TY - JOUR
AU1 - Ezra-Nimni,, Orit
AU2 - Ezra,, David
AU3 - Peleg,, Edna
AU4 - Munter,, Klaus
AU5 - Rosenthal,, Talma
AB - Abstract Background: In view of the demonstrated interaction between endothelin and the renin-angiotensin system, the antihypertensive effect of combined therapy with an endothelin antagonist LU-135252 and the angiotensin converting enzyme inhibitor trandolapril, was studied in fructose-induced hypertensive, hyperinsulinemic, hypertriglyceridemic male Sprague-Dawley rats. Methods: Forty animals were fed a fructose-enriched diet (Tekled, Harlan) for 5 weeks, as follows: group A, fructose only; group B, trandolapril 0.1 mg/kg/day added during the last 2 weeks; group C, LU-135252 100 mg/kg/day added during the last 2 weeks; group D, both trandolapril and LU-135252 added the last 2 weeks. Systolic blood pressure (BP) was measured weekly in conscious rats by the indirect tail–cuff method. Blood samples from a retro-orbital sinus puncture were taken at the beginning of the experiment and after 3 and 5 weeks and examined for insulin and triglyceride concentrations. Results: Systolic BP decreased in group B (trandolapril) from 148.8 ± 9.8 at 3 weeks to 138.3 ± 8.7 mm Hg after 5 weeks; in group C (endothelin antagonist) from 155.1 ± 5.5 to 142.5 ± 10.6 mm Hg; and in group D (combination) from 154.6 ± 10.9 to 121.2 ± 8.9 mm Hg. Triglyceride levels decreased only in the combined trandolapril/endothelin antagonist group from 167.6 ± 55.3 in the third week to 134.9 ± 53.7 mg/dL after 5 weeks. Insulin levels decreased only on combination therapy from 7.4 ± 3.6 to 5.3 ± 3.8 ng/mL during the same period. The BP decrease was additive compared with the respective individual substances. Conclusions: The trandolapril/endothelin antagonist combination appears to offer a rational antihypertensive combination that is superior to that of either drug alone. This finding applies to the specific rat model studied in which BP, insulin, and triglycerides were increased by fructose diet. Am J Hypertens 2003;16:324–328 @ 2003 American Journal of Hypertension, Ltd. Trandolapril, angiotensin converting enzyme inhibitor, endothelin antagonist, renin-angiotensin system, rats The availability of oral endothelin (ET) receptor antagonists like bosentan (ETA/ETB antagonists) and LU-135252 (selective ETA receptor antagonist) has enabled long-term studies on the ET system. There are a number of studies in rats in which acute administration of an ET antagonist resulted in a slight or no decrease in blood pressure (BP).1,2,3 However, ET antagonists might favorably affect specific kinds of hypertension; namely those that entail mineralcorticoid low renin hypertension [deoxycorticosterone acetate-salt hypertensive rats2,4,5], rats under nitric oxide (NO) blockade,6 and angiotensin II-dependent rats. The capacity of ET antagonist to lower BP was also reported in renal hypertensive dogs.7,8,9 The control of BP exerted by ET and angiotensin II (Ang II) may be attributed to their opposition to the effects of NO. An increase in NO release after combined blockade of ETA receptors and the renin-angiotensin system could account for the subsequent considerable decrease observed in mean arterial pressure.10 Administration of LU-135252 to a type I diabetes mellitus rat model lowered the ET impairment, incidence of cataracts, renal alterations, anemia, and cardiac capillary rarefication. Munter et al10 claimed that a combination of LU-135252 and