HETE, a cytochrome P-450 4A (CYP4A1)-derived arachidonic acid metabolite, is a major eicosanoid formed in renal and extrarenal microcirculation. 20-HETE inhibits Ca 2ϩ -activated K ϩ channels in vascular smooth muscle cells and thereby may modulate vascular reactivity. We transfected renal interlobar arteries with an expression plasmid containing the cDNA of CYP4A1, the low-Km arachidonic acid -hydroxylase, and examined the consequences of increasing 20-HETE synthesis on constrictor responses to phenylephrine. CYP4A1-transfected interlobar arteries demonstrated a twofold increase in CYP4A protein levels and 20-HETE production compared with arteries transfected with the empty plasmid; they also showed increased sensitivity to phenylephrine, as evidenced by a decrease in EC50 from 0.37 Ϯ 0.04 M in plasmid-transfected arteries to 0.07 Ϯ 0.01 M in CYP4A1-transfected arteries. The increased sensitivity to phenylephrine was greatly attenuated by , a selective inhibitor of 20-HETE synthesis, and by 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, a specific 20-HETE antagonist. This effect of DDMS was reversed by addition of 20-HETE, further substantiating the notion that increased levels of 20-HETE contribute to the increased sensitivity to phenylephrine in vessels overexpressing CYP4A1. These data suggest that 20-HETE of vascular origin sensitizes renal vascular smooth muscle to phenylephrine. 20-hydroxyeicosatetraenoic acid; arachidonic acid; phenylephrine; cytochrome P-450 SMALL ARTERIAL VESSELS MANUFACTURE 20-HETE, a product of arachidonic acid metabolism by cytochrome P-450 enzymes of the 4A family (CYP4A1) (8,12,17,26). Exogenous 20-HETE was reported to contract or relax vascular smooth muscle, depending on the animal species, type of vessels, and experimental conditions. Cyclooxygenase-dependent and -independent mechanisms have been implicated in 20-HETE-induced vascular contraction (6, 16, 17) and vascular relaxation (2, 4).Renal preglomerular vessels express CYP4A proteins, produce 20-HETE, and are constricted by exogenous 20-HETE. The constrictor action of exogenous 20-HETE in pressurized canine arcuate arteries, rat renal interlobular arteries, and rat renal afferent arterioles is independent of cyclooxygenase activity and has been attributed to inhibition of the opening of Ca 2ϩ -activated K ϩ channels in vascular smooth muscle cells, leading to cellular depolarization and increased Ca 2ϩ entry (8,12,14,23,28). Recent studies support the notion that endogenous 20-HETE subserves vasconstrictor mechanisms in the rat kidney. For example, inhibitors of 20-HETE synthesis were shown to increase blood flow to the kidney (29), to increase the diameter of preconstricted interlobular arteries denuded of endothelium (11), and to attenuate vasconstrictor responses elicited by endothelin (10, 22), angiotensin II (5), or increases in transmural pressure (14). 20-HETE produced by the smooth muscle isolated from renal preglomerular vessels was also shown to exert a tonic inhibitory influence on the activity of large-conductance C...
Pulmonary intralobar arteries express heme oxygenase (HO)-1 and -2 and release carbon monoxide (CO) during incubation in Krebs buffer. Acute hypoxia elicits isometric tension development (0.77 +/- 0.06 mN/mm) in pulmonary vascular rings treated with 15 micromol/l chromium mesoporphyrin (CrMP), an inhibitor of HO-dependent CO synthesis, but has no effect in untreated vessels. Acute hypoxia also induces contraction of pulmonary vessels taken from rats injected with HO-2 antisense oligodeoxynucleotides (ODN), which decrease pulmonary HO-2 vascular expression and CO release. Hypoxia-induced contraction of vessels treated with CrMP is attenuated (P < 0.05) by endothelium removal, by CO (1-100 micromol/l) in the bathing buffer, and by endothelin-1 (ET-1) receptor blockade with L-754142 (10 micromol/l). CrMP increases ET-1 levels in pulmonary intralobar arteries, particularly during incubation in hypooxygenated media. CrMP also causes a leftward shift in the concentration-response curve to ET-1, which is offset by exogenous CO. In anesthetized rats, pretreatment with CrMP (40 micromol/kg iv) intensifies the elevation of pulmonary artery pressure elicited by breathing a hypoxic gas mixture. However, acute hypoxia does not elicit augmentation of pulmonary arterial pressure in rats pretreated concurrently with CrMP and the ET-1 receptor antagonist L-745142 (15 mg/kg iv). These data suggest that a product of HO activity, most likely CO, inhibits hypoxia-induced pulmonary vasoconstriction by reducing ET-1 vascular levels and sensitivity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.