Differential effect of platelet-activating factor (PAF) receptor antagonists on peptide and PAF-stimulated prostaglandin release in unilateral ureteral obstruction.
Unilateral ureteral obstruction (UUO) results in increased renal resistance as well as in exaggerated prostaglandin (PG) release from the obstructed hydronephrotic kidney (HNK). We have reported previously that platelet-activating factor (PAF) dose-dependently stimulates the release of PGs from both the HNK and unobstructed contralateral kidney (CLK), with CLK release being 10% that of the HNK. In the present report, we studied the interaction of PAF with its receptor by examining the effects of PAF-receptor antagonists on the release of PGs from the isolated perfused rabbit HNK and CLK stimulated by PAF; angiotensin II (AII), and bradykinin (BK) were also used as agonists. In the HNK, kadsurenone (3 microM) inhibited PAF-stimulated PGE2 and thromboxane B2 (TxB2) release by 28.2 and 62.5% respectively. CV-3988 (20 microM) and triazolam (5 microM) also preferentially diminished PAF-stimulated TxB2 release. In addition, all three drugs significantly diminished BK- and AII-stimulated TxB2 release, while CV-3988 was the only antagonist to affect peptide-stimulated PGE2 release. While effective against agonist-stimulated PG synthesis, these drugs had no direct effect on arachidonic acid metabolism to PGs. Furthermore, in the CLK, CV-3988 had no effect on BK- or AII-stimulated PGE2 release, whereas it totally inhibited PAF-stimulated release of PGE2. These results show that PAF-receptor antagonists in the HNK preferentially inhibit TxB2 release whether stimulated by PAF, AII or BK; in the CLK only PAF-stimulated PG release is affected. This biochemical difference may be of physiological significance and explain some of the functional differences between the HNK and CLK. Therefore, PAF may be an important mediator of some of the biochemical and functional changes associated with UUO.
Weisman
S M
SM
Department of Surgery (Urology), James Buchanan Brady Foundation, New York, NY 10021.
Freund
R M
RM
Felsen
D
D
Vaughan
E D
ED
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D015232:Dinoprostone; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D017705:Lignans; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins; D011453:Prostaglandins / Q000378:metabolism*; D011458:Prostaglandins E / Q000378:metabolism; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled; D013929:Thromboxane B2 / Q000378:metabolism; D014229:Triazolam / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000378:metabolism*
D001572:Benzofurans; D017705:Lignans; D010455:Peptides; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011453:Prostaglandins; D011458:Prostaglandins E; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D000804:Angiotensin II; D014229:Triazolam; D013929:Thromboxane B2; C044540:kadsurenone; D015232:Dinoprostone