title: Direct evidence that thromboxane mimetic U44069 preferentially constricts the afferent arteriole.
abstract: The thromboxane A2 (TXA2) mimetic U44069 has been demonstrated to reduce the GFR and filtration fraction of the normal isolated perfused rat kidney markedly, suggesting a predominant constriction of preglomerular vessels. To assess this possibility directly, effects of U44069 on the renal microvessels of the isolated perfused hydronephrotic kidney were examined. At 10(-6) mol/L, U44069 elicited a 27 +/- 2% decrease in afferent arteriolar (AA) diameter (from 18.8 +/- 0.3 to 13.7 +/- 0.3 micron, P < 0.001). In contrast, efferent arteriolar (EA) diameter decreased by only 9 +/- 1% (from 16.4 +/- 0.5 to 15.0 +/- 0.5 micron, P < 0.001). These effects on both AA and EA were completely reversed by the TXA2 receptor antagonist SQ29548. The calcium antagonist diltiazem reversed U44069-induced AA constriction by 83 +/- 5%. The U44069-induced EA constriction was insensitive to the vasodilator action of diltiazem at concentrations from 10(-8) to 10(-6) mol/L, but at 10(-5) mol/L, diltiazem increased the EA diameter significantly, albeit modestly. Nifedipine also reversed the U44069-induced AA constriction (81 +/- 7%), but failed to inhibit the EA constriction at concentrations from 10(-9) to 10(-6) mol/L. These findings constitute the first direct evidence that a TXA2 agonist preferentially constricts the afferent arteriole. Furthermore, the ability of both the calcium antagonist and SQ29548 to reverse the renal microvascular actions of TXA2 agonists suggests a potential utility of these agents in ameliorating TXA2-induced renal hemodynamic abnormalities.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hayashi
authors.forename: R
authors.initials: R
authors.lastname: Loutzenhiser
authors.forename: M
authors.initials: M
authors.lastname: Epstein
mesh_terms: D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D004110:Diltiazem / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology; D066298:In Vitro Techniques; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009543:Nifedipine / Q000008:administration & dosage / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000031:analogs & derivatives*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002121:Calcium Channel Blockers; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; C028429:U 44069; D013928:Thromboxane A2; C045749:SQ 29548; D004110:Diltiazem; D009543:Nifedipine