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(Hypertension. 2001;38:872.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Chronic Thromboxane Synthase Inhibition Prevents Fructose-Induced Hypertension

Denise Galipeau; Emi Arikawa; Inna Sekirov; John H. McNeill

From the Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.

Correspondence to John H. McNeill, PhD, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, British Columbia, Canada, V6T 1Z3. E-mail jmcneill{at}interchange.ubc.ca

	Abstract

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Abstract—— To investigate the role of thromboxane A₂ in the development of hypertension in the fructose-fed rat, we treated male fructose-fed rats with dazmegrel (a thromboxane synthase inhibitor) and monitored blood pressure, fasting plasma parameters, and insulin sensitivity for 7 weeks. Systolic blood pressure was measured each week using tail plethysmography, and an oral glucose tolerance test was performed at the end of the study to assess insulin sensitivity. Treatment with a 60% fructose diet and dazmegrel (100 mg · kg^-1 · d^-1 via oral gavage) was initiated on the same day. Plasma triglyceride levels increased 2-fold in both fructose- and fructose/dazmegrel-treated groups, and plasma insulin levels tended to be higher in these groups, although not significantly. Systolic blood pressure increased significantly throughout the study in the fructose-fed group only (132±3 versus 112±4 mm Hg in control rats, 118±2 mm Hg in control-treated rats, 116±2 mm Hg in fructose-treated rats). Both fructose groups demonstrated a higher peak insulin response to oral glucose challenge and had 40% to 60% lower insulin sensitivity index values. The results of this study show that treatment with a thromboxane synthase inhibitor, dazmegrel, can prevent the development of hypertension but does not improve insulin sensitivity or other fructose-induced metabolic impairments. Based on these data, we conclude that the potent vasoconstrictor thromboxane is involved in the link between hyperinsulinemia/insulin resistance and hypertension.

Key Words: insulin • thromboxane • blood pressure • rats, inbred strains • fructose • endothelin-1

	Introduction

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Hypertension is often found in both humans and animal models to be associated with hyperinsulinemia and insulin resistance.^1,2 On the basis of this observation, the "insulin hypothesis" was developed, which proposes that these 2 metabolic impairments are directly related to the cause of hypertension in such individuals. The fructose-fed hypertensive rat (FHR) is a model of acquired hypertension that also exhibits insulin resistance, hyperinsulinemia, and hypertriglyceridemia.³ Several mechanisms have been proposed to mediate the link between hyperinsulinemia/insulin resistance and hypertension in the FHR.⁴ The sympathetic nervous system is believed to be involved because both chemical sympathectomy⁵ and treatment with rilmenidine, an agent that decreases sympathetic outflow,⁶ have been shown to prevent fructose-induced hypertension.

Another hypothesis that has attracted much interest is that defects in the cardiovascular actions of insulin that affect endothelial function link hypertension to hyperinsulinemia/insulin resistance. The vascular endothelium plays a key role in the regulation of vascular tone via the synthesis and release of various contracting and relaxing factors. Workers at several laboratories have demonstrated that endothelium-dependent relaxation of various vascular tissues is impaired in FHR.^7–9 This observation has been attributed to defects in vasodilatory mechanisms associated with NO⁸ and the endothelium-derived hyperpolarizing factor.⁹ Furthermore, we have shown that the endothelium-dependent vasodilation response to insulin is abolished in aortas of FHR.¹⁰ Alternatively, defects in endothelium-derived contracting factors have been suggested to play a role, particularly those related to endothelin-1 (ET-1). The treatment of FHR with the ET-1 receptor antagonist bosentan has been shown to prevent hypertension in this model, and vascular ET-1 levels are elevated in fructose-fed rats.¹¹ Furthermore, the reactivity of mesenteric arteries to ET-1 from these rats is altered.¹² An increase in the expression of both ET-1 peptide and its ET_A receptor subtype (which mediates vascular contraction) was recently demonstrated in this model of hypertension.¹³ Because insulin stimulates the secretion and expression of both ET-1 and its receptor,^14,15 it is possible that hyperinsulinemia provides a constant stimulus for elevated ET-1 production and therefore increases blood pressure via its vasoconstrictor actions.

