Treatment with Tin Prevents the Development of Hypertension in Spontaneously Hypertensive Rats

Sacerdoti, David; Escalante, Bruno; Abraham, Nader G.; McGiff, John C.; Levere, Richard D.; Schwartzman, Michal Laniado

doi:10.1126/science.2492116

Cited by 268 publications

(198 citation statements)

References 20 publications

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“…In all cases, inhibition of renal cortical 20-HETE formation was similar. A sim-ilar pattern was also found with ABT and in earlier studies with the heme oxygenase inducer stannous chloride (29,42). During the period when blood pressure rises rapidly in the SHR (5-9 wk of age), 20-HETE formation in renal microsomes is elevated relative to age-matched WKY rats (27,37), and there is a decreased diameter of interlobular and afferent arterioles that can be reversed by blockade of renal 20-HETE formation (12,15,19).…”

Section: Discussionmentioning

confidence: 54%

“…Until recently, these efforts were limited to in vitro or in situ studies because of the lack of selective inhibitors of CYP eicosanoid formation with in vivo activity. Heme oxygenase inducers are nonspecific CYP inhibitors and decrease CYP-mediated -and ( -1)-hydroxylation of arachidonic acid and blood pressure in 7-wk-old SHRs to the levels found in age-matched WKY rats (29,42). However, these results are confounded because heme oxygenase inducers also stimulate the formation of the vasodilatory gas carbon monoxide and may influence nitric oxide synthase activity and produce vasodilatory factors via the cGMP pathway (35).…”

Section: Discussionmentioning

confidence: 84%

“…Importantly, this difference in the diameter of the interlobular and afferent arterioles of young SHR and WKY rats can be reduced in the presence of CYP inhibitors (19). The first in vivo evidence that CYP eicosanoids are important in the regulation of blood pressure was a decrease in renal CYP -hydroxylase activity and blood pressure after the treatment of SHRs with the heme oxygenase inducers stannous chloride and heme arginate (29,42). More recently, mechanism-based CYP inhibitors and antisense oligonucleotides have been used to manipulate CYP eicosanoid production in vivo.…”

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confidence: 99%

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Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid ω-hydroxylase activity

Xu¹,

Straub

Pak³

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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is a potent vasoconstrictor that is implicated in the regulation of blood pressure. The identification of selective inhibitors of renal 20-HETE formation for use in vivo would facilitate studies to determine the systemic effects of this eicosanoid. We characterized the acetylenic fatty acid sodium 10-undecynyl sulfate (10-SUYS) as a potent and selective mechanism-based inhibitor of renal 20-HETE formation. A single dose of 10-SUYS caused an acute reduction in mean arterial blood pressure in 8-wk-old spontaneously hypertensive rats. The decrease in mean arterial pressure was maximal 6 h after 10-SUYS treatment (17.9 Ϯ 3.2 mmHg; P Ͻ 0.05), and blood pressure returned to baseline levels within 24 h after treatment. Treatment with 10-SUYS was associated with a decrease in urinary 20-HETE formation in vivo and attenuation of the vasoconstrictor response of renal interlobar arteries to ANG II in vitro. These results provide further evidence that 20-HETE plays an important role in the regulation of blood pressure in the spontaneously hypertensive rat.spontaneously hypertensive rat; cytochrome P-450; sodium 10-undecynyl sulfate; 20-hydroxyeicosatetraenoic acid CYTOCHROMES P-450 (CYPs) are major catalysts of renal arachidonic acid metabolism, and CYP-derived eicosanoids have been implicated in the regulation of vascular tone and renal function (9, 41). The major products of CYP-catalyzed arachidonic acid metabolism are the -hydroxylated metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) and four regio-and stereoisomeric epoxyeicosatrienoic acids (EETs). EETs are further hydrated to the corresponding dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH) (53). The major CYP eicosanoid formed in rat and human renal microsomes is 20-HETE (8, 28). 20-HETE depolarizes vascular smooth muscle cells by inhibiting Ca 2ϩ -activated K ϩ channels and increases the conductance of L-type Ca 2ϩ channels, both effects leading to Ca 2ϩ entry and potent vasoconstriction (14,56). Additional roles for 20-HETE include mediation of the myogenic response of small cerebral and renal arteries to elevations in transmural pressure, and the autoregulation of cerebral and renal blood flow, glomerular filtration rate, and tubular glomerular feedback (13,22,58). In renal tubules 20-HETE inhibits Na ϩ -K ϩ -ATPase, a Na ϩ -K ϩ -2Cl Ϫ cotransporter, and 70-pS K ϩ channels, leading to natriuresis and diuresis (3,30,38). EETs and DHETs are generally considered vasodilatory, although they exhibit both vasodilatory and vasoconstrictive properties in vitro, depending on the vascular bed and species that are studied (20,55,57). A number of studies suggest that EETs are endothelium-derived hyperpolarizing factors that mediate vasodilation by activation of Ca 2ϩ -dependent K ϩ channels in vascular smooth muscle cells (6,7,10). Both EETs and DHETs can also mediate natriuresis and diuresis by inhibition of Na ϩ -K ϩ -ATPase in rat proximal tubules (38).The effects of CYP eicosanoids in the regulation of vascular tone and renal function have pr...