angiotensin converting enzyme (ACE) inhibitors was effective in lowering BP, indicating a possible synergy between the two. The present study examines the effect of such combination therapy on metabolic parameters in the fructose-induced hyperinsulinemic, hyperlipidemic, hypertensive rats, the Reaven model. This model was used in view of the reciprocity between ET and hyperinsulinemia shown in vivo11,12,13,14,15 and in vitro.16,17,18 Methods Forty male Sprague-Dawley rats weighing 220 to 250 g were fed a fructose-enriched diet (Tekled, Harlan, Madison, WI) consisting of 21% protein, 5% fat, 60% carbohydrate, 0.49% sodium, and 0.49% potassium for 5 weeks. The 40 rats were divided into four groups, 10 animals in each group: group A, fructose only; group B, trandolapril 0.1 mg/kg/day added the last 2 weeks of the study; group C, LU-135252 100 mg/kg/day added the last 2 weeks; and group D, both trandolapril 0.1 mg/kg/day and LU-135252 100 mg/kg/day added the last 2 weeks. Drugs were administered in drinking water. Systolic BP was measured weekly in conscious rats by the indirect tail–cuff method by an electrosphygmomanometer and pneumatic pulse transducer (Narco Biosystems Inc., Houston, TX). The mean of five consecutive readings was recorded. Blood samples from a retro-orbital sinus puncture under light anesthesia were taken after 5 h of fasting at the beginning of the experiment and after 3 and 5 weeks. Samples were centrifuged, aliquoted, frozen, and assayed for insulin (I125 RIA kit Incstar, Stillwater, MN) and triglyceride concentrations (Triglycerides GPO-PAP kit, Boehringer, Mannheim, GmBH, Mannheim, Germany). The experimental protocol was approved by the hospital Helsinki Committee. Data are expressed as mean ± SD. The paired t test and nonparametric signed rank test were applied to assess paired differences between baseline and all postbaseline measurements of quantitative parameters. Repeated measured ANOVA was used to assess changes between baseline and postbaseline measurements. All tests applied were two-tailed, and a probability value of 5% or less was considered statistically significant. Data were analyzed with the SAS software (SAS Institute Inc., Cary, NC). Results The rats in all four groups were in good health during the 5 weeks of study, and showed no signs of morbidity. The rats’ body weight was not different between the groups throughout the study, at 0, 3, and 5 weeks, respectively (group A: 234 ± 8 g, 330 ± 29 g, 376 ± 38 g; group B: 230 ± 4 g, 330 ± 16 g, 355 ± 20 g; group C: 221 ± 7 g; 350 ± 32 g, 386 ± 30 g; group D: 240 ± 15 g, 341 ± 29 g, 369 ± 30 g). Blood pressure (Fig. 1, upper panel), triglycerides (Fig. 1, middle panel), and insulin (Fig. 1, lower panel) increased in all four groups after 3 weeks of fructose feeding (Table 1). In group A (control), systolic BP, triglyceride, and insulin levels continued to increase from week 3 to week 5. Blood pressure decreased significantly (Table 1) in the other three groups after 2 weeks of treatment. The most significant decrease was observed in group D (combination therapy) from 154.6 ± 10.9 to 121.2 ± 8.9 mm Hg. Table 1 Changes in blood pressure, triglycerides, and insulin levels after 3 weeks of fructose diet and 2 additional weeks of treatment . . Blood Pressure (mm Hg) . Triglycerides (mg/dL) . Insulin (ng/mL) . Group . Week . Δ SBP . P . Δ TGs . P . Δ Insulin . P . Fructose 0–3 6.88 ± 4.3 .1541 109.19 ± 27.16 .0051 5.39 ± 2.19 .0437 3–5 