Thromboxane A₂ (TXA₂) is another potent vasoconstrictor derived from the endothelium. Studies have shown that renal and/or vascular production of TXA₂ may be increased in several experimental models of hypertension. In both hyperinsulinemic spontaneously hypertensive rats (SHR)¹⁶ and rats chronically infused with insulin,¹⁷ the development of hypertension can be prevented by treatment with a thromboxane synthase inhibitor. In addition, insulin has been shown to potentiate the response of coronary blood vessels in vitro to TXA₂,¹⁸ suggesting that in vivo, hyperinsulinemia may be linked to hypertension via enhancement of the actions of TXA₂.

We designed the present study to investigate the role of thromboxane in the development of hypertension associated with hyperinsulinemia and insulin resistance in the FHR. We evaluated the effects of a thromboxane synthase inhibitor, dazmegrel (UK 38,485), on plasma insulin, glucose, triglyceride, thromboxane, and prostacyclin concentrations; systolic blood pressure; and insulin sensitivity. Furthermore, we investigated the effects of ET-1 on the vascular production of thromboxane.

	Methods

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Animals
Four experimental groups of 5-week-old Wistar rats (Charles River, Montreal, Canada) were used in this study: control (C, n=6), control dazmegrel-treated (CT, n=6), fructose-treated (F, n=8), and fructose/dazmegrel-treated (FT, n=8). At age 6 weeks, both fructose-fed groups (F and FT) were started on a diet of 60% fructose, and dazmegrel treatment (CT and FT) began concurrently at 100 mg · kg^-1 · d^-1 suspended in 1% carboxymethyl cellulose administered via oral gavage for 7 weeks.

Blood Pressure Study Procedures
Systolic blood pressure was measured via the tail-cuff method before treatment and weekly throughout the study period as previously described.¹⁹ Fasting (5 hours) plasma insulin, glucose, and triglyceride levels were measured at study weeks 0, 2, 4, and 6. An oral glucose tolerance test (OGTT) was performed after the animals were fasted overnight at study week 7. Glucose (1 g/kg) was administered via oral gavage, and blood samples were collected at 0, 10, 20, 30, and 60 minutes.

Vascular Thromboxane Production
At termination, aortas were excised, with care taken to not damage the endothelium. Each ring was placed into a glass test tube that contained modified Krebs-Ringer buffer. After a 60-minute incubation period, ET-1 (10^-7 mol/L) was added to each test tube. Aliquots of buffer were removed before and 15 minutes after ET-1 challenge for assay of thromboxane B₂ (TXB₂) and 6-keto-prostaglandin F₁ (6-keto-PGF₁) as described later.

Biochemical Analyses
All blood samples were collected from the tail vein, except samples for the determination of plasma TXB₂ and 6-keto-PGF₁, the stable metabolites of TXA₂ and prostacyclin, respectively, which were obtained via cardiac puncture. Cardiac puncture samples were collected into polypropylene tubes containing 0.95 mL EDTA (0.05 mol/L) and 0.05 mL indomethacin (0.04 mol/L) to inhibit platelet generation of prostaglandins ex vivo. Plasma insulin was determined with a radioimmunoassay kit (Linco Research), triglycerides with an enzymatic colorimetry kit (Sigma Chemical Co), and glucose with a Beckman Glucose Analyzer II. Samples containing TXB₂ and 6-keto-PGF₁ were first extracted using Amprep C2 minicolumns (Amersham) before assay with enzyme immunoassay kits purchased from Amersham.

Reagents
Fructose diet was obtained from Teklad Laboratory Diets. Indomethacin, EDTA, and methyl formate were purchased from Sigma Chemical Co. Hexane was obtained from Fisher Scientific. Dazmegrel was a generous gift from Pfizer.

Statistical Analysis
All data are presented as mean±SEM. For data with multiple time points, variables were analyzed by the general linear model ANOVA. An unpaired t test was also used to separately compare the effect of fructose treatment on insulin sensitivity within dazmegrel-treated and untreated groups. Area under the curve (AUC) values were calculated using the trapezoidal rule, and insulin sensitivity indexes (ISIs) were calculated using the formula ISI=100/[(mean plasma glucosexmean plasma insulin)x(fasting plasma glucosexfasting plasma insulin)].²⁰ A 1-way ANOVA was used to examine AUC and ISI values. Mean values were considered significant at P<0.05. When a mean difference was detected, a Newman-Keuls multiple comparison test was applied.

