Abstract
The preglomerular arteriole of the rat was used to evaluate the contribution of cytochrome P450-derived eicosanoids to the vasoconstrictor effect of endothelin (ET)-1 and to determine the receptors mediating the response. ET-1 (4 × 10−11 to 2 × 10−9 M) produced dose-dependent reductions in the intraluminal diameter of the renal arteriole ranging from 25 ± 8 to 142 ± 16 μm. BMS182874 [(5-dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; 3 μM], an ETA receptor antagonist, or BQ788 (N-cis-2,6-dimethyl-piperidino-carbonyl-l-γ-methylleucyl-d-1-methoxycarbonyl-tryptophanyl-d-norleucine; 1 μM), an ETB receptor antagonist, attenuated ET-1 vasoconstriction by 59 ± 4 and 50 ± 10%, respectively. The combined administration of both ET receptor antagonists increased inhibition of ET-1 vasoconstriction to 75 ± 4%. 17-Octadecynoic acid (17-ODYA, 2 μM) or 12,12-dibromododec-enoic acid (2 μM), inhibitors of 20-hydroxyeicosatetraenoic acid (20-HETE) production, attenuated ET-1-induced vasoconstriction by 50 ± 6 and 40 ± 3%, respectively, as did indomethacin (10 μM), an inhibitor of cyclooxygenase. Miconazole (2 μM), the epoxygenase inhibitor, was without effect. 20-HETE (10−8 and 2 × 10−8 M) elicited a dose-related vasoconstriction that was inhibited by 10 μM, but not 5 μM, indomethacin. The inhibition by 17-ODYA of ET-1 vasoconstriction was not greater when combined with BMS182874 or BQ788. Moreover, vasoconstriction induced by ET-3, an ETB-selective agonist, was inhibited by 17-ODYA. These data indicate that both ETA and ETB receptors mediate ET-1 vasoconstriction and that 20-HETE production linked to both receptors makes a major contribution to ET-1-induced renal arteriolar vasoconstriction in the rat.
Footnotes
-
Send reprint requests to: Dr. A. O. Oyekan, Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, 3100 Cleburne Ave., Houston, TX 77004. E-mail: oyekan_ao{at}tsu.edu
-
↵1 This work was supported by National Institutes of Health Grant RO1-HL25394 and RO1-HL59884. This study was presented at the Experimental Biology '99 Meeting in Washington, DC, April 7–21, 1999.
- Abbreviations:
- ET
- endothelin
- Ang II
- angiotensin II
- ID
- intraluminal diameter
- COX
- cyclooxygenase
- AA
- arachidonic acid
- LOX
- lipoxygenase
- MOX
- monooxygenase
- CYP
- cytochrome P450
- 17-ODYA
- 17-octadecynoic acid
- DBDD
- 12,12-dibromododec-enoic acid
- ETYA
- 5,8,11,14-eicosatetraynoic acid
- PE
- phenylephrine
- Received July 15, 1999.
- Accepted November 10, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|