Mechanism of arachidonic acid-induced vasoconstriction in the intact rat kidney: Possible involvement of thromboxane A2

H. M. Sakr, E. W. Dunham

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Abstract

The dose dependency and mechanism of arachidonic acid (AA)-induced alteration of total renal blood flow (RBF) was studied in anesthetized Sprague-Dawley rats. RBD of the intact, autoperfused kidney was measured with an electromagnetic flow probe. Direct measurements of arterial pressure were also obtained. Intrarenal arterial (i.a.) AA infusions producing calculated 10 to 100 μM concentrations of the fatty acid in renal arterial blood caused concentration-dependent decrements in RBF. Lower concentrations of AA lacked activity in preparations shown capable of active renal vasodilator responses to i.a.-injected methacholine and prostaglandin (PG)E2. These vasoconstrictor concentrations of AA did not significantly affect blood pressure. Basal renal vascular resistance (17 ± 1 mm Hg/ml/min/g) was increased by 4.5 to 42% by 10 to 100 μM concentrations of AA. Bolus i.a. injections of 12.5 to 50 μg of AA also caused dose-dependent vasoconstriction. In contrast to their effect on the renal vasculature, these doses of AA increased hindquarter blood flow and decreased vascular resistance. Both the renal and hindquarter vascular responses to AA were abolished by 5 mg of indomethacin/kg i.v. A dose of captopril (0.5 mg/kg) shown effective in blocking conversion of angiotensin I to angiotensin II did not affect the renal vascular response to AA. Although AA-induced renal vasoconstriction was not significantly affected by imidazole, another inhibitor of thromboxane A2 synthesis, OKY-1581, significantly (P < .005) attenuated the effect of the fatty acid on RBF at doses that did not depress the renal vascular response to angiotensin II. Intra-arterial infusions of imidazole (1 mM), but not OKY-1581, significantly increased blood pressure and decreased RBF, whereas captopril did not alter blood pressure but increased RBF. Methacholine and PGI2 caused only dose-related increments in RBF after i.a. injection; however, PGE2 elicited renal vasodilatation at low doses (5-40 ng) and a biphasic effect, when 1- to 2-μg boluses were injected. PGD2 and PGF2(α) were inactive at low nanogram doses but caused delayed decrements in RBF when 1- to 4-μg boluses were injected. These results indicate that cyclooxygenase-derived product(s) are responsible for the renal vasoconstrictor effect of AA in the intact rat kidney. Lipoxygenase-derived products and angiotensin II probably do not contribute to the effect of AA. Inasmuch as the renal vascular responses to exogenous PGD2, PGE2, PGF2(α) and PGI2 are qualitatively and temporally unlike the response to AA and because the response to AA was attenuated by OKY-1581, it is concluded that thromboxane A2, probably in concert with PG endoperoxides, participates in the renal vasoconstrictor effect of AA.

Original languageEnglish (US)
Pages (from-to)614-622
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume221
Issue number3
StatePublished - 1982

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