An expanded Methods section can be found in an online data supplement available at http://www.hypertensionaha.org.

	Results

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General Characteristics
The body weight of each group did not differ at any time point, and the pattern of food and fluid intake was generally similar for all groups throughout the study as shown previously²¹ (data not shown). Fasting parameters are given in Table 1. Plasma glucose values did not differ between groups except at week 2, when the F group had slightly but significantly elevated plasma glucose levels compared with those of the control group. Animals fed fructose were hypertriglyceridemic compared with control groups within 2 weeks of the start of the diet and continued to be so throughout the study period. Plasma insulin levels also tended to be elevated in both fructose-fed groups throughout the study, but this difference did not reach statistical significance. Plasma levels of TXB₂ were significantly increased in the F group, and treatment with dazmegrel prevented this increase (Table 2). In contrast, plasma levels of prostacyclin metabolites (6-keto-PGF₁) were not different between groups nor were they affected by treatment.

View this table: [in this window] [in a new window]   Table 1. Plasma Concentrations of Glucose, Insulin, and Triglycerides in C, CT, F, and FT Rats

View this table: [in this window] [in a new window]   Table 2. Plasma Levels of Prostacyclin and Thromboxane Metabolites in C, CT, F, and FT Rats

Blood Pressure
Systolic blood pressure was significantly increased in the F group by the fifth week of feeding with fructose (Figure 1). Treatment with dazmegrel prevented the increase in blood pressure caused by the fructose diet. Dazmegrel treatment by itself did not affect blood pressure in non–fructose-fed rats.

View larger version (21K): [in this window] [in a new window]   Figure 1. Systolic blood pressure. At least 3 measurements were taken for each individual rat each week. Values are mean±SEM. *P<0.05 vs C; #P<0.05 vs FT.

OGTT Responses
In response to an oral glucose challenge, both fructose-fed groups responded by secreting significantly more insulin, as indicated by a greater phase 1 peak insulin response and AUC, compared with control groups (Figure 2). The plasma glucose profile, on the other hand, was similar among all groups (Figure 3). A comparison of the ISIs (calculated from OGTT data) shows that fructose diet significantly impaired insulin sensitivity (Figure 4). The CT group had a significantly lower ISI than the control group, but the FT group had an even lower ISI than the CT group, indicating that fructose diet contributed to the severe impairment in insulin sensitivity observed in the FT group.

View larger version (28K): [in this window] [in a new window]   Figure 2. Plasma insulin response during an OGTT and AUC. Animals were gavaged with 40% glucose (1 g/kg), and blood samples were obtained from the tail vein at the times indicated. Values are mean±SEM. *P<0.05 vs respective control group (C or CT).

View larger version (28K): [in this window] [in a new window]   Figure 3. Plasma glucose response during an OGTT and AUC. Animals were gavaged with 40% glucose (1 g/kg), and blood samples were obtained from the tail vein at the times indicated. Values are mean±SEM. No significant differences were noted.

View larger version (31K): [in this window] [in a new window]   Figure 4. ISI values obtained from OGTT data. Values are mean±SEM. *P<0.05 vs C (ANOVA); #P<0.001 vs CT (unpaired t test).

Vascular Production of TXB₂ and 6-Keto-PGF₁
Basal secretions of TXB₂ and 6-keto-PGF₁ from the aorta did not differ between groups and did not significantly increase with time in the absence of any stimulus (data not shown). On the addition of 10^-7 mol/L ET-1, an increase in thromboxane metabolites was detected in the buffer solution from all groups (9.3±2.6, 4.9±1.3, 15.0±1.7, and 7.8±1.7 pg/mg tissue for C, CT, F, and FT, respectively). The vascular TXB₂ production observed in the F group was significantly greater (P<0.001) and was normalized by treatment with dazmegrel.

