Mediation of renal vascular effects of epidermal growth factor by arachidonate metabolites.
In the rat, intrarenal infusion of epidermal growth factor decreases renal blood flow and glomerular filtration rate, and epidermal growth factor (EGF) induces contraction of cultured rat mesangial cells. The present studies examined the role of arachidonic acid metabolites in this response. Intrarenal EGF infusion increased urinary iPGF2 alpha by 300%, and in isolated glomeruli EGF stimulated iPGF2 alpha by 38%, but did not affect thromboxane B2 production. Furthermore, the thromboxane A2 receptor antagonist, SQ29548, did not block EGF's vasoconstrictive effects. After selective cyclooxygenase inhibition with ibuprofen, intrarenal EGF infusion no longer produced local vasoconstriction but instead led to systemic vasodilation (SBP: 117 +/- 10 vs. 98 +/- 7; n = 5; P less than 0.05) that was accompanied by significant increases in RPF (3.8 +/- 0.4 vs. 5.6 +/- 0.2; P less than 0.01) and glomerular filtration rate (0.9 +/- 0.1 vs. 1.1 +/- 0.1; P less than 0.05). When total arachidonate metabolism was inhibited by the additional administration of 5,8,11,14-eicosatetraynoic acid, the EGF-induced vasodilation observed during cyclooxygenase inhibition alone was abolished, and vasoconstrictor responses to EGF were again noted. Similar effects were noted with concomitant administration of the c-P450 inhibitor ketoconazole. EGF's vasoconstrictive effects were unaltered by the simultaneous administration of the angiotensin II antagonist saralasin. Thus, the renal hemodynamic responses to EGF are mediated in part by arachidonic acid metabolites. Cyclooxygenase inhibition unmasks a potent renal and systemic vasodilator action of EGF owing to its stimulation of systemic release of noncyclooxygenase arachidonate metabolites.
Harris
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RC
Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee 37212.
Munger
K A
KA
Badr
K F
KF
Takahashi
K
K
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015237:Dinoprost / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006834:Hydrazines / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply / Q000502:physiology*; D051381:Rats; D011982:Receptors, Prostaglandin / Q000187:drug effects; D017482:Receptors, Thromboxane; D012039:Regional Blood Flow / Q000187:drug effects
D001095:Arachidonic Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D015117:5,8,11,14-Eicosatetraynoic Acid; D016718:Arachidonic Acid; D004815:Epidermal Growth Factor; C045749:SQ 29548; D015237:Dinoprost; D007654:Ketoconazole; D007052:Ibuprofen