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 99%

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Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid ω-hydroxylase activity

Xu¹,

Straub

Pak³

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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“…For example, the administration of HO-1 inducers is known to lower blood pressure and enhance tissue growth in spontaneously hypertensive rats (31), whereas the administration of HO-1 inhibitors produces systemic vasoconstriction (32)(33)(34). These effects have been correlated with the levels of cellular heme and one of the end products of heme catabolism, CO. An important role for HO in the control of vascular tone and blood pressure and in the regulation of growth is indicated by these findings.…”

Section: Discussionmentioning

confidence: 99%

Regulation of human heme oxygenase in endothelial cells by using sense and antisense retroviral constructs

Quan

Yang

Abraham

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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C ellular levels of heme are regulated by the rates of its synthesis and degradation. Heme catabolism occurs by oxidative cleavage of the ␣-methene bridge of the tetrapyrrole, eventually leading to the formation of equimolar amounts of biliverdin and CO and the release of the contained iron atom (1, 2). Biliverdin is then rapidly reduced to form bilirubin (3, 4). The heme oxygenase (HO) system controls the rate-limiting step in heme catabolism (5). To date, three HO isoforms (HO-1, HO-2, and HO-3) have been identified that catalyze this reaction (6-8). HO-1 is a 32-kDa heat shock protein (9-11) that is inducible by numerous noxious stimuli (12-17). HO-2 is a constitutively synthesized 36-kDa protein that is abundant in brain and testis (6). HO-3 is related to HO-2, but is the product of a different gene, and its ability to catalyze heme degradation is much less than that of .Overexpression of HO-1 can lead to hyperbilirubinemia in humans with certain hepatic disorders, especially patients in whom bilirubin disposition is impaired for developmental or genetic reasons, i.e., in newborns and in patients with the Crigler-Najjar type I syndrome. Pharmacological agents such as the inhibitor of HO, tin mesoporphyrin, can inhibit HO activity significantly and have been shown to be highly effective in single dose in controlling hyperbilirubinemia in newborns and other patients (19-23). However, such agents can exert only transient control of the activity of HO-1. Further, the long-term overexpression or underexpression of human HO-1 (HHO-1) would have considerable experimental value in elucidating the role of the enzyme in physiological and pathological processes.The objective of this study was to examine the feasibility of using the retrovirus-mediated transfer of an HHO-1 sense (S) and antisense (AS) orientation sequence under the control of the HHO-1 promoter to regulate endogenous HO-1 expression and function and thus permit development of a gene transfer technology to regulate the rate of heme catabolism over the long term.Our data demonstrate that selective delivery of the HHO-1 gene in AS orientation into human endothelial cells results in an attenuation of HHO-1 protein leading to a decrease in the rate of catabolism of cellular heme and that this effect is brought about without altering endogenous HO-2 protein. Thus, by the use of the retroviral HO-1 AS methodology it is possible to envisage prolonged down-regulation of the rate of heme catabolism to its degradation product bilirubin in clinical or experimental circumstances where this might prove useful. Materials and MethodsCell Culture Conditions. The amphotropic retroviral packaging cell line PA317 (American Type Culture Collection) or PT67 (CLON-TECH) was used for the generation of replication-deficient recombinant retroviruses. PA317 and PT67 cells were grown in DMEM (GIBCO͞BRL, Grand Island, NY) supplemented with 10% heatinactivated FBS. NIH 3T3 fibroblasts were cultured in DMEM with 10% calf serum. Human dermal microvessel endothelial cells (HMEC-1 cells...

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“…Previous studies have localized 20-HETE formation in rat and/or rabbit kidney to proximal tubules (5), TALH (6), and renal microvessels (7) in the cortex and outer medulla. Inhibition of 20-HETE formation in rat kidney in vivo has been reported to block autoregulation of renal blood flow and tubuloglomerular feedback (8 -10), perturb chloride (Cl Ϫ ) transport within TALH (11), and interfere with the long term control of arterial blood pressure (12,13). As a physiological correlate, there is considerable evidence suggesting that 20-HETE plays a role in the pathogenesis of hypertension in the spontaneously hypertensive rat (5, 12, 14 -16).…”

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confidence: 99%

Formation of 20-Hydroxyeicosatetraenoic Acid, a Vasoactive and Natriuretic Eicosanoid, in Human Kidney

Lasker¹,

Chen²,

Wolf³

et al. 2000

Journal of Biological Chemistry

284

265

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20-Hydroxyeicosatetraenoic acid (20-HETE), an -hydroxylated arachidonic acid (AA) metabolite, elicits specific effects on kidney vascular and tubular function that, in turn, influence blood pressure control. The human kidney's capacity to convert AA to 20-HETE is unclear, however, as is the underlying P450 catalyst. Microsomes from human kidney cortex were found to convert AA to a single major product, namely 20-HETE, but failed to catalyze AA epoxygenation and midchain hydroxylation. Despite the monophasic nature of renal AA -hydroxylation kinetics, immunochemical studies revealed participation of two P450s, CYP4F2 and CYP4A11, since antibodies to these enzymes inhibited 20-HETE formation by 65.9 ؎ 17 and 32.5 ؎ 14%, respectively. Western blotting confirmed abundant expression of these CYP4 proteins in human kidney and revealed that other AA-oxidizing P450s, including CYP2C8, CYP2C9, and CYP2E1, were not expressed. Immunocytochemistry showed CYP4F2 and CYP4A11 expression in only the S2 and S3 segments of proximal tubules in cortex and outer medulla. Our results demonstrate that CYP4F2 and CYP4A11 underlie conversion of AA to 20-HETE, a natriuretic and vasoactive eicosanoid, in human kidney. Considering their proximal tubular localization, these P450 enzymes may partake in pivotal renal functions, including the regulation of salt and water balance, and arterial blood pressure itself.

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Treatment with Tin Prevents the Development of Hypertension in Spontaneously Hypertensive Rats

Cited by 268 publications

References 20 publications

Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid ω-hydroxylase activity

Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid ω-hydroxylase activity

Regulation of human heme oxygenase in endothelial cells by using sense and antisense retroviral constructs

Formation of 20-Hydroxyeicosatetraenoic Acid, a Vasoactive and Natriuretic Eicosanoid, in Human Kidney

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