Direct evidence that thromboxane mimetic U44069 preferentially constricts the afferent arteriole.
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.
Hayashi
K
K
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Loutzenhiser
R
R
Epstein
M
M
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*
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