Role of thromboxane and angiotensin in cyclosporine-induced renal vasoconstriction in the dog.
Cyclosporine is associated with renal insufficiency characterized by a reduction in glomerular filtration rate that may result from renal vasoconstriction. Injection of cyclosporine in the isolated renal artery perfused at a constant flow induces a potent dose-dependent vasoconstriction of renal arterial vessels in the dog. The present study was designed to investigate the role of thromboxane A2, angiotensin, and endothelial-dependent vasodilation in the cyclosporine-induced renal vasoconstriction. A specific thromboxane A2-receptor antagonist (pinane-thromboxane A2), administered at a dose of 150 micrograms, significantly decreased the renal vasoconstriction response to cyclosporine from 103 +/- 26 mm Hg to 45 +/- 11 mm Hg (p < 0.05), with cyclosporine serum levels at the end of injection averaging 382 +/- 105 and 421 +/- 150 nmol/L before and after injection of the antagonist. In contrast, pharmacologic blockade of angiotensin receptors by saralasin had no effect on the cyclosporine arterial vasoconstriction in the kidney. The endothelium-dependent vasodilation to acetylcholine was not modified during cyclosporine injection. Thus cyclosporine renal vasoconstriction appears independent of the renin-angiotensin system and of endothelium-dependent vasodilation. It is at least partly mediated by thromboxane A2. Prevention of cyclosporine vasoconstriction by thromboxane A2-receptor antagonist may likely be possible, with more potent agents having more affinity to thromboxane A2 renal receptors.
Carrier
M
M
Department of Cardiovascular Surgery, Montreal Heart Institute, Quebec, Canada.
Tronc
F
F
Pelletier
L C
LC
Latour
J G
JG
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000081008:Bicyclic Monoterpenes; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D011945:Receptors, Angiotensin / Q000187:drug effects; D017482:Receptors, Thromboxane / Q000187:drug effects; D012077:Renal Artery / Q000187:drug effects* / Q000503:physiopathology; D012079:Renal Circulation / Q000187:drug effects; D012504:Saralasin / Q000494:pharmacology; D013729:Terpenes / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D057911:Angiotensin Receptor Antagonists; D000081008:Bicyclic Monoterpenes; D011945:Receptors, Angiotensin; D017482:Receptors, Thromboxane; D013729:Terpenes; D000804:Angiotensin II; C030216:pinane; D009569:Nitric Oxide; D013928:Thromboxane A2; D016572:Cyclosporine; D012504:Saralasin; D000109:Acetylcholine