this compound acts as a TP receptor antagonist in this experimental model.
Valentin
J P
JP
Division of Cardiovascular Diseases, Centre de Recherche Pierre Fabre, Castres, France.
Jover
B
B
Maffre
M
M
Bertolino
F
F
Bessac
A M
AM
John
G W
GW
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology*; D004656:Enalapril / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D006400:Hematocrit; D006834:Hydrazines / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D010953:Plasma Volume / Q000187:drug effects; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000502:physiology*; D017482:Receptors, Thromboxane / Q000502:physiology*; D012709:Serum Albumin / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011453:Prostaglandins; D011956:Receptors, Cell Surface; D017482:Receptors, Thromboxane; D012709:Serum Albumin; D014662:Vasoconstrictor Agents; D004656:Enalapril; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D019808:Losartan