9.38 ± 3.18 .0216 97.89 ± 58.02 .1354 1.47 ± 1.39 .3234 0–5 16.25 ± 5.31 .0183 207.08 ± 38.08 .001 6.86 ± 1.58 .0034 Trandolapril 0–3 9.2 ± 4.43 .0675 100.62 ± 19.46 .0006 3.01 ± 0.4 .0001 3–5 −10.5 ± 4.02 .0282 166.75 ± 36.78 .0014 5.26 ± 1.54 .0077 0–5 −1.3 ± 5.37 .8141 267.37 ± 39.47 .0001 8.27 ± 1.43 .0003 ET antagonist 0–3 19.67 ± 4.16 .0015 122.07 ± 19.41 .0002 8.93 ± 1.2 .0001 3–5 −12.56 ± 3.27 .005 36.42 ± 17.71 .0699 3 ± 3.68 .438 0–5 7.11 ± 6.07 .2749 162.96 ± 31.32 .0008 11.93 ± 3.62 .0109 Trandolapril + ET antagonist 0–3 10.4 ± 6.08 .1216 158.51 ± 37.05 .0021 5.2 ± 0.96 .0004 3–5 −33 ± 2.05 .0001 −89.51 ± 41.87 .065 −2.24 ± 2 .2944 0–5 −22.78 ± 6.56 .0084 72.86 ± 20.92 .0083 3.12 ± 1.24 .0363 . . Blood Pressure (mm Hg) . Triglycerides (mg/dL) . Insulin (ng/mL) . Group . Week . Δ SBP . P . Δ TGs . P . Δ Insulin . P . Fructose 0–3 6.88 ± 4.3 .1541 109.19 ± 27.16 .0051 5.39 ± 2.19 .0437 3–5 9.38 ± 3.18 .0216 97.89 ± 58.02 .1354 1.47 ± 1.39 .3234 0–5 16.25 ± 5.31 .0183 207.08 ± 38.08 .001 6.86 ± 1.58 .0034 Trandolapril 0–3 9.2 ± 4.43 .0675 100.62 ± 19.46 .0006 3.01 ± 0.4 .0001 3–5 −10.5 ± 4.02 .0282 166.75 ± 36.78 .0014 5.26 ± 1.54 .0077 0–5 −1.3 ± 5.37 .8141 267.37 ± 39.47 .0001 8.27 ± 1.43 .0003 ET antagonist 0–3 19.67 ± 4.16 .0015 122.07 ± 19.41 .0002 8.93 ± 1.2 .0001 3–5 −12.56 ± 3.27 .005 36.42 ± 17.71 .0699 3 ± 3.68 .438 0–5 7.11 ± 6.07 .2749 162.96 ± 31.32 .0008 11.93 ± 3.62 .0109 Trandolapril + ET antagonist 0–3 10.4 ± 6.08 .1216 158.51 ± 37.05 .0021 5.2 ± 0.96 .0004 3–5 −33 ± 2.05 .0001 −89.51 ± 41.87 .065 −2.24 ± 2 .2944 0–5 −22.78 ± 6.56 .0084 72.86 ± 20.92 .0083 3.12 ± 1.24 .0363 SBP = systolic blood pressure; TGs = triglycerides; ET = endothelin. Open in new tab Table 1 Changes in blood pressure, triglycerides, and insulin levels after 3 weeks of fructose diet and 2 additional weeks of treatment . . Blood Pressure (mm Hg) . Triglycerides (mg/dL) . Insulin (ng/mL) . Group . Week . Δ SBP . P . Δ TGs . P . Δ Insulin . P . Fructose 0–3 6.88 ± 4.3 .1541 109.19 ± 27.16 .0051 5.39 ± 2.19 .0437 3–5 9.38 ± 3.18 .0216 97.89 ± 58.02 .1354 1.47 ± 1.39 .3234 0–5 16.25 ± 5.31 .0183 207.08 ± 38.08 .001 6.86 ± 1.58 .0034 Trandolapril 0–3 9.2 ± 4.43 .0675 100.62 ± 19.46 .0006 3.01 ± 0.4 .0001 3–5 −10.5 ± 4.02 .0282 166.75 ± 36.78 .0014 5.26 ± 1.54 .0077 0–5 −1.3 ± 5.37 .8141 267.37 ± 39.47 .0001 8.27 ± 1.43 .0003 ET antagonist 0–3 19.67 ± 4.16 .0015 122.07 ± 19.41 .0002 8.93 ± 1.2 .0001 3–5 −12.56 ± 3.27 .005 36.42 ± 17.71 .0699 3 ± 3.68 .438 0–5 7.11 ± 6.07 .2749 162.96 ± 31.32 .0008 11.93 ± 3.62 .0109 Trandolapril + ET antagonist 0–3 10.4 ± 6.08 .1216 158.51 ± 37.05 .0021 5.2 ± 0.96 .0004 3–5 −33 ± 2.05 .0001 −89.51 ± 41.87 .065 −2.24 ± 2 .2944 0–5 −22.78 ± 6.56 .0084 72.86 ± 20.92 .0083 3.12 ± 1.24 .0363 . . Blood Pressure (mm Hg) . Triglycerides (mg/dL) . Insulin (ng/mL) . Group . Week . Δ SBP . P . Δ TGs . P . Δ Insulin . P . Fructose 0–3 6.88 ± 4.3 .1541 109.19 ± 27.16 .0051 5.39 ± 2.19 .0437 3–5 9.38 ± 3.18 .0216 97.89 ± 58.02 .1354 1.47 ± 1.39 .3234 0–5 16.25 ± 5.31 .0183 207.08 ± 38.08 .001 6.86 ± 1.58 .0034 Trandolapril 0–3 9.2 ± 4.43 .0675 100.62 ± 19.46 .0006 3.01 ± 0.4 .0001 3–5 −10.5 ± 4.02 .0282 166.75 ± 36.78 .0014 5.26 ± 1.54 .0077 0–5 −1.3 ± 5.37 .8141 267.37 ± 39.47 .0001 8.27 ± 1.43 .0003 ET antagonist 0–3 19.67 ± 4.16 .0015 122.07 ± 19.41 .0002 8.93 ± 1.2 .0001 3–5 −12.56 ± 3.27 .005 36.42 ± 17.71 .0699 3 ± 3.68 .438 0–5 7.11 ± 6.07 .2749 162.96 ± 31.32 .0008 11.93 ± 3.62 .0109 Trandolapril + ET antagonist 0–3 10.4 ± 6.08 .1216 158.51 ± 37.05 .0021 5.2 ± 0.96 .0004 3–5 −33 ± 2.05 .0001 −89.51 ± 41.87 .065 −2.24 ± 2 .2944 0–5 −22.78 ± 6.56 .0084 72.86 ± 20.92 .0083 3.12 ± 1.24 .0363 SBP = systolic blood pressure; TGs = triglycerides; ET = endothelin. Open in new tab Systolic blood pressure (upper panel), triglycerides (middle panel), and insulin (lower panel) at baseline (week 0), after 3 weeks of fructose diet (week 3), and 2 additional weeks of treatment (week 5). Group A (control), open circle; group B (trandolapril), closed circle; group C (ET antagonist), closed square; group D (trandolapril + ET antagonist), open square. Data are presented as mean ± SEM. ϑ P < .05 week 5 v week 3. *P < .05 ET antagonist + trandolapril versus all other treatment groups. Figure 1. Open in new tabDownload slide Figure 1. Open in new tabDownload slide Triglycerides and insulin levels continued to increase in groups B and C despite 2 weeks of treatment with trandolapril and ET antagonist. Combination therapy (group D) was the only treatment that decreased the triglyceride and insulin levels, from 167.6 ± 55.3 to 134.9 ± 53.7 mg/dL, and from 7.4 ± 3.6 to 5.3 ± 3.8 ng/mL, respectively. The decrease of triglyceride and insulin levels in group D was significant when compared with groups B and C. Discussion Our data clearly showed an improvement of metabolic parameters like hyperinsulinemia and hyperlipidemia in addition to the antihypertensive effect of ACE inhibitor/ET antagonist combination therapy. The number of experimental studies on the effects of selective ETA or selective ETA/ETB receptor antagonists on BP is small. Those published results have shown a mild or no decrease in BP after acute administration of an ET antagonist.1,2,3,6,19 Chronic treatment with the receptor blocker LU-135252 did not significantly alter systolic arterial pressure in Wistar Kyoto and spontaneously hypertensive rat (SHR) strains but did increase the flow-induced dilation in SHR.20 However, the BP-lowering effect of LU-135252 in renin-dependent hypertension could be observed in Ang II-induced hypertension. This might be explained by the finding that induced vasoconstriction of isolated small arteries is partially mediated by ET,21,22 in contrast to the relative ineffectiveness of ET receptor antagonists in hypertension models such as SHR.23,24 Hence, conditions involving activation of the renin-angiotensin system may be more susceptible to ET receptor antagonists, although reports are not uniform.25,26 It was shown by Douglas et al3 that selective endothelin receptor antagonist lowers BP in renin hypertensive rats after arterial renal ablation. The response of combined treatment between ACE inhibitors and ET antagonist in the present study may suggest that the interaction between Ang II and ET-1 is important in the regulation of BP. This aspect was shown previously by a few investigators. Moreau et al27 showed that giving LU-135252 in combination with Ang II prevented the increase in systolic BP and endothelial dysfunction that occur when Ang II is given alone. They considered LU-135252 a useful alternative for lowering BP and restoring vascular structural changes and vascular function in hypertensive conditions that entail exaggerated activation of Ang II formation.28 The interaction between ET and the renin-angiotensin system has been shown in several studies.8,9,27,28,29,30,31 Munter et al10 combined LU-135252 with trandolapril