	Discussion

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The results of this experiment demonstrate that treatment with dazmegrel, an inhibitor of thromboxane synthase, prevents the development of fructose-induced hypertension in male rats. The FHR exhibits the characteristics of "metabolic syndrome X," namely, hyperinsulinemia, hypertriglyceridemia, insulin resistance, and hypertension.³ We, and workers from other laboratories, have shown that the treatment of FHR with various compounds that improve insulin sensitivity, such as metformin, vanadium compounds, and pioglitazone, also ameliorated the hypertension that typically develops in this model.^21–23 Furthermore, increasing insulin levels to those seen before treatment with the insulin sensitizer vanadyl sulfate reverses the beneficial effects of treatment on blood pressure.²² These experiments provide evidence for the causal role of hyperinsulinemia and insulin resistance in hypertension in FHR.

Because the factors that we believe are responsible for hypertension in this model, namely, hyperinsulinemia and insulin resistance, were not altered in this experiment by dazmegrel treatment, thromboxane may be involved in the link between these 2 conditions. A previous study with a hypertensive model induced by chronic insulin infusion also demonstrated that hypertension could be prevented by the administration of U63557A, a different thromboxane synthase inhibitor.¹⁷ Our experiment shows that fructose-induced hypertension is also dependent on TXA₂ synthesis and shows for the first time that plasma levels of thromboxane metabolites are increased in this type of hypertension. Under normal conditions, prostacyclin production in tandem with TXA₂ typically provides a counterregulatory mechanism to the vasoconstriction and procoagulation effects of thromboxane. However, we have shown that levels of the prostacyclin metabolite 6-keto-PGF₁ were not elevated in FHR, indicating that the balance between the actions of these 2 hormones is tipped in favor of TXA₂. Taken together, these studies provide strong evidence for the role of thromboxane in hypertensive models associated with hyperinsulinemia and insulin resistance.

Insulin, when incubated in vitro with rings of porcine coronary arteries, potentiates the vasoconstrictive actions of TXA₂.¹⁸ Although it is not yet known whether the same phenomenon exists in FHR, this observation led us to hypothesize that hyperinsulinemia in vivo may provide similar conditions to enhance the pressor effects of TXA₂ and thus cause hypertension. There also is much evidence to support a role for ET-1 in hypertension associated with hyperinsulinemia/insulin resistance. These 2 mechanisms may not be exclusive of each other. ET-1 has been shown to stimulate the production of TXA₂ and prostacyclin from endothelial cells.²⁴ A functional interaction between ET-1 and TXA₂ has also been demonstrated in an experiment that showed blockade of ET-1 receptors significantly reduces the sensitivity of vascular tissue to TXA₂-induced contraction.²⁵ Hence, it is possible that hyperinsulinemia causes elevations in ET-1, which in turn stimulates TXA₂, and the resulting hypertension may be due to the additive vasoconstrictor effects of both hormones. Conversely, it has been shown that the administration of dazmegrel to allograft kidney-transplanted rats reduces the release of ET-1 from the renal endothelium.²⁶ Therefore, just as insulin stimulates the expression of ET-1 and its receptor,^14,15 insulin may also directly affect TXA₂ synthesis and increase ET-1 levels via this mechanism. It is possible that dazmegrel altered ET-1 levels in these animals and prevented the blood pressure increase by reducing ET-1 as well as TXA₂ concentrations. Further studies are needed to investigate the role of these 2 pathways in FHR.

We investigated the possibility that ET-1 may be responsible for the elevation in thromboxane levels observed in this experiment. We have previously shown that ET-1 levels are increased in vascular tissue of FHR,¹¹ and an increase in expression of the ET_A receptor subtype (which mediates vascular contraction) has been demonstrated in this model.¹³ We demonstrated in the present study that ET-1 stimulates the synthesis of TXA₂ in vascular tissue and that this effect is greater in FHR than in control animals. These data lend support to our hypothesis that there is an interaction between ET-1 and TXA₂ in this model of hypertension. Furthermore, preliminary data from our laboratory demonstrate that cyclooxygenase (COX) inhibition reduces norepinephrine-induced contraction in aorta from FHR, but not from control rats, suggesting that there is enhanced production of COX-derived vasoconstrictor products, possibly TXA₂, in vascular tissue of FHR (unpublished data). However, platelets also produce TXA₂, and it is possible that the increase in plasma levels observed in this experiment are from this source. Further experiments are required to elucidate the nature and cell types involved in the interactions among insulin, ET-1, and TXA₂ in fructose-induced hypertension.

