title: Sequential agonist activation and site-specific mediation of acute cyclosporine constriction in rat renal arterioles.
abstract: Evidence suggests that acute and chronic cyclosporine (CsA) nephropathy may be related to its renal vasoconstrictor effects. While the mechanism of CsA-induced renal vasoconstriction is uncertain, several studies indicate that endogenous constrictor agonists including endothelins (ET), platelet activating factor (PAF), and thromboxane A2 (TXA2) play a mediating role. In this study, two possible mechanisms explaining the participation of multiple constrictor agonists in CsA vasoconstriction were investigated: sequential activation of agonists initiated by CsA and site-specific mediation of CsA constriction by different agonists. The acute constrictor effects of CsA were examined in isolated rat renal afferent (AA) and efferent arterioles (EA) without and with specific receptor antagonists of ETA (BQ123, 10(-7) M), PAF (L-659,989, 10(-7) M), and TXA2/PGH2 (SQ29,548, 10(-7) M) in the bathing media. Both BQ123 and L-659,989 completely inhibited CsA, constriction in AA, but had no significant inhibiting effect in EA. Constriction to ET-1 was also blocked by the PAF antagonist L-659,989 in AA, but not EA. There was no effect of SQ29,548 on CsA constriction in AA--however, there was partial attenuation of CsA constriction in EA. Based on these results in isolated rat renal arterioles, it is suggested that CsA-induced constriction in AA is likely mediated by sequential activation of ET and PAF. However, CsA constriction of EA involves a different mechanism or mediator that, in part, may involve TXA2/PGH2 stimulation.
authors: Department of Medicine, University of Colorado Health Sciences Center, Denver 80220.
authors: D M
authors: DM
authors: Lanese
authors: S A
authors: SA
authors: Falk
authors: J D
authors: JD
authors: Conger
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016572:Cyclosporine / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology; D005231:Fatty Acids, Unsaturated; D005663:Furans / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000502:physiology; D011463:Prostaglandins H / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D005231:Fatty Acids, Unsaturated; D005663:Furans; D006834:Hydrazines; D010456:Peptides, Cyclic; D010972:Platelet Activating Factor; D011463:Prostaglandins H; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; C054893:L 659989; D013928:Thromboxane A2; D016572:Cyclosporine; C045749:SQ 29548; C072247:cyclo(Trp-Asp-Pro-Val-Leu)