or the Ang II (subtype AT1) receptor antagonist losartan in a dog model. As in our study the decrease of BP with the combination therapy was highly significant. There is well-documented evidence of the reciprocity between ET and hyperinsulinemia: namely, the increased release of ET-1 by physiologic insulin concentrations from human endothelial cells,11 bovine endothelial cells,16 and vascular smooth muscle cells17; and increases in plasma concentrations of ET-1 in humans11,12 and animals13,18 induced by hyperinsulinemia. In view of the known modulation of ET release by plasma insulin, Verma et al14 hypothesized that hyperinsulinemia may provide a continuous stimulus for ET release, which in turn alters ET levels of plasma or blood vessels and increases the BP. Chronic bosentan treatment evoked lasting decreases in BP in fructose-induced hypertensive rats.14 Further evidence is the increase in ETA receptors in vascular tissue from hyperinsulinemic obese Zucker15 and fructose hypertensive32 rats. These data confirmed our choice of the fructose-induced hypertensive rats to study the effect of LU-135252 and trandolapril combination on insulin and triglycerides. When researchers sought a nonobese model to study the biochemical mechanisms responsible for impaired insulin sensitivity,33,34 they chose a fructose-induced hyperinsulinemic rat model19,20,21,22,23,24 originally described by Tobey et al.35 The combination of LU-135252 and trandolapril lowered urinary proteins by 45%, although each one alone lowered proteinuria by 23% to 25%.36 Glomerulosclerosis and tubulointerstitial damage were more reduced by combination therapy than by LU-135252 or trandolapril alone.37 The trandolapril–LU-135252 combination was also given to type I diabetic rats by Dhein et al,38 who concluded that ACE inhibition and blockade of ETA receptor is a promising approach to antiangiopathy therapy. Our study was of short duration, therefore proteinuria had not yet developed, which meant that the advantages of the combination could be observed only in metabolic parameters and the antihypertensive response. A small dosage of trandolapril did not decrease triglyceride and insulin levels, and ET antagonist given alone did not decrease these metabolic parameters. The 0.1 mg/kg/day dose was used by several other investigators,39,40 although higher doses of trandolapril were also given. Sassy-Prigent et al40 found that the high dose of ACE inhibitor was significantly effective in reducing renal pathology in the diabetic rat, whereas a small dosage of trandolapril was less effective. Thus, it is not surprising that the dose of trandolapril given in our experiment was not very effective when given alone. Our results demonstrate significant beneficial effects of the combination therapy of ET antagonist LU-135252 and ACE inhibitor trandolapril on the metabolic state and hypertension in fructose-induced hypertensive, hyperinsulinemic, hypertriglyceridemic Sprague-Dawley rats. References 1. 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TI - Trandolapril and endothelin antagonist LU-135252 in the treatment of the fructose-induced hypertensive, hyperinsulinemic, hypertriglyceridemic rat
JF - American Journal of Hypertension
DO - 10.1016/S0895-7061(03)00003-7
DA - 2003-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/trandolapril-and-endothelin-antagonist-lu-135252-in-the-treatment-of-0d3PJvyaQQ
SP - 324
EP - 328
VL - 16
IS - 4
DP - DeepDyve
ER -