Interestingly, dazmegrel treatment caused a reduction in insulin sensitivity in normal rats not fed fructose. This is due to a prolonged phase 1 insulin response after the initial glucose challenge, compared with control. Both fructose groups demonstrate different insulin secretion patterns, with the peak of the first phase insulin response twice that of control, which is reflected in an increase in AUC and a reduction in ISI. We believe that the decrease in insulin sensitivity in the CT group was not severe enough to affect blood pressure, because the ISI value obtained for this group is within the typical range for male control rats in our previous experiments. The ISI values for C and CT groups in this experiment were 22±5 and 14±1, respectively, compared with 15±1 for control normotensive, insulin-sensitive rats from previous experiments (unpublished data). Calculation of ISI values from OGTT data has been shown to correlate highly with the euglycemic hyperinsulinemic clamp method, considered the gold standard for the assessment of insulin sensitivity.²⁰

In summary, the results of the present study provide evidence for the role of thromboxane in the development of hypertension associated with hyperinsulinemia. Fructose treatment is associated with hyperinsulinemia, insulin resistance, hypertension, and elevations in plasma thromboxane levels. Long-term treatment of FHR with dazmegrel, a thromboxane synthase inhibitor, lowered plasma thromboxane levels and completely prevented the increase in blood pressure caused by the fructose diet but did not affect plasma insulin levels or insulin sensitivity. The mechanisms by which hyperinsulinemia stimulates TXA₂ production may be related to elevations in ET-1, which is also observed in this form of hypertension. Further experiments into the mechanisms of hypertension associated with hyperinsulinemia are beneficial, because they may provide insight into new targets for therapy of essential hypertension in the human population.

	Acknowledgments

 
This work was supported by a grant from the Heart and Stroke Foundation of British Columbia and the Yukon (HSFBC&Y). Dr Galipeau is supported by Rx&D Health Research Foundation/Canadian Institutes for Health Research. Dr Arikawa is supported by the HSF of Canada. Dr Sekirov was supported by HSFBC&Y at the time of this study. The gift of dazmegrel from Pfizer, UK, is gratefully acknowledged. We thank Dr Subodh Verma for providing constructive comments on the manuscript. The technical assistance of Violet Yuen, Linfu Yao, and Mary Battell is gratefully acknowledged.

Received January 19, 2001; first decision February 7, 2001; accepted March 23, 2001.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991; 14: 173–194.[Abstract]

2. Reaven GM. Insulin resistance, hyperinsulinemia, and hypertriglyceridemia in the etiology and clinical course of hypertension. Am J Med. 1991; 90: 7S–12S.[Medline] [Order article via Infotrieve]

3. Hwang IS, Ho H, Hoffman BB, Reaven GM. Fructose-induced insulin resistance and hypertension in rats. Hypertension. 1987; 10: 512–516.[Abstract/Free Full Text]

4. Verma S. Insulin resistance and hypertension: pharmacological and mechanistic studies. Can J Diabetes Care. 2000; 23: 23–42.

5. Verma S, Bhanot S, McNeill JH. Sympathectomy prevents fructose-induced hyperinsulinemia and hypertension. Eur J Pharmacol. 1999; 373: R1–R4.[Medline] [Order article via Infotrieve]

6. Penicaud L, Berthault MF, Morin J, Dubar M, Ktorza A, Ferre P. Rilmenidine normalizes fructose-induced insulin resistance and hypertension in rats. J Hypertens Suppl. 1998; 16: S45–S49.[Medline] [Order article via Infotrieve]

7. Verma S, Bhanot S, Yao L, McNeill JH. Defective endothelium-dependent relaxation in fructose-hypertensive rats. Am J Hypertens. 1996; 9: 370–376.[Medline] [Order article via Infotrieve]

8. Kamata K, Yamashita K. Insulin resistance and impaired endothelium-dependent renal vasodilatation in fructose-fed hypertensive rats. Res Commun Mol Pathol Pharmacol. 1999; 103: 195–210.[Medline] [Order article via Infotrieve]

9. Miller AW, Katakam PV, Ujhelyi MR. Impaired endothelium-mediated relaxation in coronary arteries from insulin-resistant rats. J Vasc Res. 1999; 36: 385–392.[Medline] [Order article via Infotrieve]

10. Verma S, Bhanot S, Yao L, McNeill JH. Vascular insulin resistance in fructose-hypertensive rats. Eur J Pharmacol. 1997; 322: R1–R2.[Medline] [Order article via Infotrieve]

11. Verma S, Bhanot S, McNeill JH. Effect of chronic endothelin blockade in hyperinsulinemic hypertensive rats. Am J Physiol. 1995; 269: H2017–H2021.[Abstract/Free Full Text]

12. Verma S, Skarsgard P, Bhanot S, Yao L, Laher I, McNeill JH. Reactivity of mesenteric arteries from fructose hypertensive rats to endothelin-1. Am J Hypertens. 1997; 10: 1010–1019.[Medline] [Order article via Infotrieve]

13. Juan CC, Fang VS, Hsu YP, Huang YJ, Hsia DB, Yu PC, Kwok CF, Ho LT. Overexpression of vascular endothelin-1 and endothelin-A receptors in a fructose-induced hypertensive rat model. J Hypertens. 1998; 16: 1775–1782.[Medline] [Order article via Infotrieve]

14. Ferri C, Pittoni V, Piccoli A, Laurenti O, Cassone MR, Bellini C, Properzi G, Valesini G, De Mattia G, Santucci A. Insulin stimulates endothelin-1 secretion from human endothelial cells and modulates its circulating levels in vivo. J Clin Endocrinol Metab. 1995; 80: 829–835.[Abstract]

15. Frank HJ, Levin ER, Hu RM, Pedram A. Insulin stimulates endothelin binding and action on cultured vascular smooth muscle cells. Endocrinology. 1993; 133: 1092–1097.[Abstract/Free Full Text]

16. Uderman HD, Jackson EK, Puett D, Workman RJ. Thromboxane synthetase inhibitor UK38,485 lowers blood pressure in the adult spontaneously hypertensive rat. J Cardiovasc Pharmacol. 1984; 6: 969–972.[Medline] [Order article via Infotrieve]

17. Keen HL, Brands MW, Smith MJJr, Shek EW, Hall JE. Inhibition of thromboxane synthesis attenuates insulin hypertension in rats. Am J Hypertens. 1997; 10: 1125–111.[Medline] [Order article via Infotrieve]

18. Yanagisawa-Miwa A, Ito H, Sugimoto T. Effects of insulin on vasoconstriction induced by thromboxane A2 in porcine coronary artery. Circulation. 1990; 81: 1654–1659.[Abstract/Free Full Text]

19. Bhanot S, McNeill JH, Bryer-Ash M. Vanadyl sulfate prevents fructose-induced hyperinsulinemia and hypertension in rats. Hypertension. 1994; 23: 308–312.[Abstract/Free Full Text]

20. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999; 22: 1462–1470.[Abstract/Free Full Text]

21. Verma S, Bhanot S, McNeill JH. Antihypertensive effects of metformin in fructose-fed hyperinsulinemic, hypertensive rats. J Pharmacol Exp Ther. 1994; 271: 1334–1337.[Abstract/Free Full Text]

22. Bhanot S, Michoulas A, McNeill JH. Antihypertensive effects of vanadium compounds in hyperinsulinemic, hypertensive rats. Mol Cell Biochem. 1995; 153: 205–209.[Medline] [Order article via Infotrieve]

23. Kotchen TA, Reddy S, Zhang HY. Increasing insulin sensitivity lowers blood pressure in the fructose-fed rat. Am J Hypertens. 1997; 10: 1020–1026.[Medline] [Order article via Infotrieve]

24. Muck AO, Seeger H, Korte K, Lippert TH. The effect of 17 beta-estradiol and endothelin 1 on prostacyclin and thromboxane production in human endothelial cell cultures. Clin Exp Obstet Gynecol. 1993; 20: 203–206.[Medline] [Order article via Infotrieve]

25. Moreau P, Takase H, Luscher TF. Effect of endothelin antagonists on the responses to prostanoid endothelium-derived contracting factor. Br J Pharmacol. 1996; 118: 1429–1432.[Medline] [Order article via Infotrieve]

26. Buyukgebiz O, Aktan A, Haklar G, Bilsel S, Dulger M. The effects of thromboxane synthase inhibition on reperfusion injury and endothelin-1,2 levels in allograft kidney transplantation in rats. Res Exp Med. 1999; 198: 289–298.[Medline] [Order article via Infotrieve]

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